In May of 2006 a 20 year-old woman presented to the National Institutes of Health (NIH) Clinical Center for evaluation. Her chief complaint was “I am not feeling like myself.” She reported experiencing hot flashes, night sweats, insomnia, occasional crying episodes, sadness, and an unpleasant jittery feeling. She had experienced loss of interest in activities she normally enjoyed. She also complained of waking up in the middle of the night with intense hunger. At age 18, she developed symptoms of severe depression that required her to take medical leave from her freshman year of college. Since then she was on numerous psychotropic medications and at the time of admission was on an extensive and complex regimen. By report of the patient and her mother, her depression had been relentless and difficult to treat.
Here is how the patient described the situation:
“I left my university on medical leave and spent my freshman year in bed or at doctors’ offices. No one knew what was wrong with me, so they kept referring me to different doctors and prescribing more medicines to treat the symptoms. The psych docs sent me to the medical docs and the medical docs sent me to the psych! It was the most frustrating, upsetting, and debilitating year of my life.”
Cascade genetic testing at 4 years old had uncovered the patient carried an FMR1 premutation (100–110 CGG repeats). Her older brother was found to have fragile X syndrome by genetic testing at age 9 years. Her mother and aunt also carried an FMR1 premutation and both had experienced “premature menopause.” The patient reported menarche occurred at age 11. She never established regular menses. She began taking the oral contraceptive at age 13 due to debilitating dysmenorrhea and menorrhagia. She stopped the oral contraceptives at age 16. From age 16 to 18 she experienced only “spotting” every 3 to 4 months. Between age 17 and 18 she began having night sweats. Her endocrinologist began her on levothyroxine replacement despite normal free T4 and TSH levels. Subsequent endocrinologic evaluation at a referral center suggested possible Cushing’s syndrome. She had an elevated morning serum cortisol, an elevated urinary free cortisol (twice the upper limit of normal), and an abnormal overnight dexamethasone suppression test.
On admission to the NIH Clinical Center, the woman had normal vital signs. Her body mass index (BMI) was 28.3 kg/m2. Physical exam revealed no stigmata of Cushing’s syndrome. Initial psychiatric consultation at the NIH concluded the young woman had a mood disorder due to her general medical condition, possibly primary ovarian insufficiency. Diurnal serum cortisol levels and 24-h urine free cortisol were normal. Transvaginal ultrasound findings were consistent with a diagnosis of POI [a 2 mm endometrial stripe, a very small left ovary (1.2 × 1.6 × 1.0 cm) with no visible follicles, and the right ovary could not be convincingly demonstrated]. Serum gonadotropins were in the menopausal range (FSH 46 and LH 26 IU/L). Serum estradiol was also in the menopausal range (23.3 pg/ml). Serum 21-hydroxylase antibodies, thyroid peroxidase antibodies, and thyroglobulin antibodies were all negative. Serum prolactin and MRI of the pituitary were normal. TSH and free T4 were normal.
The NIH discharged the woman with the newly recognized diagnosis of FXPOI. She began taking hormone replacement therapy (a daily dose of 100 microgram of estradiol by transdermal patch and cyclic medroxyprogesterone acetate by mouth 10 mg per day for the first 12 days of each month). She kept a menstrual calendar as instructed. After discharge her psychotropic medications and thyroid replacement were tapered, she menstruated regularly on the hormone replacement regimen, and her symptoms of anxiety and depression resolved.
Here is how the patient described the situation:
“Therefore, when NIH diagnosed me with FXPOI, I was thrilled. It was the first time in 3 years somebody understood me and could help me. All I wanted to do was to go to college and experience a typical 20-year-old life. I did, and it was fabulous!”
The young woman married in August 2012. She conceived shortly thereafter without medical intervention while on hormone replacement therapy. She terminated the pregnancy as prenatal genetic testing showed a full mutation in FMR1 in the fetus. Thereafter, she conceived two more pregnancies without medical intervention while on hormone replacement therapy, one in 2013 and one in 2016. Shortly prior to the conception in 2016 a physician at an IVF clinic suggested she proceed to egg donation and quoted a current chance of conception of less than 0.1%. This is despite her history of having had two prior pregnancies subsequent to the diagnosis of FXPOI. Both pregnancies and deliveries were unremarkable with the birth of two healthy girls.


A 14-year-old adolescent boy was referred to our Endocrinology Department for evaluation of short stature. As no medical records were available, previous growth velocity could not be evaluated. The patient reported that he had always been short for his age throughout his childhood.
