The patient was a 52-year-old woman with a prior history of chronic thyroiditis. Her sister was diagnosed as having congenital hydrocephalus and her mother as having heart valve disease. Her father died of myocardial infarction. The patient had a fall and sustained a head injury. Brain T2-weighted magnetic resonance imaging (MRI) revealed alternating isointense and hyperintense bands in the left cerebellar hemisphere (Fig. a). Surgical resection of the tumor in the cerebellar hemisphere was performed, and the histopathological diagnosis was dysplastic gangliocytoma. The patient was subsequently referred for genetic counseling. Genetic testing of her leukocytes and resected tumor revealed mutation in the exon 8 insertion of the PTEN gene (Fig. ), leading to a diagnosis of CS associated with LDD.
After genetic diagnosis, computed tomography (CT) whole-body screening revealed an adenomatous goiter (Fig. b) and uterine cancer (Fig. c). Thus, abdominal total hysterectomy with bilateral salpingo-oophorectomy was performed. The histopathological finding was endometrioid adenocarcinoma with no lymph node metastasis. At the age of 55 years, the follow-up CT for uterine cancer incidentally revealed a tumor in the right breast. Mammography (MMG) showed a smooth mass in the left breast (Fig. a). An irregular indistinct mass (12 × 11 × 10 mm) was detected in the right breast by ultrasonography (US) (Fig. b). However, she did not visit our hospital for the required additional examination. Two years later, a breast mass was detected in the breast cancer screening. A spiculated mass was observed in the right breast on MMG (Fig. a), and the tumor increased in size (20 × 20 × 11 mm) as shown by US (Fig. b). Core needle biopsy revealed invasive ductal carcinoma: estrogen and progesterone receptor-positive, Her2 2+, and Ki-67 20%. The patient underwent breast-conserving surgery and sentinel lymph node biopsy. Histopathological examination confirmed an invasive micropapillary carcinoma measuring 2.5 × 2.1 × 1.3 cm.
Immunohistochemistry revealed estrogen receptor-positive and progesterone receptor-positive staining, Her2 2+, and Ki-67-positive staining of 10% (Fig. ). The lymph nodes were not involved. She was given 50 Gy radiation and hormone therapy as adjuvant therapy. Any sign of recurrent disease has not been found in the 3 years since the last surgery for her breast cancer.
Previous studies have shown that approximately 20 to 34% of patients with CS carry germ line mutations of PTEN, a gene located on chromosome 10q23 [–]. These include 19–29% missense mutations, 19–33% nonsense mutations, 20% insertions, 2–14% small deletions, 10–11% splice site mutations, 1–29% frameshift mutations, 3% large deletions, and 3% promoter mutations [, , ]. In the present case, adenine was inserted in the codon of exon 8, resulting in the rearrangement of the amino acid sequence from valine to serine (Fig. ). There were 27 reported cases of CS with deleterious mutation in Japan from 1984 to 2017 (May) according to Igaku Chuo Zasshi which is updated by the Japan Medical Abstracts Society.
PTEN participates in regulating the phosphoinositide 3 kinase (PI3K)-AKT and mTOR signaling pathways for negative regulation, controls cell proliferation and cell cycle progression, and promotes apoptosis. Thus, a loss of PTEN function correlates with the development of various human cancers []. It has been reported that PTEN is a gene in which mutation is most frequently found in primary breast cancers []. It remains controversial how the abnormality of this gene function may affect the prognosis of breast cancer patients. Previous reports of cases with CS revealed that most breast cancers were hormone receptor-positive including the present case (Table ) [–]. Based on the history of the present case representing a slow-growing tumor, the clinical course of this case may be favorable. CS has a high risk of transforming into malignant tumors; thus, cancer surveillance is an important management for other organs []. The National Comprehensive Cancer Network (NCCN) recommendation is to undergo thyroid ultrasound, colonoscopy, renal ultrasound, annual dermatologic examination, and annual endometrial biopsies. After genetic diagnosis, we performed screening for breast, thyroid, and endometrial malignancies. Endometrial adenocarcinoma was found. Usually, the recommended treatment for hereditary breast cancer associated with BRCA1 mutation is mastectomy because it is a more aggressive cancer with a poor prognosis. However, as PTEN-related breast cancer tends to grow slowly, patients are not always required to undergo mastectomy. We therefore performed breast-conserving surgery in the present case.
The American Cancer Society and NCCN guidelines recommend MRI in addition to MMG for high-risk patients including those with PTEN hamartoma tumor syndrome [, ]. It may be necessary to apply screening of breast MRI to patients with a high risk for high-grade hereditary breast cancers such as BRCA1 mutation carriers. However, screening breast MRI may not be practical to apply to all hereditary breast cancer cases because of its relatively low specificity and the high cost of enhanced breast MRI. It is also difficult to perform pathological examination if the lesion is detected only by MRI.
However, the usual screening management for breast cancer may be insufficient for patients with CS, because the mean age at diagnosis of breast cancer is reported to be about 40 years old in women with CS [], which is younger than in the usual population. Thus, it is necessary to consider starting MMG screening at an earlier age and performing it more frequently such as once a year. Ultrasound could be another option, which may be useful for younger women and women with dense breasts [].


A 24 year old Caucasian male with a history of asthma, atopic dermatitis, and schizoaffective disorder was started on clozapine therapy for persistent auditory hallucination after trials of numerous other therapies including olanzapine, risperidone, aripiprazole, ziprasidone, haloperidol, and fluphenazine. Clozapine was added to an existing regimen of paliperidone, benztropine, divalproex sodium, and escitalopram. About three weeks after initiating therapy, he was admitted to a hospital with nausea, vomiting, cough, chills, and chest pain. Evaluation during his admission revealed the following: computed tomograph (CT) of the chest showing diffuse bilateral hazy opacities with small bilateral pleural effusions; echocardiogram with tachycardia, mildly decreased left ventricular systolic function with an ejection fraction of 45–50%, moderate to severe hypokinesis of the right ventricle, and moderate pericardial effusion without evidence of tamponade. Laboratory evaluation showed normal electrolytes, renal function, and hepatic function. White blood cell count was 14.7 K/μl with an absolute eosinophil count of 1.5 K/μl. It was thought that symptoms most likely represented pneumonia with viral pericarditis and viral myocarditis. Medication additions at discharge included levofloxacin for pneumonia, colchicine for pericarditis, and lisinopril and metoprolol for myocarditis. His psychiatric medication regimen was not changed.
The day following discharge he presented with profuse, watery diarrhea complicated by dehydration and acute kidney injury. Abdominal exam on admission was benign. White blood cell count on admission was 21.2 K/μl with an absolute eosinophil count of 2.9 K/μl. Liver function tests were normal, no rash was present, and he remained afebrile. Colchicine was stopped, but diarrhea continued. The patient revealed that his source of water is a fresh water stream. However, evaluation for Giardia and parasites was negative, as was evaluation for clostridium difficile, human immunodeficiency virus (HIV), cytomegalovirus (CMV), cryptosporidium, and Churg-Strauss. The inpatient psychiatric team was consulted shortly after admission to assess the need to stop clozapine in the setting of eosinophilia. They were initially reluctant to stop clozapine given the patient’s significant psychiatric improvement on clozapine, prior failure on multiple other medication regimens, and possibility of parasitic infection while work-up was pending. During his hospital stay, his eosinophils continued to increase with a peak absolute eosinophil count of 19.1 K/μl. Additionally, esophagogastroduodenoscopy and colonoscopy biopsies revealed diffuse eosinophilic infiltration of the esophagus, gastric antrum, duodenum, ileum, and colon. With the guidance of the psychiatry consultants, clozapine was subsequently tapered off while paliperidone was increased. Benztropine, divalproex sodium, and escitalopram were continued. He tolerated this medication adjustment well without return of his hallucinations. As his eosinophilia improved, his diarrhea resolved. On 1 month hospital follow up, eosinophils had decreased to an absolute count of 1.1 K/μl.