His recent medical history was negative for headaches, vomiting, or vision changes. There were no reports of fatigue, cold intolerance, constipation, and skin or hair changes. Appetite was normal with no recent weight loss. There were no academic concerns. He regularly played football, with no history of traumatic or nontraumatic fractures. He took no medications. For several months, he had reported minor bilateral symmetrical crookedness on his second fingers, without any pain or local symptoms.
He had been born at 36 gestational weeks, weighing 2450 g with no history of abnormal gestation, breech presentation, ischemic insult at birth, or other neonatal events.
Parental heights were normal, with a target height of 177.5 cm. Parental pubertal timing was also within normal limits. Family history was negative for short stature, endocrine, or autoimmune conditions.
Clinical examination revealed a dysmorphic, proportionate, and relatively short adolescent with normal vital signs. His anthropometric parameters were −2 SDs (standard deviations) for weight (37 kg) and between −2 SDs and −2.5 SDs for height (148 cm) (Belgian charts). His height was below his midparental genetic interval. His upper:lower segment ratio and arm span were normal. His hands and feet appeared short, with middle, painless tumefaction of soft tissue around the index proximal interphalangeal joints. No spinal abnormalities were noted, but a mild pectus excavatum was present. There was no thyromegaly. Testicular and pubic hair development was in Tanner stage II (testicular volume 6 ml). The most prominent dysmorphic features were a pear-shaped nose, a thin upper lip with small lower jaw, prominent ears, and markedly thin and sparse blonde hair with rarefaction of the lateral eyebrows (). The teeth examination was difficult because he wore dental braces to correct dental irregularities.
An extensive biological workup was performed. Complete blood count and serum levels of inflammatory markers, electrolytes, glucose, renal function, liver enzyme, and tissue transglutaminase antibody levels were normal. The laboratory findings showed normal thyroid and adrenal function and normal growth hormone secretion (normal levels of insulin-like growth factor and insulin-like growth factor binding protein). Additional pituitary and gonad testing revealed a normal prolactin level and pubertal testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels (). The bone age was evaluated at 12 years 6 months.
A renal and cardiac ultrasound looking for other possible somatic malformations [] wasperformed and showed normal morphological kidneys, ureters, and urinary bladder and no cardiac abnormalities.
After this first clinical, biological, and radiological evaluation, the working diagnosis was constitutional growth delay with late normal puberty, but skeletal dysplasia (dysmorphic features in the context of short stature) was considered for differential diagnosis.
During the follow-up 6 months later, the initial apparent soft tissue tumefaction of his indexes had progressed to localized noninflammatory and painless deformity, causing limited difficulty in writing and typing on a keyboard. This sign was isolated, and the patient did not complain of pain or history of local trauma or infection. At this time, his clinical appearance was normal, except for the aforementioned dysmorphic traits. His growth velocity (5 cm/6 months) was normal in the context of spontaneous pubertal progress (Tanner stage III, testicular volume 8–10 ml).
Clinical examination of his hands revealed isolated ulnar deviation of the second fingers and symmetrical deformity of proximal interphalangeal joints of both hands (). He had no other painful or deformed joints.
His feet look normal, but the toes are short ().
Theoretically, a differential diagnosis with inflammatory arthritis was considered, but the clinical findings (dysmorphic features, short stature, and relatively asymptomatic finger abnormalities) were more suggestive of a skeletal dysplasia. Radiographs of hands, feet, and pelvis were performed and allowed the definitive diagnosis.
The plain radiograph of his wrists showed cone-shaped epiphyses of the middle phalanges of the second digit of both hands with moderate deviation of the phalangeal axis (Figures and ).
Similar cone-shaped epiphyses were found in the proximal phalanx of the great toe and up to the fourth one of both feet with shortness of all toes ().
No other radiological joint impairments (juxtaarticular osteopenia or erosions) were found. Radiographs of the pelvis and whole-body magnetic resonance imaging (looking for fine abnormalities, particularly long bone cysts not visible on plain radiographs) [] were normal. The bone age was retarded at 12 years 6 months (the chronological age was 14 years 6 months).
Taking together the clinical and particularly the radiological findings, the correct diagnosis of trichorhinophalangeal syndrome (TRPS) was achieved. This was a delayed diagnosis, and our explanations for this include the underrecognition of the dysmorphic features (in our first examination), the underinterpretation of fingers tumefaction in the clinical context, and consecutively no hand radiological exam being conducted.
Other entities associating ectodermal and skeletal phenotypes were reviewed, particularly Albright osteodystrophy, acrodysostosis, and other brachydactyly syndromes, but several features of the presentation were inconsistent with these diagnoses.
Cytogenetic analysis was not performed. The family history appeared to be negative, his parents and his sister do not manifest the syndrome phenotype, and in such conditions, a sporadic case of TRPS type I was considered highly possible.


A 64-year-old woman with a history of Crohn’s disease (CD) was referred to Siriraj Hospital located in Bangkok, Thailand in June 2017 due to worsening of abdominal pain and watery diarrhea for 2 weeks. She was diagnosed with CD in 2010 after she presented with abdominal pain and palpable mass at the right lower quadrant (RLQ) of her abdomen. She was treated successfully with prednisolone 40 mg/day, azathioprine 50 mg/day, and mesalazine 2400 mg/day. Her disease was then controlled with prednisolone 5 mg/day and the same dose of azathioprine and mesalazine. One year after her CD diagnosis, she developed severe abdominal pain and diarrhea. A colonoscopy was performed, which showed inflamed mucosa and a clean-based ulcer at the cecum. Biopsy revealed an intracytoplasmic inclusion body, which is consistent with cytomegalovirus (CMV) colitis. Her symptoms gradually subsided after 3 weeks treatment of intravenous ganciclovir 5 mg/kg twice daily. Two years after her CD diagnosis, she began experiencing recurrent abdominal pain. Abdominal computed tomography (CT) and colonoscopic findings revealed a large polypoid mass at the ascending colon with partial colonic obstruction that was suspected to be caused by active CD. She was managed conservatively and was discharged home with prednisolone 30 mg/day, azathioprine 150 mg/day, and mesalazine 2400 mg/day after making substantial improvement. Even though she remained stable for about 4 years after her most recent discharge, she still required prednisolone 5 mg/day, azathioprine 150 mg/day, and mesalazine 2400 mg/day to control her disease activity. Her last colonoscopy with biopsy, which was performed 6 months earlier to monitor her disease activity, revealed a shallow 1 cm2 ulcer that was covered with white exudate at the cecum, and multiple polypoid masses at the ileocecal (IC) valve. The histopathologic findings revealed a chronic ulcer with marked active inflammation, a hyperplastic polyp with chronic ileitis, and no viral inclusion, dysplasia, or malignancy. Eight weeks ago, she started complaining of intermittent cramping at the RLQ of her abdomen. The dose of azathioprine was increased to 175 mg/day for presumed exacerbation of CD; however, her pain worsened, and she eventually developed a low-grade fever and watery diarrhea for 2 weeks before admission. She denied having any pulmonary symptoms. On examination, her body temperature was 38.6 °C and she had abdominal tenderness and a palpable mass at the RLQ of her abdomen. All other examination findings were unremarkable.
Laboratory investigations revealed a white blood cell (WBC) count of 2010 cells/mm3 with 90.5% neutrophils and 8.5% lymphocytes, and a hemoglobin level of 8.2 g/dl. Chest X-ray showed an oval-shaped cavitary lesion at the right lower lung (Fig. a). A CT scan of the chest revealed a large cavitary lesion (5.4 × 3.2 cm) with irregular wall thickening at the right lower lobe, and an adjacent focal centrilobular nodule with tree-in-bud pattern. A CT scan of the abdomen revealed chronic wall thickening at the cecum, IC valve, and terminal ilium, with submucosal edema and pericolic fat stranding. The patient underwent colonoscopy and biopsy, and a polypoid mass was observed at the IC valve with multiple clean-based ulcers at the cecum (Fig. a). Since the initial diagnosis was active CD, the tissue was sent only for histopathology. No fresh tissue was submitted for fungal culture. Pathologic examination of the tissue biopsy revealed active ileitis and colitis with multiple round shape organisms. The capsules of the observed organisms could be visualized by hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), Grocott-Gomori’s methenamine silver (GMS) staining, and mucicarmine stain, which is compatible with Cryptococcus spp. (Fig. ). Even though serum cryptococcal antigen was positive with a titer of 1:128, blood, bone marrow, and cerebrospinal fluid cultures for fungus were all negative.