A 31-year-old, African woman with no significant medical background presented to the emergency department with 6 weeks history of fever, difficulty in breathing, and weakness of proximal limb muscles. There was no history of skin rash. She was 18 weeks primigravida with an uneventful antenatal course. Initial assessment showed an averagely built female with a body mass index (BMI) of 23.7 kg/m2 (normal range: 18.5–24.9 kg/m2), temperature of 37.1 °C, heart rate of 90 beats/minute (regular), blood pressure of 144/84 mm Hg, respiratory rate of 22 breaths/minute and pulse oximetry 99% on room air. A respiratory system examination was unremarkable apart from reduced air entry at both lung bases. A neurological examination revealed intact higher mental functions, reduced power in both upper and lower limbs (proximal muscles 3/5 and distal muscles 4/5) [], intact reflexes, sensations, cranial nerves, and cerebellar function. An abdominal examination showed gravid uterus appropriate for gestational age and a cardiovascular examination was unremarkable. Blood investigations revealed elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), troponin T (Table ) and arterial blood gas on room air was suggestive of acute on chronic respiratory acidosis [pH – 7.31, partial pressure of carbon dioxide in arterial blood (PaCO2) – 58 mm Hg, partial pressure of oxygen in arterial blood (PaO2) – 79 mm Hg, bicarbonate (HCO3) – 28 mEq/L]. Our patient had normal blood leukocyte count and no organism was isolated from sputum, urine and blood cultures, excluding underlying infection. An electrocardiogram (ECG) and bedside 2D transthoracic echocardiography were not suggestive of acute coronary syndrome or structure heart lesions. A chest X-ray showed hazy opacity in her left lower lung field (Fig. ). A computed tomography (CT) scan of her chest revealed bilateral basilar dependent atelectasis and excluded pulmonary embolism, pleurisy, pneumothorax, consolidation, and interstitial lung disease (ILD) (Fig. ). A pelvic ultrasound showed a single viable fetus with size and weight appropriate for gestational age, fetal movements were seen, fetal cardiac pulsations recorded, and amniotic fluid was adequate. Our patient was admitted to the medical intensive care unit (MICU) for further investigation and management. She was started on intermittent noninvasive bilevel positive airway pressure (BiPAP), with inspiratory positive airway pressure (IPAP) of 10 cm H2O and expiratory positive airway pressure (EPAP) of 5 cm H2O, to improve her hypercapnic respiratory failure. However, our patient was not compliant to the prescribed noninvasive ventilation (NIV) therapy.
On the second day of hospitalization, our patient developed severe respiratory acidosis (pH: 7.13 and PaCO2: 101 mm Hg) leading to deterioration in her level of consciousness with Glasgow Coma Scale (GCS) score [] of 8/15 (eye opening - to pain 2/4; verbal response - incomprehensible sounds 2/5; best motor response - withdraws from pain 4/6). She was initiated on invasive mechanical ventilation for severe hypercapnic respiratory failure. After correction of respiratory acidosis by invasive ventilation, our patient regained her level of consciousness. Bedside needle electromyography (EMG) revealed electrophysiological evidence of diffuse irritable myopathy in sampled muscles (Fig. ). Based on Bohan and Peter criteria (Table ) [] patient was diagnosed as probable polymyositis and started on pulse steroid therapy with intravenous methylprednisolone 500 mg daily for 3 days, followed by maintenance oral prednisolone 60 mg daily and azathioprine 50 mg daily. After 5 days of initiating steroid therapy there was significant improvement in respiratory muscle function as evident from adequate gas exchange on low-setting pressure support ventilation [5 cm of water (H2O)] and increasing maximal inspiratory and expiratory pressures (MIP and MEP), so the patient was weaned off invasive ventilation. Extensive immunological workup did not reveal any positive autoantibodies. Four days postextubation there was deterioration in respiratory function (blood gas on room air: pH 7.25 and PaCO2 93 mm Hg) necessitating initiation of intermittent noninvasive BiPAP (IPAP - 12 cm H2O and EPAP – 6 cm H2O), averaging 16 hours per day. After counselling the patient for compliance to NIV therapy, good adherence to BiPAP was maintained. Due to relapse in respiratory muscle weakness, intravenous immunoglobulins (IVIG) (0.4 grams/kg/day) were started for a total of five doses. After completion of immunoglobulin therapy, our patient was gradually weaned off NIV and transferred to the general medical ward.
During her stay in the medical ward, our patient underwent magnetic resonance imaging (MRI) of both thighs, which showed edema of bilateral vastus lateralis, vastus medialis, adductor magnus, and gluteal muscles. (Fig. ). A muscle biopsy taken from her right deltoid was suggestive of inflammatory myopathy (scattered fibers with necrosis and regeneration, macrophages invading necrotic planes, collection of mononuclear cells at perivascular sites in perimysium and endomysium, and increase in perimysial fibrous and fatty connective tissue). After the muscle histopathology report, our patient was confirmed to have definite PM (Table ). Due to a rise in transaminases, not attributed to disease activity, azathioprine had to be stopped and our patient was kept on a tapering dose of oral corticosteroids. After 1 month of total hospitalization, our patient was discharged in good general condition with appropriate fetal growth, on maintenance oral prednisolone 20 mg daily and advised to follow up with her rheumatologist, obstetrician, and neurologist.
At 27 weeks of gestation, our patient was found to have intrauterine growth retardation (IUGR) on routine antenatal pelvic ultrasound. Fetal growth was estimated to be 24 weeks based on femoral length, biparietal diameter, head circumference, and fetal weight was calculated to be 627 grams. During a multidisciplinary meeting between obstetrician, neonatologist, rheumatologist, and anesthetist/intensivist, it was decided to continue the pregnancy with close monitoring of our patient in the obstetric ward. In case of clinical deterioration, an urgent delivery would be carried out using spinal anesthesia with administration of a stress dose of steroids. At 31 weeks gestation, cardiotocography (CTG) was nonreassuring with repeated unprovoked decelerations and our patient underwent emergent lower segment cesarean section (LSCS) using combined spinal and epidural anesthesia. A baby boy with severe IUGR, weighing 1160 grams was delivered and immediately required invasive ventilation for respiratory distress syndrome (RDS). The baby had a prolonged neonatal intensive care unit (NICU) stay complicated by Acinetobacter sepsis. He was gradually weaned of mechanical ventilation and transferred to the neonatal ward. The mother had an uneventful postoperative course and was discharged after 7 days of delivery with follow-up in the obstetric and rheumatology clinics.


A 60-year-old man of Chinese Han nationality coughed with a little white sputum for 1 month. A physical examination showed coarse breath sounds in bilateral lungs with moist rales in the lower lobe of his right lung. The tumor marker cancer antigen 125 (CA-125) was 45.84 U/ml (0 to 35.0) and cytokerantin-19-fragment (CYFRA21-1) was 17.79 ng/ml (0 to 3.3). A chest computed tomography (CT) scan showed multiple plaques and nodules with air bronchograms in bilateral lungs; infectious lesions were suspected.
He fasted for at least 6 hours before an intravenous injection of 18F-fluorodeoxyglucose (18F-FDG) at a dose of 0.2 mCi/kg. After resting for 60 minutes, he was given 300 to 500 mL of pure drinking water followed by bladder emptying before a positron emission tomography (PET)/CT examination (Discovery® VCT; GE Healthcare, Milwaukee WI, USA). Before PET scanning, full body CT scanning from his skull base to his mid-femurs was acquired for attenuation correction and anatomic localization with the following scanning parameters: voltage, 120 kV; current, 130 mA; slice thickness, 3.75 mm; and interlayer spacing, 3.27 mm. The PET scanning conditions were as follows: during quiet breathing, the scan time for each bed position was 3 minutes. For the diagnostic chest CT scan, he was trained in breath holding before the examination, and the scan was conducted from his thoracic inlet to the level of his adrenal glands with inspiratory breath hold [].
Irregular subpleural nodules and plaques accompanied by air bronchograms involved the lower lobe of his right lung (Fig. , ). There was slightly increased radioactivity uptake, with maximum standardized uptake value (SUVmax) of 3.5 (Fig. ). Multiple irregular nodules accompanied by air bronchograms involved the subpleural regions of bilateral lungs with slightly increased radioactivity uptake and SUVmax was 1.7. A soft tissue density lesion was found in the left adrenal gland with increased radioactivity uptake and SUVmax was 4.1 (Fig. , ).
He underwent transthoracic needle biopsy of the lesion of the lower lobe of his right lung. On histological examination, the lesion was composed predominantly of pools of mucin and we suspected colloid adenocarcinoma (Fig. ). CDX2, MUC2, CK7, and TTF-1 were positive in this case.


49-year-old Saudi male was operated on electively for second- and third-degree hemorrhoids after two ER visits with rectal blood spotting. His past medical and surgical history were unremarkable apart from morbid obesity and recurrent urinary tract infections that required intravenous therapy in other hospital.
Indications for surgery were recurrent bleeding with second- and third-degree hemorrhoids.
Surgery was done under spinal anesthesia and intravenous sedation.
No Foley's catheter was inserted. Patient was placed in lithotomy posture.
Examination under general anesthesia revealed second- and third-degree hemorrhoids.
Procedure started by placing the anal dilator and fixing it with 2/0 silk interrupted sutures.
Purse string anoscope was then used to place the purse string sutures on rectal submucosal level using Prolene 2/0, placing 5-6 bites at 4 cm distance from the anal verge.
Stapler device 33 mm Ethicon proximate (fixed anvil) stapler was then introduced and purse string snugly tied; the Prolene suture ends were then retrieved through the device housing using the suture threader.
Device was closed by marking and then fired.
An evenly excised mucosa was then retrieved, width of which is about 1.5 cm.
Hemostasis was well secured with interrupted vicryl 3/0 sutures.
No major complications were present during the procedure.
As the patient weight was 114 kgm, height 172 cm, and BMI 38.5., the only difficulty encountered during surgery was in placing the anal dilator and fixing it in a correct position.
The patient was stable during the procedure with minimal blood loss and was discharged to the postanesthesia recovery room.
Five days after discharge, he came back to ER with fever, dysuria, frequency, and urgency for two days. His temperature was 38.2°C and the rest of exam was unremarkable. His complete blood count and renal function tests were normal. Urinalysis showed leucocytes +2, WBC 40/HPF, and negative nitrates.
He was treated as acute cystitis with ciprofloxacin 500 mg twice daily orally.
He visited ER again after another two days with fever, rigors, abdominal pain, repeated vomiting, and generalized weakness. No rectal bleeding, pain, or discharge was present.
He denied any history of extramarital sexual relation or sexually transmitted disease before.
By examination, he looked sick and dehydrated. Temperature was 38.9°C, BP 110/70, pulse 120/min regular, and oxygen saturation 97% at room air.
His abdominal exam showed tender suprapubic area and perineum. There was no discharge or bleeding from anal orifice. Cardiac and respiratory exam were unremarkable.
His CBC complete blood count and renal function tests were normal. Urinalysis showed leucocytes +3, WBC > 100/HPF with negative nitrates.
Urine culture of previous ER visit was negative.
His CRP was raised 64 mg/l (0–5 mg/l) and PSA total was 6 ug/l (0–4.4 ug/l).
Both blood culture and urine cultures came to be negative. Both Chlamydia and gonococci antibody were negative.
Histopathology of the previous resected hemorrhoids specimen was reviewed.
It showed hemorrhoids comprised of dilated, thick walled, congested submucosal blood vessels (). A portion of rectal muscularis propria was identified at the deep aspect of the specimen ().
Abdomen and pelvis ultrasound at ER were unremarkable apart from enlarged prostate 45 cc. Patient was started empirically on meropenem intravenously 1 gm every 8 hours and he continued to be febrile for another 2 days.
On third day after admission, MRI of pelvis showed fluid intensity lesion within posterolateral aspect of the prostate gland measuring 24 × 12 × 14 mm with marginal enhancement (prostatic abscess) ().
Infectious disease consultant and urologist suggested ultrasound guided transrectal aspiration of the abscess.
Purulent fluid of 5 ml was aspirated and sent for microbiology. It grew gram negative bacilli Klebsiella pneumoniae (morphology was done according to CDC algorithm). Klebsiella pneumoniae was resistant to cefuroxime, ceftazidime, ceftriaxone, and piperacillin/tazobactam and sensitive to ciprofloxacin, meropenem, imipenem, and gentamicin, that is, extended spectrum beta lactamase (ESBL) producing (culture sensitivity was done; MIC results obtained using automated Vitek 2 AST-GN69 and AST –XN06 cards).
Fever subsided next day after aspiration of abscess and patient felt well.
Meropenem continued for total of 14 days and then changed to ciprofloxacin 500 mg bid and clindamycin 300 mg q8 hours orally for total of 30 days. He was followed at infectious diseases clinic and repeated CRP was 6 mg (0–5 mg/l) and MRI showed resolution of the previous intraprostatic collection with residual edema along left perianal area due to previous surgery ().