The final diagnosis was disseminated cryptococcosis due to gastrointestinal and presumed pulmonary involvement. Initial induction therapy with amphotericin B deoxycholate (AmBD) 0.7 mg/kg per day was given for 6 weeks, followed by consolidation therapy with fluconazole 800 mg/day for 8 weeks. After consolidation, maintenance treatment with fluconazole 200 mg/day was prescribed for up to 1 year. After diagnosis of disseminated cryptococcosis, the immunosuppressive agents were adjusted as follow: discontinued azathioprine, decreased the dose of prednisolone to 15 mg/day, and maintained mesalazine at 2400 mg/day. Her clinical status was gradually improved, and the colonoscopy that was performed at 10 weeks after the start of treatment showing marked improvement in the polypoid mass-like lesion at the cecum (Fig. b). Even though the diagnosis of pulmonary cryptococcosis was not confirmed by pathology or microbiology, her chest X-ray the 3-month follow-up showed marked improvement (Fig. b).


A 75-year-old nonsmoking woman presented to our emergency department due to progressive shortness of breath for 3 days. She denied fever, abdominal pain, diarrhea, bloody stool, or tenesmus. She had been diagnosed with ulcerative colitis at our hospital and received mesalazine 2 g per day for 2 years and 8 months.
Her initial vital signs were a blood pressure of 131/79mm Hg, pulse rate of 80 bpm, respiratory rate of 28/min and body temperature of 36.0°C. On physical examination, chest auscultation revealed coarse breathing sounds with bilateral crackles. Laboratory investigations revealed a white blood cell count of 10,600/μL with 79% neutrophils, hemoglobin level of 9.7 g/dL, and platelet count of 464,000/μL. Biochemistry profile showed an elevated level of C-reactive protein (79.7 mg/L), mildly impaired renal function (blood urea nitrogen level of 21.2 mg/dL and creatinine level of 1.23 mg/dL), and a normal alanine aminotransferase level (13 U/L).
Electrocardiography showed a normal sinus rhythm, and echocardiography of her heart was normal (left ventricular ejection fraction of 77%). Chest radiography revealed increased infiltration with patchy consolidations in both lungs and lower lobe predominance (Fig. A). She was then given oxygen via a nasal cannula. Under the impression of community-acquired pneumonia, she received antibiotic treatment and was admitted to our chest ward.
Episodic high fever was noted since admission, and chest radiography showed progression of bilateral infiltrates. Further investigations were thus warranted, and a computed tomography (CT) scan showed diffuse peribronchial and subpleural consolidations in bilateral lungs with minimal interstitial thickening. The differential diagnosis included cryptogenic OP, acute interstitial pneumonia, and metastasis (Fig. A). In the following days, her respiratory condition deteriorated, and she was given noninvasive ventilator support (bi-level positive airway pressure, BiPAP) (Fig. B). Under the consideration of mesalazine-induced OP, mesalazine was discontinued on the 8th day of admission, and intravenous hydrocortisone 100 mg Q6H was started. She was then transferred to our medical intensive care unit.
We performed infection surveys for viruses, fungi, and mycobacteria. Due to positive cytomegalovirus (CMV) serologic tests including both IgM and IgG, intravenous ganciclovir was given for 7 days until the results of CMV antigenemia assays and qualitative CMV polymerase chain reaction (PCR) assays were negative. We also surveyed her autoimmune condition and vasculitis markers, and positive results of antinuclear antibodies and p-ANCA (antineutrophilic cytoplasmic antibodies, perinuclear pattern) were attributed to ulcerative colitis.
Her respiratory condition improved in the following days, although only a mild improvement was shown on serial chest plain films (Fig. C). Hydrocortisone 100 mg Q6H was maintained for 8 days and then tapered. BiPAP was shifted to an oxygen mask in the 2nd week of ICU admission.
Bronchoscopy with bronchoalveolar lavage (BAL) was performed, and a specimen was sent for bacterial, fungal, and viral cultures, PCR testing of tuberculosis and Pneumocystis jirovecii, galactomannan, total and differential cell counts, CD4/CD8 ratio, and cytology. The results showed 81% macrophages, 10% lymphocytes, 8.2% neutrophils, and 0% eosinophils, with CD4 and CD8 counts of 24.6% and 22.7%, respectively (CD4/CD8 ratio: 1.08). The BAL culture showed growth of Actinomyces odontolyticus, which may have been caused by aspiration of oropharyngeal secretion. A transbronchial lung biopsy was done, and the pathology report showed mild chronic inflammation with OP (Fig. ). There was no evidence of granuloma, malignancy, or vasculitis.