An 89-year-old woman with sick sinus syndrome was referred to our institute for an ulcer located at her pacemaker pocket site in the left pectoral region, which had been present for 2 weeks. She had been fitted with a dual-chamber pacemaker with two passive leads (Bipolar Membrane EX model 1474 T, Pacesetter, Jarfalla, Sweden, for the ventricular lead and Bipolar Membrane II model 1452 T, Pacesetter, for the atrial lead) 12 years ago in her left pectoral region. One year prior to this admission, she had developed a pocket abscess and had undergone an unsuccessful lead extraction procedure at another hospital, during which attempts to remove the leads by simple traction failed. Subsequently both of the proximal lead segments were pulled out and cut, leaving a short length of looped leads in the pacemaker pocket. A new pacemaker was then implanted on the opposite site. Her presenting symptoms were ulceration at the pacemaker pocket site with serous drainage. Physical examination revealed the following vital signs: body temperature, 36.9°C; pulse, 70 beats/min, regular; and blood pressure, 131/82 mm Hg. An electrocardiogram revealed a pacing rhythm of 70 beats/min. Although blood cultures remained negative, wound cultures were positive for Escherichia coli. A chest X-ray revealed the location of the older two leads to be at her left pectoral region, confirming the proximal segments had been cut in a previous procedure; the newer two leads on her right side could also be seen (Fig.
). After formal heart team discussion, the newer and older leads were scheduled to be fully extracted by simple traction, a laser sheath (SLS II, Spectranetics, Colorado Springs, CO, USA), and a needle's eye snare (Cook Medical Inc., Bloomington, IN, USA). The lead extraction procedure was performed in a hybrid operating room under general anesthesia by both interventional cardiologists and cardiac surgeons, with extracorporeal circulation on standby. Initially, the newer leads implanted from the right subclavian vein were successfully extracted using simple traction with the help of a locking stylet (Liberator, Cook Medical Inc.). Then, the infected pocket in the left pectoral region was widened, and the pocket was heavily debrided of all inflammatory tissue. The free end of the ventricular lead in the left pectoral region was able to be secured and removed using a locking stylet (Lead Locking Device, Spectranetics) and a laser sheath. However, the atrial lead's cut point was too deep in the pacemaker pocket region, and it was impossible to grasp its free end via the subclavian route. Therefore, right femoral vein access was obtained through which a 16-Fr introducer sheath was advanced over a 0.035-inch guidewire into the RA. The needle's eye snare retriever (13 mm) and the accompanying 12-Fr sheath were introduced through the 16-Fr sheath to snare the lead in the RA. However, several attempts failed to grasp the lead body using the needle's eye snare. Therefore, the snare was gently advanced into the superior vena cava (SVC) and the lead twisted around like “twisting spaghetti around a fork.” After the snare had wound up the lead, a second loop or threader secured the snare around the lead body. Once secured, the 12-Fr sheath was pulled into the 16-Fr introducer sheath. The 16-Fr introducer sheath was advanced over the doubled-up leads, which were successfully extracted into the sheath (Figs. , , , Movies , and ). The procedure was completed without any complications. The patient complained of no symptoms related to bradycardia after a pacemaker was removed. The rest of the patient's stay in hospital was uneventful, and she was discharged 2 weeks after the procedure.


Here we present a case of a 31-years-old woman (Fig. , IV:7), born in Fiumedinisi, a small Sicilian (Italy) town. Her parents, also native of Fiumedinisi, are not consanguineous. About the proband, at the age of five, myopia was diagnosed; two years later, she began suffering from night vision disturbance. Fundus revealed the typical “salt and pepper” aspect (Fig. ), without macula involvement; additionally, optical coherent tomography (OCT) examination showed the presence of numerous well-demarcated homogenous dome-shaped lesions, originating from the RPE layer (Fig. ). One year later, fundus analysis confirmed the progressive kind of phenotype, so RPA was diagnosed. Thereafter, she has report continuous worsening with also reduction of the visual field due to “retinal-tapetum” degeneration (Fig. ). No evidences of eye diseases were reported neither for her parents nor for younger sister.


A 27-year-old housewife, resident of Uttarakhand, presented to the dermatology department with complaint of progressive papulonodular lesions on the right leg for the last 8 years. Initially, she developed asymptomatic erythematous to brownish papules 5 x 5 mm in size on the lower part of the right leg, which later increased in number and size. No history of trauma or injury was recalled. She gave the history of prior treatment with terbinafine 250 mg BD for 6–7 months and itraconazle 100 mg BD for 1 year and 200 mg BD for 2 years. As the lesions remained static, she was referred to our tertiary care hospital in November 2014. On examination, multiple discrete, round, erythematous papules coalescing to form plaques were observed on the anterior aspect of lower third of the right leg. Each papule was 6 x 7 mm, firm, and nontender. The plaques were arranged in an annular pattern with central clearing. She was advised to continue itraconazole 200 mg BD for another 2 weeks. Failing to achieve clinical improvement in December 2014, the treatment modified to itraconazole 100 mg BD and ketoconazole 200 mg BD for 5.5 months. Initially, signs of clinical improvement were evident. There was reduction in erythema, lesions were flattened, and no new lesions developed. In May 2015, ketoconazole was stopped and itraconazole was increased to 200 mg BD. However, no evidence of improvement was further noticed. The rest of the history and physical examination were unremarkable. Routine haematological and biochemical investigations were within normal limits. The skin biopsy was taken from the lesion and sent for histopathological examination and fungal and mycobacterial culture. On histopathology, chronic inflammatory infiltrates comprising lymphocytes, plasma cells, and giant cells containing brown pigmented structures were seen. Microscopic examination of the biopsy specimen using 20% KOH showed small, round, thick-walled, brownish, septate sclerotic bodies measuring 6–12 μm. The specimen was cultured on Sabouraud dextrose agar (SDA) with antibiotics and incubated at 25°C and 37°C. Slowly growing colonies were observed at 25°C after 7–10 days. The colonies were jet black, velvety, and embedded in the medium with reverse black. Based on lactophenol cotton blue (LPCB) preparation and slide culture, the isolate was identified as F. pedrosoi. The identity of the isolate was confirmed by sequencing the internal transcribed spacer (ITS) region by using the ITS1 and ITS4 primers. Comparison of the nucleotide sequence of our isolate with the GenBank database using the BLAST algorithm yielded 99% homology with F. pedrosoi (accession number KX793110). The patient was started on liposomal amphotericin B (2 mg/kg x 18 days) and cryosurgery was done. The lesions regressed completely by the end of 11 months.


A 66-year-old woman was consulted for evaluation of hypercalcemia. She had been treated for acute pancreatitis twice (3 years and 6 months earlier) and had a long history of hypercalcemia (calcium 12.3 mg/dL (albumin 3.5 g/dL) and calcium 12.7 mg/dL (albumin 4.7 g/dL), resp.). Abdominal computed tomography (CT) had shown the presence of multiple renal stones, but not gall stones or pancreatic calcifications (not shown). She usually consumed 350 mL of beer 4 times/week. She had no palpable mass in her neck. Endocrine evaluation was performed according to relevant clinical guidelines, and the patient gave written informed consent for all tests performed. Renal function was within normal. As shown in , serum calcium was 12.4 mg/dL (reference range: 8.3–10.3), albumin 4.0 g/dL, and intact PTH (iPTH) level 253 pg/dL (reference range: 8.7–79.5). Urinary calcium/creatinine ratio was 0.39. Serum phosphorus was 2.4 mg/dL (reference range: 2.4–4.7).
Contrast-enhanced CT of the neck revealed a heterogeneous soft tissue mass (28 mm transverse diameter), clearly defined, within the left thyroid (). T-scores of femoral and lumbar bone mineral density were −1.3 and −2.7, respectively. Technetium-99m-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy demonstrated focal accumulation of increased radiotracer uptake in the left lobe of the thyroid on both early and delayed images ().
Left hemithyroidectomy was performed due to the clearly defined soft tissue mass within the left thyroid. Histopathology showed no signs of invasion, and this is consistent with parathyroid adenoma. The adenoma was composed mainly of chief cells and oxyphil cells, covered with a fibrous capsule (). Evaluation of chromogranin A expression showed positive chromogranin A immunostaining (). Evaluation for PTH expression showed positive PTH immunostaining (). Soon after surgery, the elevated calcium and iPTH were normalized. The patient has had no episodes of pancreatitis for one year after the operation.


A 15-year old Caucasian male initially presented to his family practice physician with palpable bilateral cervical lymph nodes. The enlargement of the nodes was interpreted to be of viral association and was treated conservatively. Approximately one month later, the patient developed episodic oral pain while eating which evolved into gingival bleeding, cheek swelling, and was associated with development of generalized superficial ulcers with clustering in the posterior soft palate and the vestibules. The patient also developed confluent flesh-colored papules in the bilateral posterior vestibule, buccal mucosa, and retromolar pad areas of his mouth (Fig. A,B). He was referred to an Otolaryngologist who started the patient on a 10 day course of antibiotics and referred the patient to an oral surgeon for an incisional biopsy. Following results of the incisional biopsy of the left retromolar pad, the patient was next referred to Gastroenterology and underwent endoscopy and colonoscopy. Additional history obtained by the Gastroenterologist prior to endoscopic evaluation was significant for a ten pound weight loss over approximately one year associated with intermittent right-sided abdominal discomfort and episodes of blood on the toilet paper. The patient’s family history is notable for Crohn’s disease in a paternal grandmother, lymphocytic colitis in a paternal aunt, and ulcerative colitis in a paternal great-grandfather.
Fecal calprotectin prior to endoscopy was 477 mcg/g. Rheumatoid factor was normal. Erythrocyte sedimentation rate was 18 mm/hr. C-reactive protein was 13 mg/L. Serum protein electrophoresis demonstrated a broad gamma increase, with a non-specific pattern and no monoclonal proteins. Quantiferon gold test was negative for tuberculosis.
As requested by the oral surgeon, biopsy of the left retromolar pad area was performed.
Histologic sections demonstrated mucosal ulceration with discrete non-caseating granulomas, sialadenitis, and plasmacytosis with patchy infiltrates of monotypic kappa restricted light chain plasma cells (Fig. C,D). Testing for Epstein-Barr Virus was negative as well as fungal, mycobacterial, and spirochete special stains. A diagnosis of non-caseating granulomatous inflammation was rendered with a comment mentioning Crohn’s disease as a possible etiology.
On subsequent examination by endoscopy, the upper gastrointestinal tract was notable for mild patchy erythema in the duodenum. The entire colon demonstrated scattered areas of mildly erythematous mucosa and multiple aphthous ulcers similar to those noted in the oral cavity. Multiple biopsies were taken. The terminal ileum contained a patchy area of mucosa that was mildly erythematous. Scattered white exudates and mucosal hemorrhages were appreciated and, again, multiple biopsies were taken. The perianal and digital rectal examinations were normal (Fig. A,B). MRI enterography demonstrated no radiographic evidence of bowel inflammation.
Biopsies taken at the time of endoscopy were remarkable for mild to moderate chronic active inflammation with multifocal discrete non-caseating granulomas in both the upper and lower gastrointestinal tract similar to those of the oral cavity lesions. The stomach and colon had multifocal discrete granulomas (Fig. C,D). The esophagus and duodenum were more mildly affected. The terminal ileum had focal prominent surface infiltration by neutrophils with underlying granulation changes and subtotal villous architecture atrophy.
The differential diagnosis for this patient’s clinical presentation included CD, infectious diseases (fungal, mycobacterial, spirochetes), drug-induced reactions, response to foreign body, nutritional deficiencies, and rheumatological disease. A variety of infectious or drug-related conditions have been shown to clinically mimic CD, although those etiologies often present more acutely. Granulomas can occur in infectious diseases including tuberculosis and Yersinia pseudotuberculosis.
Based on results of the oral biopsy, endoscopic evaluation and associated biopsies, and laboratory values, a diagnosis of Crohn’s disease was rendered. After discussion with the patient and family, the decision was made to start both corticosteroids and enteral nutritional therapy, with 80% of daily calories from an intact protein formula (). The patient and family were interested in considering nutritional therapy long-term. The patient began a steroid wean and has not had recurrence of oral lesions or gastrointestinal symptoms. The decision to start maintenance immunosuppressive therapy was made six weeks after diagnosis as the family decided that primary nutritional therapy would be difficult to maintain long-term.