The patient was discharged on the 28th day of hospitalization with oral prednisolone 20 mg per day. She was regularly followed up at our chest out-patient department. One month after discharge, she had greatly reduced exertional dyspnea, and a chest plain film showed substantial improvements (Fig. D). A follow-up chest CT scan 3 months after disease onset showed resolution of most of the infiltration (Fig. B).


A 37-year-old male patient presented to the emergency department complaining of three days history of abdominal pain, bleeding per rectum, nausea and recurrent attacks of vomiting. The pain was recurrent for the past three months and increased over the last month. On examination, the patient was malnourished and pale. He was vitally stable. His abdomen was soft, lax, without evidence of peritonitis. No masses could be appreciated. Digital rectal examination revealed blood on the glove with no masses or hemorrhoids. Routine blood tests were within normal ranges.
Abdominal ultrasonography US showed a well-defined oval-shaped hypoechoic lesion in the right lower quadrant area (). Contrast-enhanced abdominal computed tomography CT showed a well-defined cystic lesion within the lumen of cecum with thick septations measuring 4 × 4 cm (). As well, a doughnut shape was seen suspecting ileocecal intussusception. No enlarged or suspicious lymph nodes were detected in CT. As well, no free intraperitoneal fluid was seen. Colonoscopy revealed a cystic swelling in the cecal submucosa occupying half of its circumference. Biopsy from the mass was technically difficult. Advancement of the scope was impossible due to obstruction of the ileocecal valve by the mass.
The patient was kept nil per mouth and on intravenous fluid. He underwent elective diagnostic laparoscopy. He was placed in supine, Trendelenburg position. Closed pneumoperitoneum was created using a Veress needle in Palmer’s point. The scope was inserted through a supra-umbilical incision using an 11-mm Visi-port trocar. Two trocars were inserted five centimeters below the costal margins at right and left midclavicular lines. Diagnostic laparoscopy showed a mass involving the appendix, the ileocecal junction and the cecum with no free fluid in the peritoneal cavity. Devascularization was done starting five centimeters proximal to the ileocecal junction up to the hepatic flexure. Transection of distal ileum and transverse colon distal to hepatic flexure was done using Endo-GIA tristapler. Side-to-side ileo-transverse anastomosis was created using Endo-GIA tristapler. The specimen was retrieved en-bloc using Endo-bag. The patient tolerated the procedure well. He started clear liquid on the third postoperative day. He was discharged home on the sixth postoperative day.
Histopathological examination of the specimen showed mucinous cystadenoma of the appendix with extravasation of mucinous material into the submucosa of the cecum, leading to formation of a pseudocyst. No malignant cells were found in the resected ileocolic lymph nodes. All margins were free from malignant cells. After multidisciplinary meeting with medical oncology, pathology and radiology teams, there was no need for any further surgical intervention nor follow-up imaging. He was followed up regularly in the surgical clinic for two years with no symptoms or signs.


A 64-year-old female presented to our medical center with abdominal pain, nausea, and vomiting for one day. The pain was diffuse, sharp, and it was concentrated in the lower abdomen. Her past medical history was significant for breast carcinoma status post bilateral mastectomy, hysterectomy, Helicobacter pylori infection successfully treated with triple therapy and metastatic squamous cell carcinoma of the esophagus. Four years ago, she underwent an uneventful placement of a fully covered 19 x 100-mm esophageal Wallflex® stent (Boston Scientific, Natick, MA, USA). Her family history was unremarkable and her home medications included iron and vitamin C supplementation. The patient was non-alcoholic, non-smoker and drug-free. On physical examination, she appeared comfortable; well-oriented in time, space and person; well nourished; and there was no acute distress. Cardiac examination was notable for tachycardia. The chest was clear to auscultation with good air entry bilaterally. The abdomen was tender in the hypogastrium and left-lower quadrant, but it was soft and non-distended. Vital sign examination revealed blood pressure 112/68 mm Hg, heart rate 111 beats per minute, temperature 98.5°F and respiratory rate of 18 breaths per minute.
The patient underwent an extensive diagnostic evaluation. The details of her laboratory workup are provided in Table .
Computed tomography abdomen identified the esophageal stent in the left-lower quadrant of the abdomen with the presence of free air in the abdominal cavity, consistent with the gastrointestinal tract perforation (Figure ).