The case was of a 22-year-old woman complaining of headache for 18 months with severe episodes lasting around 6 hours, recurring about twice a month. Pain was located on the parietal regions, spreading to the orbit. Attacks were accompanied by nausea severe enough to hinder routine activities. The case was assessed by several specialists ruling out neurological, ophthalmological, and otorhinolaryngological pathologies. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) revealed no pathology. Previous treatments considered nonsteroidal analgesics, physical therapy, hot and ice packs applications, and low-level laser therapy. All of them did not relieve pain to a satisfactory level. Her neurologist referred her to the orthodontic clinic suspecting a dilemma somewhere in her braces. The patient had fixed orthodontic appliance in the lower arch only with right first premolar extracted and space was closed with a satisfactory treatment outcome.
Clinical examination showed good oral hygiene with no signs of periodontal disease. Panoramic radiography (OPG) was normal. Occlusion was normal with no temporomandibular joint disorders. However, the patient reported that headache started 4 weeks after brackets bonding. At this stage, the patient was referred to a specialized center to test salivary biochemistry, particularly nickel and chromium levels. The chemical analyses were performed with a graphite furnace atomic absorption spectrometer using unstimulated salivary sample.
After consultation with patient's neurologist, a decision was made to remove braces as soon as possible and provide her with a CAD/CAM zirconium bar as a bonded mandibular fixed retainer as the patient refused to wear any removable appliance. The treatment objectives were to (1) remove braces and retain teeth at their present position and (2) fabricate a bonded mandibular fixed retainer being biocompatible in attempt to relieve the patient's complaint.


A 79-year-old female presented to the emergency room with confusion, agitation, and visual hallucinations after sustaining a fall. Although the patient was a poor historian, her family members did not report prior history of abdominal complaints including trauma, fever, weight loss, abdominal mass, or surgery. Abdominal examination revealed soft, nontender, palpable fullness in the paraumbilical region. Gastroenterology service was consulted for a nontender abdominal fullness on physical examination as well as laboratory findings of severe iron deficiency anemia. The rest of her laboratory findings were unremarkable.
A supine and upright abdominal film showed bowel loops displaced to the left with a large amount of stool in the colon (
). A noncontrast computed tomography (CT) of the abdomen and pelvis revealed a large right retroperitoneal cystic structure measuring at least 26.6 × 11.7 × 16.7 cm. The cyst was displacing the right kidney and right colon medially (
and
). These findings were consistent with a giant retroperitoneal cyst (RPC). Though her presenting complaints were attributed to her history of fall with possible concussion, the diagnosis of RPC was found via thorough physical exam revealing a large, palpable abdominal mass.
The patient was taken to the operating room with a high suspicion that the CT findings were consistent with a giant liver cyst. Upon entering the abdomen using a Hasson technique and placing a 12-mm trocar, a diagnostic laparoscopy revealed a large cyst with a blue hue. Given that the CT findings showed no evidence of nodularity, septation, or intracystic masses and the laparoscopic findings were consistent, the suspicion of malignancy was very low. Upon drainage of the cyst, it was clearly noted that it was easily separable from the posterior liver and was in fact retroperitoneal in origin. The posterior peritoneum was incised. The wall of the cyst was carefully dissected from the anterolateral wall of the kidney, adrenal, and the posterior wall of the ascending colon keeping in mind the significant distortions in anatomy secondary to its size. A plane between the cyst and the posterior peritoneum was established, and the cyst was separated using a combination of electrocautery and sharp dissection. The cyst was then placed in an endocatch bag and removed through the 12-mm port. Thus, the patient underwent a complete cyst excision using a laparoscopic transperitoneal approach. Intraoperatively, the retroperitoneal location of the cyst was confirmed as the cyst wall was separated from visceral peritoneum with ease (
). Macroscopically, the cyst appeared to have thick walls and measured approximately 28 × 17 cm in size and containing 6 L of clear liquid (
). Histopathology revealed a benign serous cystadenoma (
). Should there have been a preoperative suspicion of malignancy based on imaging or, diagnostic laparoscopy, an open approach with en bloc resection would have been undertaken. A subsequent CT revealed interval removal of large RPC with properly repositioned loops of bowel. The patient followed up in 3 months with no further surgical complications or recurrence. We believe that the patient’s presenting symptoms were attributable to her fall, concussion, and dehydration that resolved with hydration and supportive therapy and not related to the findings of RPC or its surgical removal.


A 49-year-old Indian female presented with dull aching pain of both upper limbs of 1-week duration. The patient also had episodes of difficulty in moving both upper limbs. There was no significant past illness. General examination was normal. The patient was afebrile with a pulse rate of 82 per minute and blood pressure of 140/80 mm Hg. She was conscious and oriented. PEARL [Pupils equal and reacting to light]. There were no motor deficits. All the deep tendon reflexes were normal. The plantar responses were flexor bilaterally. All other systems were within normal limits.
Hemogram, liver function, renal function, and coagulation profile were all within normal limits. Magnetic resonance imaging (MRI) of cervical spine (
and
) showed cord edema and swelling from C3 to C7 levels with two enhancing intramedullary cord lesions in anterior and right anterolateral aspect of cervical cord at C5–C6 level measuring 0.4 × 0.4 × 0.8 cm and 0.6 × 0.7 × 1.1 cm, respectively. Cerebrospinal fluid (CSF) study was inconclusive (CSF was clear; CSF pressure: 120 mm H
2
O; CSF sugar: 48 mg/dL; CSF protein: 21 mg/dL; 5 cells/mm
3
with occasional lymphocytes; and CSF culture was negative for pus cells, bacteria, and acid fast bacilli). At this stage, the possibility of an intramedullary tumor was considered. However, since the symptoms were rather acute in presentation, patient was treated with a course of steroids (intravenous methylprednisolone, 1 g, once daily for 5 days).
Patient had partial relief of symptoms with steroid treatment. Repeat MRI done 1 month later revealed mild interval enlargement of the intramedullary lesions. However, the repeat MRI study also showed multiple enlarged mediastinal and hilar nodes (
). Subsequent computed tomography of the thorax revealed extensive mediastinal and hilar adenopathy with no parenchymal lung lesion.
Endoscopic ultrasound-guided fine-needle aspiration cytology of mediastinal nodes showed several epithelial cell granulomas and lymphoid cells suggestive of granulomatous inflammation with suspicious small foci of necrosis (
). Hence, SIMT was considered as the probable diagnosis. The patient was started on anti-TB therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol.
Repeat MRI of cervical spine (
and
) after 3 months of ATT showed resolution of the cervical intramedullary lesions and oedema. There was minimal diffuse residual enhancement at the C5-C6 level. The patient completed 7 months of ATT with isoniazid, rifampicin, pyrazinamide, and ethambutol. Rifampicin and isoniazid was continued for another 2 months. She had total relief of her symptoms following the ATT. A repeat MRI was not done due to financial reasons. On follow up at 2 years following ATT, she is asymptomatic and has no neurological deficits.


Written informed consent for publication was obtained from the patient.
While feeding a 5-year-old male black mamba, a 34-year-old snake breeder suddenly noticed a tiny bloody mark on his forearm and, at the same time, a slight tingling of his lips. He immediately realized that he had been bitten and called a befriended snake expert to seek advice. The patient was thus able to provide the first responders with detailed information about the snake and on where to obtain the corresponding antivenin. He instructed his wife to apply a pressure bandage to the forearm. Within the next five minutes, chest tightness, generalized paresthesia, and fasciculation occurred. Upon arrival of the ambulance, the patient was unable to walk, was tachypneic, and had prominent dysarthria. Assuming a concomitant allergic reaction, the paramedics administered methylprednisolone, clemastine, and adrenaline before transferring the patient to the nearest hospital. In the meantime, the Swiss helicopter ambulance collected the antivenin from one of the 8 national antivenin depots.
Forty minutes after the bite, the patient arrived in the emergency department, complaining of worsening fasciculations and paresthesia affecting the extremities and the face. On physical examination, he was fully conscious with a heart rate of 105/min and a blood pressure of 165/80 mmHg. He was tachypneic at 30/min. Pulse oximetry revealed an oxygen saturation of 95% on room air. There were two tiny puncture wounds with local swelling and redness on the left forearm. Motor function was normal, except for mild ptosis. Seventy minutes after the bite, the patient was given 2 vials (20 ml) of “SAMIR Polyvalent Snake Antivenin” together with 2.5 mg of IV midazolam for ongoing hyperventilation. Thereafter, the patient was transferred to our tertiary intensive care unit for further treatment.
Upon arrival in our ICU, the patient was hemodynamically stable but still tachycardic and tachypneic. Fasciculations, dysarthria, and ptosis had slightly improved. ECG showed a grade 1 atrioventricular block without any other abnormalities. Initial laboratory tests were unremarkable, apart from moderate respiratory alkalosis. Over the next few hours, sweating, chills, and difficulty with swallowing as well as nausea occurred. However, the airway was never compromised, coughing reflex was intact, and respiratory failure did not occur. Therefore, and because of initial concerns about a possible allergic reaction, we decided against further antivenin administration. On the next day, symptoms of envenomation had improved, but the patient developed cellulitis of the bitten forearm and rhabdomyolysis, with a peak serum creatine kinase level of 16,049 U/L. Upon treatment with intravenous fluids and amoxicillin/sulbactam, his condition gradually improved. After four days in the hospital, he was discharged home with muscular pain as the only residual symptom. A few weeks later, the patient had fully recovered.


A nulliparous woman aged 30 years was referred to our perinatology unit for evaluation because of oligohydramnios at 12 weeks of gestation. An antenatal ultrasonographic scan revealed a single live fetus with oligohydramnios. The upper half of the fetus appeared normal with both upper extremities seen separately and moving normally. However, the lower extremities appeared to be fused together in fixed extension and mobility at the hip and knee joints was restricted (). A single umbilical artery was demonstrated using color Doppler (). Thus, the diagnosis of sirenomelia was made prenatally. Medical termination of pregnancy was performed with the informed decision of the parents. On postnatal examination, the fetus weighed 150 grams. External examination revealed fusion of both lower extremities (). Based on the external examination, sirenomelia was diagnosed.


The first patient was a 45-year-old woman who presented with abdominal pain, weight loss, and diarrhea. She underwent a colonoscopy in October 2014, which revealed a 3-cm tumor in her cecum. A right colectomy was performed in January 2015, and a well-differentiated mucinous adenocarcinoma of 2.5 × 1.5 × 1.5 cm invading into the muscularis propria was identified. No perineural or lymphovascular invasion was observed, but a mild tumor inflammatory infiltrate was present. Margins were free, and metastasis to one of 24 lymph nodes was documented. Ileal schistosomiasis was found in the specimen. MSI was confirmed by immunohistochemistry (loss of MLH1 and PMS2). All RAS mutations were negative. She received 6-month adjuvant capecitabine- and oxaliplatin-based chemotherapy. Last follow-up visit was on June 13, 2016.


The second patient was a 47-year-old man who had a personal history of hepatosplenic schistosomiasis. In 2012, he underwent a right hemicolectomy as a result of complications of appendicitis. In March 2014, splenectomy and an esophageal varices clamp were performed as a result of GI hemorrhage. In November 2014, he presented with diarrhea, and colonoscopy showed a 2-cm tumor next to the ileum–transverse colon anastomosis. In March 2015, the specimen analyzed from a segmental colectomy showed a 3.5 × 1.8 cm mucinous moderately differentiated adenocarcinoma infiltrating subserosa, with free margins, presence of lymphovascular invasion, no perineural infiltration, and a mild lymphocytic infiltrate observed. No lymph nodes were identified in the specimen, but a granulomatous reaction in response to Schistosoma eggs in his ileum and colonic mucosa and Merkel diverticula were described by the pathologist. MSI was negative by immunohistochemistry, but exon 2 KRAS mutation (c.38G>A:p.G13D) was identified. Because of his comorbidities, he did not receive adjuvant chemotherapy. Last follow-up visit was on June 13, 2016.
In both patients, KRAS/NRAS exons 2, 3, and 4 were amplified by polymerase chain reaction, and second-generation sequencing was performed using MiSeq (Illumina, San Diego, CA). The patients were tested for MSI using the immunohistochemistry antibodies MLH1, MSH2, MSH6, and PMS2.


A 56-year-old lady presented with severe right anterior chest pain radiating into her arm and back, with significant arm paresthesia, following a fall on her extended arm 11 months earlier. There was no evidence on the CT chest scan of any rib fractures. She had a past medical history of discectomy on her lower spine and a right carpal tunnel decompression. Diagnosis of TOS was based on clinical history, physical examination, and imaging. MRI confirmed compression in her right subclavian artery within the interscalene triangle triangle distally (). There was no evidence of either cervical rib involvement of the brachial plexus. These findings supported the possibility of the arterial compression to be the origin of her symptoms and surgical option was discussed with her after failure of symptoms improvement following 6 months of intense physiotherapy.
She underwent VATS first rib resection. After intubation with double lumen tube, the patient was placed in the lateral decubitus position with the arm abducted to 90 degrees. Three standard VATS ports were utilized. Two ports were placed in the anterior third and the lateral fourth intercostal spaces, while the third scope port was placed laterally in the fifth intercostal space. While being on single lung ventilation, the apex of the right lung was gently freed from all the adhesions. The first rib was identified, and both the parietal pleura and periosteum overlying it were stripped off (). With blunt dissection, the rib was freed from the neurovascular bundle from above. Gentle retraction of the neurovascular bundle was performed using a peanut before passing an endoscopic rib cutter (). The rib was cut anteriorly near the costoclavicular junction and posteriorly at the costovertebral junction. Dissection and nibbling of both stumps were then performed. All periosteal remnants were trimmed releasing the neurovascular bundle completely.
The postoperative course was uncomplicated and patient was discharged within 24 hours following surgery. At the initial follow-up, the patient had marked improvement of her main symptoms.


A 46-year-old male Korean patient presented to the referring dermatologist with a ten-month history of a nonpruritic, nontender, and insidious rash on the face, neck, and trunk. The patient had no prior medical history and did not take any medications. He specifically denied fevers, chills, weight loss, lymphadenopathy, dyspnea, abdominal pain, and changes in urination. He had not attempted any treatment for the rash prior to the visit.
Physical examination revealed numerous disseminated well-demarcated red-brown nonscaly plaques on the patient's face, neck, chest, and back. Plaques ranged from 0.5 cm to 2 cm in size and were distributed haphazardly (Figures and ). Dermoscopic exam was overall nondiagnostic and remarkable for a slight pink hue and prominence of network (). Laboratory evaluations of complete blood count and metabolic panel were normal. HIV, RPR, hepatitis serologies, and QuantiFERON Gold were negative. A skin biopsy was performed, and the patient was referred to our clinic for further care.
Histopathology revealed prominent superficial and deep perivascular and periadnexal infiltrate of hyperchromatic mononuclear cells (), with focal localization to small nerve twigs. Higher power examination revealed predominance of plasma cells lacking atypia in a background of small lymphocytes (). Immunohistochemical stains highlighted the aggregates of CD20+, CD79A+, and B-lymphocytes () amidst more numerous CD138+ (), IgD+, IgG+, and IgM− plasma cells (Figures and ). Kappa and lambda in situ hybridization labeled the plasma cell population with a polytypic pattern including slight kappa predominance (normal finding) (Figures and ). The findings were compatible with cutaneous plasmacytosis.
A peripheral blood analysis identified a polyclonal gammopathy with elevated IgG; however, there was no indication of any associated lymphoproliferative process. Positron emission tomography (PET) and CT scans showed prominent bilateral inguinal lymph nodes measuring 1.5 centimeters. Interleukin-6 was elevated at 11.8 picograms per milliliter.
The patient was offered a lymph node biopsy of his inguinal lymph nodes, which he deferred. He is currently being followed up by his primary provider and is applying topical clobetasol in weekend pulse dosing, with improvement of most skin lesions and without any evidence of systemic progression.


A 9-year-old male child was brought to the Department of Paediatric Dentistry of K.D. Dental College and Hospital, Mathura, Uttar Pradesh, India, by his parents with a complaint of an ugly looking small tooth between maxillary permanent central incisors (). Intraoral examination and intraoral periapical (IOPA) radiograph confirmed the maxillary mesiodens (). The posterior teeth had unsettled occlusion because of premature occlusal contacts in incisor region. After taking all necessary records and informed consent, the mesiodens was extracted under local anesthesia (2% lignocaine hydrochloride) at the Paediatric Dentistry Department. Patient was called back after a week. When he returned, an 8 mm large diastema was clearly visible while speaking or smiling, which further added to the patient’s psychological trauma. The parents stated that the child had developed low self-esteem and depression and could not concentrate in his studies because of a large space between his front teeth. It had affected his confidence.
Orthodontist’s opinion was sought. The orthopan-tomogram (OPG) was taken, which revealed that the permanent canines were unerupted and were erupting in mesial angulation and the premolars were present in their normal position beneath the roots of deciduous molars (). The incisor occlusal interference caused cusp to cusp posterior occlusion.
It was decided to close this large diastema of 8 mm by bodily movement of central incisors. Edgewise brackets (0.022"" × 0.028"" slot) were bonded on the maxillary central incisors and a 0.018"" round nickel-titanium sectional wire was initially ligated for their derotation and alignment ( and ). Once that was accomplished, a 0.018"" round stainless steel full-arch wire with curve of Spee was ligated for slight intrusion of central incisors. A rubber sleeve was placed on the large posterior sections of wire to prevent trauma to cheek. Thereafter, closure of median diastema was started using power chain with a force of 120 gm applied to BPA ligated to both central incisors ().
The large median diastema was completely closed in 5 months period. Spaces opened distal to central incisors and distal to lateral incisors and posterior occlusion settled (). The brackets were then ligated by figure of 8 wire ligatures to maintain diastema closure. Intraoral periapical radiograph was taken, which revealed that the central incisor roots were almost parallel (), indicating a bodily movement of these teeth during dia-stema closure. Thereafter, direct bonded flexible spiral wire retainer was placed on palatal surfaces of crowns of central incisors well clear of incisor occlusion (). The brackets, wire, and BPA were then removed and photographs, IOPA and OPG radiographs, and study casts were obtained. The final result was esthetically pleasing (), and hence, psychologically satisfying for the patient.


A 67-year-old postmenopausal female patient was found to have a mass in the upper outer quadrant of her left breast a year ago. She was diagnosed with ductal carcinoma in situ (DCIS) after surgical biopsy (T1NXMO). Following the diagnosis, a breast-conserving surgery was done. The tissue sent for pathological analysis was reported to be estrogen receptor positive (ER+), progesterone receptor negative (PR−), and grade II DCIS. Median pathologic tumor size was 8 mm. She received radiotherapy to the chest wall following the surgery. After the radiotherapy, 5-year adjuvant hormone therapy with tamoxifen was planned. However, after 4 months of tamoxifen treatment, the patient came to the clinic with complaints of urinary incontinence. Assessments with 2 standardized questionnaires, the Incontinence Impact Questionnaire (IIQ-7) and the Urogenital Distress Inventory (UDI-7), revealed a severe incontinence.[ Her thorough gynecological examination, which was performed by a gynecologist, was reported to be normal. It was therefore thought that the urinary incontinence was due to the use of tamoxifen and the drug was stopped. Two weeks later the patient visited the clinic and stated that the complaints had stopped and the IIQ-7/UDI-7 assessments confirmed her statement. Prior to the diagnosis of breast cancer, the patient had entered menopause at the age of 52 after a total abdominal hysterectomy-bilateral salpingo-oophorectomy performed for the treatment of myoma uteri. After the procedure, the patient underwent hormone replacement therapy for 96 months, and urinary incontinence arose similarly, which also resolved after the treatment was stopped.


A 49-year-old African American male with a history of anxiety and schizophrenia presented to the Emergency Department complaining of epigastric pain. He reported the abdominal pain as aching in nature and associated with nausea and vomiting. He endorsed a 5-pack-year smoking history. Upon chart review, he was noted to have a history of foreign body ingestion requiring laparotomy for spoon removal. Physical examination was unremarkable and his stool was guaiac negative. His laboratory investigations including blood cell counts, biochemical markers, and urinalysis were normal. Plain abdominal radiographs demonstrated a foreign body resembling a cigarette lighter visualized within the stomach (). No abnormal air fluid levels, free intraperitoneal air, or pathologic calcifications were seen.
He underwent emergent upper endoscopy for foreign body removal. The examined esophagus was normal. Diffuse moderate inflammation characterized by congestion, erythema, and friability was found in the entire examined gastric mucosa. One nonbleeding cratered gastric ulcer, 5 mm in largest diameter, was found at the incisura (). Diffuse mild duodenitis was found in the first and second part of the duodenum. A small handheld cigarette lighter was found in the gastric fundus. It was successfully removed endoscopically with polypectomy snare (). The patient tolerated the procedure well; he was treated with pantoprazole 40 mg twice daily for eight weeks. Psychiatry consult and H. pylori serology was recommended. He was scheduled for a repeat endoscopy two months later to monitor treatment response.


A 66-year-old lady with history of diabetes mellitus was referred for evaluation of painless progressive jaundice for six months associated with fatigue. Physical findings of café-au-lait spots, multiple neurofibromas over the trunk (Fig. ) along with family history of first degree relative (sister) affected by neurofibromatosis type 1 confirmed the diagnosis of neurofibromatosis type 1 [, ]. Generalized icterus was noted however no abdominal lump was palpable. Laboratory analysis showed anemia (hemoglobin - 8.7 g/dl) and deranged liver function tests (total bilirubin – 246 umol/L, conjugated bilirubin – 132 umol/L, AST – 97 U/L, ALT – 70 U/L, GGT – 461 U/L, alkaline phosphatase – 659 U/L). Levels of carcinoembryonic antigen and carbohydrate antigen 19–9 were within normal range. Abdominal computed tomography showed a 3 × 2 cm lesion in the periampullary area of the duodenum showing heterogenous enhancement with mild dilation of the common bile duct and another 2 × 1.7 cm lesion in the fourth part of the duodenum (Figs. and ). Endoscopy showed a bulging mass at the site of major papilla. Biopsy was performed and histologic analysis revealed infiltration of lamina propria and muscularis mucosa with carcinoid cells that were strongly positive for synaptophysin and chromogranin. Urine 5-hydroxyindoleacetic acid levels were within normal limits. The patient underwent pancreatoduodenectomy. Intraoperatively, multiple small nodules were found on the hepatic hilum with the maximum size of approximately 4 cm. Thought to be metastatic lymph nodes, frozen section was performed which revealed spindle cell tumor. The patient had an uneventful postoperative recovery.
The operative specimen (Fig. ) showed a 3 × 2 × 2 cm non-ulcerated tumor located close to the ampulla of Vater. In addition, firm white-tan submucosal nodule sized 2 cm in greatest diameter was located in the fourth part of duodenum. Microscopically, the later was GIST, consisting of spindle cells arrange in a fascicular pattern without necrosis (Fig. ). The nuclei were elongated without any significant pleomorphism. The cytoplasm was variably abundant with indistinct cell borders. Mitotic figures were infrequent. Immunohistochemical staining was strongly positive for CD34, CD117 and DOG1 supporting the diagnosis of GIST (Table ) (Figs. and ). S100 stain was negative. Histopathological examination of periampullary tumor revealed well-differentiated endocrine tumor Grade 1 with strong immunohistochemical expression of chromogranin, synaptophysin and Ki67 < 1% (Figs. , and ). Also, CK7 and S100 were negative which ruled out adenocarcinoma and paraganglionoma respectively. Histologic examination of hepatic hilar nodules showed a spindle cell tumor arranged in fascicular pattern within fibrillar stroma. Nuclei were elongated, thin, without mitotic figures. Tumor cells were positive for S100 and were negative for CD34, CD117 and DOG1 suggestive of plexiform neurofibroma. All the resection margins were free of tumor. At two months of follow-up after surgery patient was doing well.


We report the case of a 27-year-old female, with no history of previous breast surgery or irradiation. She reported after four months of breastfeeding a history of painless progressive lump in her left breast.
On examination the patient was in good condition. The right breast was slightly increased in volume. We found a 5 cm lump involving all quadrants of the breast with no cutaneous involvement. Ganglionic area and axilla were free. The sonography showed a hypo echoic (Doppler vascularized) nodular formation with fuzzy limits. The mammography revealed a homogeneous opacity, dense, with poorly defined contours, on the two internal quadrants with a retromammelonal contingent (labelled ACR-3). The trucut biopsy was in favour of a lactating tubular adenoma. The radioclinic discordance, the morphological aspect and the exiguous nature of the material, an immunohistochemical complement was requested. An absence of pancytokeratin labelling contrasted with strong expression of CD31, CD34 (endothelial markers) is described. The proliferation index (Ki67) was estimated at 30%. This led to the conclusion that the phenotypic aspect is related to a vascular proliferation that evokes an angiosarcoma. After a multidisciplinary reassessment, the patient benefited from a conservative treatment by an enlarged excision of the tumour (Fig. ). The histopathological examination of the surgical specimen found an infiltrating mesenchymal proliferation made of vessels of variable sizes anastomosed to vascular slits with lesional limits (Fig. ). The endothelial cells were often spindle shaped, with anisocaryotic nuclei and numerous mitoses and reduced cytoplasm (Fig. ). The immunohistochemical examination on the surgical specimen showed to the same phenotypic profile on biopsy (Fig. ). The final diagnosis was a high-grade mammary angiosarcoma of incomplete excision.
The patient refused any additional surgical management or external radiotherapy and close supervision were prescribed. After eight months of evolution, no local or remote recurrence was reported.


Patient 1 is a 15-year-old boy with Noonan syndrome and a (medication-resistant) focal epilepsy. Since the age of 12 years, he was diagnosed with a left-sided brain tumor in the central region close to the primary motor cortex and has been evaluated for brain surgery. The boy attends normal school without any motor or cognitive deficits. Histology (after tumor resection) revealed a dysembryoplastic neuroepithelial tumor (DNET) WHO I.


Patient 2 is a 6.5-year-old boy with a brain tumor in the left central region and has been suffering from complex-focal seizures since the age of 6 years and 2 months. The boy had no further neurological symptoms and no motor or cognitive deficits. DW-MRI acquisition was performed as part of a presurgical assessment. Histology (after tumor resection) revealed a DNET WHO I.


Patient 3 is a 31-year-old woman with ARSACS. Her first symptoms occurred at the age of 11 years and consisted of generalized epilepsy, followed by an unsteady gait at the age of 13 years due to the development of a spastic ataxia, as well as dysphagia, dysarthria, cerebellar oculomotor dysfunction, and mild cognitive deficits. Molecular genetic testing revealed a homozygous frameshift mutation (p.Leu3102Phefs*8) in the SACS gene which is responsible for ARSACS.


Patient 4 is an 11-year-old girl with metachromatic leukodystrophy (MLD) []. Her first symptoms occurred at the age of 10 years and consisted of a progressively unsteady gait and deterioration of cognitive function. At the time of MRI, she underwent the Wechsler Intelligence Scale for Children and scored an intelligence quotient (IQ) of 79. She had a gross motor function measure of 100 % despite her polyneuropathy. The diagnosis was made biochemically by reduced enzyme activity of the arylsulfatase A and increased sulfatide excretion in urine. In MRI, diffuse T2-hyperintensities are thought to represent this demyelinating process [–].


A 58-year-old man (fair skinned with a history of sun exposure) presented in 2016 for evaluation of newly appearing scaly red plaques on his left shoulder and left clavicle. His past medical history was significant for not only multiple primary cutaneous basal cell carcinomas, but also metastatic basal cell carcinoma with involvement of the brain, bone, liver, and lungs. The new skin lesions had appeared in the setting of near complete remission of his metastatic disease on continued nivolumab treatment; the successful management of his metastatic disease—prior to the onset of his recently developed cutaneous tumors—has previously been described []. This study was performed and consents obtained in accordance with UCSD IRB guidelines (NCT02478931).
The history of the present illness reveals that, in 2012, he developed a basal cell carcinoma on his left posterior shoulder. The tumor was excised and recurred. The subsequent postoperative wound margins were positive for carcinoma, and the site was treated with radiotherapy. Two years later, in 2014, an evaluation of back pain revealed metastatic basal cell carcinoma not only to his axial skeleton, but also to his liver and lungs. The diagnosis was confirmed with biopsies from the bone and liver. A soft tissue specimen of metastatic tumor also demonstrated basal cell carcinoma.
In August 2014, he started vismodegib. The treatment was discontinued after three months when he developed brain metastases. Following successful stereotactic radiosurgery, he began cisplatin and paclitaxel in November 2014. In March 2015, after four cycles of chemotherapy, the drugs were discontinued secondary to progressive bone and liver metastatic disease. Sonidegib combined with buparlisib (a pan-class I PIK3 inhibitor) was started in May 2015, and was discontinued six weeks later after disease progression in the liver. He received vismodegib and paclitaxel from July 2015 to September 2015; they were discontinued secondary to a lack of response.
Hybrid capture-based next generation sequencing (236 genes) was performed by Foundation Medicine on a liver tumor biopsy specimen from July 2015 (; Available online: ) []. The sequencing demonstrated a tumor mutational burden of 103 mutations per megabase (reference: >19 mutation per megabase = high tumor mutation burden) and multiple genomic alterations, including an amplification of PD-L1, PD-L2, and JAK2. In October 2015, based on the high tumor mutational burden and PD-L1 amplification, both of which are associated with a response to checkpoint inhibitors, he was started on the checkpoint inhibitor nivolumab at 240 mg intravenously every 2 weeks, with a remarkable and rapid improvement of performance status, and tumor shrinkage to near complete remission.
He presented with new erythematous plaques on his left anterior shoulder (6 mm × 6 mm) and left chest (8 mm × 6 mm) in June 2016 (). He was still receiving nivolumab, and the near complete remission of his metastatic basal cell carcinoma was ongoing. Biopsy specimens from both skin lesions showed similar pathologic changes, confirming the diagnosis of superficial basal cell carcinoma: superficial buds of basaloid tumor cells extending from the overlying epidermis into the dermis ().
Next generation sequencing of the specimen from his left anterior shoulder primary cutaneous basal cell carcinoma was performed (). The sequencing demonstrated a tumor mutational burden of 45 mutations per megabase and eight characterized genomic alterations. In contrast to the metastatic basal cell carcinoma in his liver, the primary skin cancer did not demonstrate amplification of PD-L1, PD-L2 or JAK2.
The superficial basal cell carcinomas on his left anterior shoulder and left chest were each treated with electrodessication and curettage. A follow up examination in February 2017 showed complete healing of the treated skin cancer sites without tumor recurrence. He was still receiving nivolumab every other week, and his metastatic basal cell carcinoma continued to demonstrate over 95% regression on imaging.


A 31-year-old man, originally from Morocco, was admitted to Leiden University Medical Center (LUMC, The Netherlands) complaining of leg edema in February 2000. The patient had a history of recurrent episodes of inflammation, fever and serositis. The patient was diagnosed with nephrotic syndrome due to amyloidosis secondary to FMF. His family had 7 siblings with consanguineous parents. At that time, no genetic mutations were found. After another episode of FMF in 2009, the patient presented with renal failure and nephrotic syndrome that did not respond to conservative therapy (angiotensin-converting-enzyme inhibitors, diuretics, nonsteroidal anti-inflammatory drugs, cyclosporine and colchicine). He was suspected not to be compliant with treatment. A bilateral nephrectomy was performed to halt the progressive catabolism due to unrestrained renal protein loss. The patient, a Dutch resident, required chronic dialysis. At this time, there was no evidence of clinical cardiac involvement by amyloidosis. In 2011, he received a left kidney transplant from his elder brother, a resident of Spain, who had no medical history of note (the preoperative evaluation of his clinical status and renal function were unremarkable). The kidney donation and transplantation were performed in the Netherlands. The recipient received a standard immunosuppression protocol (cyclosporine, mycophenolic acid and prednisolone). After transplantation, the recipient’s postoperative course was unsatisfactory, with a 10% decrease in serum creatinine levels on 3 consecutive days during the first postoperative week. His renal function subsequently improved, although slowly, and he developed massive proteinuria (18 g/day) and elevated serum amyloid A levels and was diagnosed with nephrotic syndrome. A graft transplant biopsy showed extensive amyloid deposition. The patient underwent treatment with colchicine (0.5 mg/12 h, adjusted for renal function), anakinra (100 mg/day), prednisolone (10 mg/day), mycophenolic acid (540 mg/12 h) and cyclosporine (150 mg/12 h). After 6 months, the patient presented a serum creatinine level of 2.10 mg/dL (185.6 μmol/L) and proteinuria of 0.25 g/day. After 20 months, the graft was functioning well, with a serum creatinine level of 2.40 mg/dL (212.1 μmol/L), undetectable serum amyloid A levels and proteinuria of 0.20 g/day. After 62 months and at the time of this report, his serum creatinine was 2.05 mg/dL (182 μmol/L), Modification of Diet in Renal Disease (MDRD) value of 35 mL/min/1.73 m2 and proteinuria of 0.44 g/day.
An apparently healthy 45-year-old man, originally from Morocco and a resident of Spain for 12 years, was considered a living kidney donor for his younger brother. His medical history and examination was compatible for a living related kidney donation procedure. A thorough physical examination showed no abnormalities, and the laboratory work-up included urine analysis, urine culture, blood test and liver function, the results of which were all within normal ranges. Other studies revealed a serum creatinine level of 1 mg/dL (88.4 μmol/L), creatinine clearance of 113 mL/min/1.73 m2, a 24-h urine protein level of 100 mg and a C-reactive protein (CRP) level of 6 mg/dL (normal range < 5 mg/dL). A computed tomography (CT) angiography of his abdomen showed both kidneys had a perfect configuration with a single renal artery and vein, a normal excretory system and normal appearance of the bladder. After the kidney donation in 2011, the patient presented nausea, vomiting and diarrhea and developed an erysipelas-like erythema of the lower legs. On the fifth postoperative day, he presented a serum creatinine level of 2.08 mg/dL (184 μmol/L). With the diagnosis of prerenal renal failure, the patient was started on IV fluids, which resulted in partially improved renal function. He was released from hospital on the seventh day after the kidney transplantation and was readmitted 3 days later for dyspnea and chest pain. At that time, his serum creatinine level had increased to 2.20 mg/dL (197 μmol/L). Nineteen days after the transplantation, the patient presented a serum creatinine level of 4.80 mg/dL (424.3 μmol/L), proteinuria of 25 g/day and a serum amyloid A level of 85 mg/L. A renal biopsy showed 8 glomeruli, one of which was globally sclerosed and all were pathological. There was extensive expansion of the mesangium, with periodic acid-Schiff (PAS)-positive eosinophilic material, which also caused occlusion of the glomerular capillaries. The eosinophilic material also invaded the blood vessels and was stained with Congo Red. The interstitium presented fibrosis and a diffuse lymphocytic infiltrate. There was also a component of acute tubular necrosis with regeneration. The patient underwent treatment with colchicine (0.5-1 mg/12 h, adjusted for renal function) and anakinra (100 mg/day). After 4 weeks, the patient presented a serum creatinine level of 3.80 mg/dL (339 μmol/L), proteinuria of 16 g/day and an undetectable serum amyloid A level. Treatment with candesartan (2 mg/day) was then started. Fourteen weeks after the kidney donation, the patient had a serum creatinine level of 1.93 mg/dL (171 μmol/L) and proteinuria of 7.5 g/day. He remained on regular colchicine (0.5 mg/12 h), anakinra (100 mg/48 h), candesartan (4 mg/day) and enalapril (5 mg/day) for 4 months. After 20 months, the patient was in good clinical condition. The serum creatinine level had stabilized at 1.50 mg/dL (132.6 μmol/L), creatinine clearance was 61 mL/min/1.73 m2 (MDRD of 53.3 mL/min/1.73 m2), and proteinuria was 2.6 g/day. An echocardiogram revealed an ejection fraction of 60%. Although the possibility of anakinra withdrawal was considered, we decided on indefinite therapy with anakinra and colchicine due to the satisfactory response. After 62 months and at the time of this report, the patient was taking colchicine (0.5 mg/12 h), anakinra (100 mg/48 h) and atorvastatin (40 mg/day). His serum creatinine level was 1.40 mg/dL (123.7 μmol/L), his creatinine clearance was 67.4 mL/min/1.73 m2 (MDRD of 55.7 mL/min/1.73 m2) and his proteinuria was 1.1 g/day.
An initial genetic study on the recipient was conducted in 2000 with negative results. A second genetic analysis was performed in 2011 after the living transplantation on both brothers. Briefly, genomic DNA was prepared from 200 μL of whole blood, using a commercial kit. Hot spot testing for exons 2 (c.278 to c.910) and exon 10 (c.1900 to c.2346) of the FMF gene (MEFV), as well as exons 3, 4-5, 6-7 including introns 2,4 and exons 6 9, 11, by direct PCR and automated sequencing revealed homozygosity in the MEFV gene (c.2082G > A; p.M694I; National Amyloidosis Centre, University College London Medical School, London, UK). The reason p.M694I was not found in 2000 is not known, given that this founder mutation had been already described in 1998 [, ]. This missense mutation has a founder effect in the African Mediterranean population (Lebanon 12.6%; Tunisia; 13%, Syria 4.8%; Egypt 20.6%), and dates back more than 8500 years (Lebanon) (Mediterranean Founder Mutation Database). This change has been established as a pathogenic variant (Clin Var: RCV000220431.2) in a recessive condition.


Mrs. A is a 68-year old female with metastatic lung cancer with a symptomatic PE, initially treated with LMWH for 12 months, then was switched to a DOAC when her cancer was stable and she was on a chemotherapy holiday. She presents with a recurrent symptomatic PE while on this DOAC.


Mr. S is a 56-year old male with metastatic melanoma with a symptomatic DVT. He was initially treated with LMWH for 6 months, then switched to a DOAC after he had completed immunotherapy and his imaging showed stable disease. He presents with a hemodynamically significant gastrointestinal bleed while on this DOAC.


A 43-year-old white man presented with a newly found splenic mass 4 years ago to our Department of Gastroenterology, Hepatology and Diabetology. The splenic lesion was found by his general practitioner in a routine ultrasound examination of his abdomen which was conducted 8 weeks before he presented to our Department of Gastroenterology, Hepatology and Diabetology. He was diagnosed as having a superficial spreading malignant melanoma localized at his left instep 7 years ago and was successfully treated with radical local resection (pT1a, Clark-level II, 0.2 mm thickness, R0). He was concerned about a possible relapse of the above-mentioned malignant disease and agreed to further diagnostic procedures and treatment. Anamnesis of current ailments and physical examination were inconspicuous. His family and psychosocial history had no abnormalities. There were no abnormal laboratory values. In the following 3 weeks, diagnostic procedures such as esophagogastroduodenoscopy, ultrasound, contrast-enhanced ultrasound (CEUS; SonoVue®), computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, and ultrasound-guided fine-needle aspiration (FNA) were performed to rule out metastasis. The esophagogastroduodenoscopy revealed a discrete chronic type-C-gastritis, which was treated accordingly with proton pump inhibitors. Ultrasound showed a hypoechoic lesion in the inferior pole of his spleen with a diameter of 2 cm, blurred boundaries, and inhomogeneous interior pattern. CEUS (SonoVue®) was inconclusive and showed only discrete contrast enhancement of the lesion with accentuated nodule-like enrichment of the boundaries in the arterial phase (see Fig. ). A contrast-enhanced CT scan showed two hypodense lesions of 2.3 cm and 3.5 cm in diameter, which were highly suspicious of metastasis. Contrast-enhanced MRI of his upper abdomen also revealed two suspicious lesions of 2.5 cm and 4.0 cm in diameter, which were hyperintense in T1 and inhomogeneous and hypointense in T2 (see Fig. ). MRI of his head was inconspicuous. Bone scintigraphy showed no abnormal results. The first FNA was inconspicuous. The second one contained atypical, hyperchromatic, and polymorphic cells and therefore was highly suspicious of malignoma. Immunohistochemical analysis of the specimen revealed overexpression of HMB45, S100, and vimentin, strongly indicating metastasis of the above-mentioned malignoma. The case was presented and discussed at our local tumor board. A splenectomy was recommended. Two weeks prior to surgery, he was vaccinated against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis according to national recommendations of the Robert Koch Institute. We conducted a laparoscopic splenectomy approximately 6 weeks after his initial presentation. His intraoperative and postoperative course were uneventful. He recovered well from surgery and was discharged from our hospital 5 days after the procedure. The obtained spleen was examined by our Institute of Pathology. In contrast to the result of the second FNA, the presence of metastasis of melanoma could not be confirmed. The spleen contained two suspicious lesions of 3.5 cm and 1.7 cm in diameter. Histological analysis revealed a nodule-like arrangement of fibroblasts with low cell density and a predominance of dilated capillaries, indicating SANT of the spleen (see Fig. ). The histological specimen was sent to a reference pathologist (Prof. Rosenwald, University of Würzburg, Germany) for further immunohistochemical staining and validation of our diagnosis. The following immunohistochemical analysis showed positive expression of CD31 and CD34 in capillaries with no expression of CD8, CD20, and Ki67. The diagnosis of SANT of the spleen was verified. Follow-up care is carried out by our Department of Gastroenterology, Hepatology and Diabetology. Until now, no further abnormalities could be detected. For an overview of the medical history timeline, see Table .


A 45-year-old male blood type A+ was enlisted for heart transplantation in December 2016 after entering stage D ischemic heart failure. His past history included a large anterior myocardial infarction (MI) in 2015 treated with alteplase and stent placement to the left anterior descending artery, abandoned smoking habits (60 pack-years), hypertension and bouts of self-terminating paroxysmal AF diagnosed during his various admissions for decompensated heart failure (left ventricular ejection fraction of 23%). Since he had a CHA2DS2-VASc of 3 [(Congestive heart failure, Hypertension, Age (doubled), Diabetes, Stroke/Transient ischemic attack/systemic thromboembolism (doubled), VAscular disease, Sex category), expected annual stroke rate of 3.2%], he was initially put on oral anticoagulation with rivaroxaban 20 mg (milligrams) once daily. His remaining medication was composed of carvedilol 6.25 mg bid (bis in die), ramipril 2.5 mg od (omni die), spironolactone 25 mg od, furosemide 40 mg bid, metolazone 10 mg od and atorvastatin 40 mg od. Laboratory evaluation showed a creatinine of 1.0 mg per deciliter (dL) [creatinine clearance of 119 milliliters (mL) per minute (min) by Cockroft-Gault’s formula] and a N-terminal-proB-type natriuretic peptide of 2566 picograms (pg) per mL, with no other relevant abnormalities. After being accepted for heart transplantation, he was given a priority of 6 out of 7, the highest for outpatients, 1–5 being reserved for inpatients in the waiting list. Following availability of idarucizumab at our institution, he was switched from rivaroxaban to dabigatran 110 mg bid, which was started 24 h (h) after the last dose of rivaroxaban.
On the 5th February 2017, a potential donor in brain death was deemed suitable for organ procurement. After a negative crossmatch and direct surgical inspection, the heart was excised at 11h45min and arrived at our institution, where the receiver was waiting in the operating room under general anesthesia. His laboratory workup 6 h previously showed a hemoglobin of 14.6 g per dL, platelet count of 104 000 per microliter, an activated partial thromboplastin time (aPTT) of 39.6 s (s) [1.35 times the mean reference value (reference range: 23–38 s)], a prothrombin time (PT) of 18.5 s (reference <14 s) and a fibrinogen of 4.2 g per liter (L) (reference range: 1.50–4 g per L). As the patient had taken the last dose of dabigatran in the night before (12 h previously) and both dilute thrombin time (dTT) and ecarin time (ET) were unavailable at the time at our institution, prompt restoration of hemostasis was considered necessary so that heart transplantation could be safely performed. After median sternotomy (16h15min) and pericardiotomy, cannulation of the aorta and both caval veins, idarucizumab was administered as two consecutive boluses of 2.5 g and the patient was cooled to 25° Celsius under nasopharyngeal monitoring. 50 mg of tranexamic acid were also administered intravenously, followed by a continuous infusion of 90 mg per hour during 2h30 min. First measured activated clotting time [(ACT), minutes after idarucizumab administration) was 147 s (reference range 80–160 s). After an intravenous bolus of 27 000 international units [(IU), 300 per kg of body weight] of non-fractionated heparin targeting an ACT between 400 and 480 s (together with priming of the extracorporeal circuit with 5000 IU), cardiopulmonary bypass (CPB) was started and orthotopic heart transplantation ensued. Peak ACT was >1000 s during CPB and 146 s after protamine (1 mg per 10 IU of heparin) and just before CPB exit. Hemoglobin was 14.5 g per dL pre-CBP and 11.9 g per dL post-CPB. Total blood products given during CBP amounted to 1 pool of platelets, 4 units of fresh frozen plasma and 1000 mL of recovered blood from the surgical field via Cellsaver®.
The patient was easily weaned off CPB and was transferred to the Intensive Care Unit (ICU) under dopamine [2 micrograms (μg) per kilogram (kg) per min] and isoproterenol (0.04 μg per kg per min). Cardiopulmonary bypass time was 120 min, aortic cross clamping time was 75 min and cold ischemia time was 165 min.
The following post-operative course was uneventful. Total pericardial and pleural drain yield was 300 mL by the 6th post-operative hour (baseline 300 mL in each drain after sternal closure) and total drainage was 1125 mL. No further blood products were administered.


A 50-year-old female patient with chewing pain in the left posterior teeth visited the doctor. An intraoral examination revealed anterior teeth with a deep inward overbite and the loss of the normal protrusive guidance. The maxillary left second molar was empty, and the mandibular left second molar was extended by 5 mm. The maxillary right second molar and the mandibular right first molar were restored with crowns. The bilateral posterior teeth had severe attrition, exposed dentin, and probing sensitivity. The patient had a normal open-type, bilateral temporomandibular joint with mild click and no soreness of the mastication muscles. The lower vertical dimension of one-third of her face was 11 mm less than the vertical dimension of the middle one-third of her face, and the freeway space was 8-9 mm. The mandibular left first incisor had a labial apical fistula (Figures and ). An X-ray showed that the maxillary right second molar and the mandibular left first incisor had a root canal therapy, and there was an apical shadow in the mandibular left first incisor. The patient denied any history of bruxism.
The patient could not achieve the normal mandibular protrusion in the process of chewing food, with the anterior teeth inclined to a deep bite. The lateral movement was abnormal due to a collision between the mandibular left first incisor, whose position was the most anterior in the mandibular dentition, and the maxillary anterior teeth; thus, the patient could only exercise a linear mortar-and-pestle process when chewing food, which increased the posterior teeth load. In addition, the patient was missing a maxillary left second molar, causing more severe attrition of the left posterior teeth. Furthermore, the abnormal mortar-and-pestle mandibular movement also increased the burden of the temporomandibular joint. An interdisciplinary team including prosthodontist, oral and maxillofacial surgeon, orthodontist, and endodontist was formed to treat the patient. Alternative treatment projects were proposed to the patient. She refused orthodontic treatment due to the duration of treatment procedure. Meanwhile, surgery and restoration of the edentulous posterior region with an implant were offered. This option was also refused for the patient's fear of implant surgery. Therefore, prosthodontic treatment was chosen. The treatment plan was to regain the vertical dimension by reconstruction, then recover the anterior guidance through a mock-up of the anterior teeth, and finally remove the lock of the anterior teeth for full mouth rehabilitation.
In a conventional centric relation (CR) position when making a maxillary overlay splint, elevation is 5-6 mm at the posterior area, with adjustments to the occlusal contact points between the maxillary and mandibular dentition resulting in an anterior-posterior protected occlusion. The anterior teeth have no contact at the central occlusion, the bilateral posterior teeth have uniform contact. The posterior teeth have no contact at the anterior and lateral protrusive position and this establishes canine protected occlusion.
After 3 months, the patient had adapted to the new vertical dimension of occlusion (VDO) and anterior guidance. The occlusal relationship was stable without joint and muscle symptoms, and definitive restoration was started. During the 3-month trial period, the endodontic practitioner treated the mandibular left first incisor with root canal therapy and performed periapical surgery, which revealed a 5 mm apical longitudinal crack. The endodontist resected the apical granulation tissue and cut the 5 mm apical root.
The prosthesis includes 3 steps. The first step involves the left maxillary and mandibular posterior fixed prosthesis. Cut the overlay splint into 2 sections from the distal border of the maxillary left canine. Continue to wear the right two-thirds part of the splint (Figures and ) to support the transition relation, transfer the vertical dimension and the occlusal relation record as determined by the adapted trial treatment to the articulator, make the fixed reconstruction of the maxillary and mandibular posterior teeth with full porcelain crowns (), and operate conventional occlusal adjustment ().
The second step involves the anterior fixed prosthesis. Make an impression of the maxillary and mandibular dentition with the maxillary remaining two-thirds part of the splint worn in the mouth, mount on an articulator using a face bow, transfer the protrusive condylar guide inclination and the lateral condylar guide inclination using the anterior and lateral protrusive jaw position recording silicone rubber, and make a personalized anterior guidance disk with lightly cured resin (). According to this anterior guidance, make the maxillary and mandibular anterior teeth wax-up () and then remove the anterior part of the rest of the splint. According to the tooth preparation silicone guide to prepare the maxillary and mandibular incisors, make a polyether impression, make the temporary crowns, mount the maxillary and mandibular models in turn on the articulator (Figures –), and eventually place the full ceramic crowns (). The maxillary and mandibular anterior fixed reconstruction retains the anterior guidance of the transitional splint ().
The third step is the removal of the left segment of the splint. This step completes the ceramic crown restoration for the right maxillary and mandibular posterior teeth in accordance with the occlusal relationship ().
After the transitional restoration of the normal vertical dimension and the anterior guidance adaptation by the splint and the eventual full mouth rehabilitation using the ceramic crowns, the patient's left masticatory pain disappeared. After 4-month follow-up, examination was done and the minor occlusion registration was checked; there was no other discomfort and the denture appearance and shape were improved (). It was recommended that the patient have an implant to restore the left maxillary second molar, and she planned to have the treatment later.


A five year old boy of north Indian origin, born out of a non-consanguineous marriage (
) presented to the hospital with headache, fever and a history of recurrent infections requiring hospitalization. The antenatal and perinatal periods were uneventful. His clinical history revealed that the child had been hospitalized for septicaemia and underwent treatment with intravenous (IV) antibiotics for 2 weeks at one year of age. Later, at 2.5 years, the child developed fever with swelling in right knee joint that was diagnosed as septic arthritis. The child was again hospitalized at 5 years of age for pyogenic meningitis. The culture of cerebrospinal fluid was found to be positive for
Pseudomonas aeruginosa. On close examination, the tonsils were found to be absent and there was no peripheral lymphadenopathy. The immunoglobulin profile revealed serum level of IgG 50 mg/dl (200–700 mg/dl), IgA 5 mg/dl (40–200 mg/dl) and IgM 9 mg/dl (50–200 mg/dl). The hemogram showed hemoglobin concentration of 9.5 g/dl (11.5–15.5 g/dl), total leukocyte count 14800/cumm (6000–13500/cumm), platelet count 931000/cumm (150000–400000/cumm) and erythrocyte sedimentation rate ESR 18mm/1st hr (0–14 mm/1st hr).
The blood flow cytometric analysis of the affected child was performed to evaluate the status and count of mature B cells. The patient (III.1) has only CD3+ lymphocytes as observed on CD19/CD3 dot plot and there was complete absence of CD19+ cells (0.02%) (
). The staining for BTK protein on CD14+ monocytes showed decreased (20.71%) expression of BTK in proband as compared to control (72.07%) (
). This observation was consistent with the diagnosis of XLA
. The patient had no family history of immunodeficiency and no such characteristics were present in any other family members.
The blood samples were collected and processed for genomic DNA isolation by salting out method
. We performed the whole exome sequencing using trio-based approach (patient, mother and father). In brief, the whole-exome library was prepared using Nextera rapid capture expanded exome kit (Illumina Inc., USA) according to manufacturer’s standard protocol. Sequencing was performed on Illumina Hiseq2500 platform (Illumina Inc., USA) with 130bp paired-end reads. Reads were trimmed using Trimmomatic v0.33
 and aligned to reference genome hg19 (GRCh37) by Stampy v1.0.23
 along with BWA v0.7.12-r1039
. PCR duplicates were marked using Picard tools v1.127. Variations were called using Platypus v0.7.9
 and annotated using ANNOVAR
. Analysis revealed a novel frameshift insertion c.1325dupT in exon 14 of the
BTK gene. The mutation was found to be homozygous in child and heterozygous in mother. The identified mutation c.1325dupT has not yet been reported in the BTKbase
 and absent in ExAC, 1000genome as well as internal control databases from South Asia and Middle East (
), which confirms the novelty of the variation. The mutation evaluation by SIFT Indel tool (
,
) was predicted to be damaging and caused nonsense mediated decay (confidence score 0.858). Further
in silico analysis suggested that the mutation causes Isoleucine at 443 residue in BTK to be replaced by Histidine and introduces a premature stop codon at 444 residue, which lies in the kinase domain of the BTK protein (
).
The variation was further validated by PCR amplification of region encompassing the variation using specific primer sets (Forward primer: 5’-CCCCAAATGCTACTGAGATGGT-3’ and Reverse primer: 3’-CCTATTTCTACCCCAGTAGGGA-5’) with the annealing temperature of 59°C using Brazilian
taq polymerase (Invitrogen, USA) according to manufacturer instruction. PCR products were purified using Qiaquick PCR purification kit (QIAGEN, Germany). Capillary sequencing was performed using BigDye-terminator chemistry on 3130xl Genetic Analyzer (Applied Biosystems, USA). Analysis revealed that the mutation was homozygous in child (III.1), heterozygous in mother (II.3) and absent in father (II.2) and maternal grandmother (I.4) (
).