The migrated stent-related perforation of the jejunum with multiple loops of small bowel measuring up to 4.5 cm, bowel-wall edema, and thickening of the loops proximal to the stent were evident (Figure ).
The patient was emergently shifted to an operating room. An uneventful exploratory laparotomy was performed. It showed a moderate collection of a purulent fluid within the abdomen. The esophageal stent was palpated 16 cm into the jejunum in the pelvis, with markedly dilated proximal small bowel. The stent along with the perforated distal jejunum was resected and an end-to-end anastomosis was performed. The post-procedure clinical course of the patient was unremarkable. After she resumed enteral feeds, she was discharged from the hospital in stable condition. On the one-month follow-up, she reported a good recovery without any inadvertent events or recurrence of the gastrointestinal complaints.


We present a female born via Caesarean section at 32 weeks gestational age to a 31-year-old gravida 4 para 3 (now para 4) mother. The pregnancy course was uncomplicated, and no prenatal genetic testing was indicated. Delivery was emergent due to fetal heart rate decelerations, and after delivery a nuchal cord was noted. Birth weight was 1304 g (10–25%ile for gestational age). The patient stayed in the neonatal intensive care unit for 2 months, during which her course was complicated by intraventricular hemorrhage of unknown grade.
Paternity testing was obtained a few months after birth due to court regulations involving the patient’s parents. Samples from the patient, mother, and alleged father were analyzed using PowerPlex© 16 and CS7 in accordance with standard laboratory practices. A total of 21 polymorphic loci were genotyped. Initial results appeared to exclude the alleged father from paternity due to genetic inconsistencies at loci F13A01 and D5S818. However, the mother insisted on the alleged father’s paternity, and additional testing was subsequently performed. As part of the process for resolution of this unique case, the lab tested PowerPlex© ESX, PowerPlex© Fusion, and PowerPlex© LC5 test batteries. HLA testing was performed as well. Of note was the finding that the patient was homozygous for maternal alleles for all loci located on chromosome 6 (see Table ). These findings prompted the laboratory to recommend that the patient receive a medical genetics evaluation for possible maternal uniparental disomy. Table summarizes the genetic irregularities associated with chromosome 6 that led to suspicion of the underlying condition.
The patient presented for a medical genetics consultation at 10 months of age following the updated test results. During the visit, her mother reported that the patient appeared to be developing well and reaching milestones appropriately. No concerning symptoms were discovered on review of systems. Upon physical examination, her weight was less than the 3rd percentile (even when corrected for prematurity) and length was less than the 3rd percentile (10th percentile when corrected for prematurity). Head circumference was at the 25th percentile. The exam was otherwise unremarkable except for small preauricular pits. Her family history was notable for a maternal half-brother with attention-deficit/ hyperactivity disorder and grandparents with hypertension.
Due to potential health implications of UPD, chromosomal microarray (CMA) testing was ordered to confirm chromosomal composition. CMA analysis using Agilent 4x180k aCGH+SNP array supported the diagnosis of maternal UPD6 (Fig. ). Of note, after confirming this diagnosis, the additional inconsistency on chromosome 5 was concluded to be an unrelated single inconsistency. A single inconsistency in paternity testing is usually interpreted as an inconsequential mutation, and for the D5S818 locus these single inconsistencies are seen in about 0.17% of paternity cases [].
The patient was next seen at 14 months of age to discuss the results of the CMA. At this time, her weight and length were at the 5th percentile (10–25th percentile when corrected for prematurity). She had continued to reach developmental milestones and had no new symptoms or concerning physical exam findings. The family was counseled on the possibility of the patient developing an autosomal recessive condition due to unmasking caused by the UPD. Overall, however, her prognosis is good based on her reassuring first two visits.


A 43-year-old female with a past medical history of severe allergy-induced asthma and chronic nasal drip presented to the clinic with worsening cough and chest tightness for 10 days and was treated for bronchitis with steroids and antibiotics. She then presented to the emergency department with severe and acutely worsening shortness of breath, sudden onset pleuritic chest pain, and sharp radiating pain between both shoulder blades with deep inspiration. At time of presentation, the patient was afebrile with vital signs within the normal limits. Lab work was insignificant with negative leukocyte count and negative cardiac enzymes. A chest X-ray demonstrated an abnormal right cardiomediastinal silhouette with large opacity over the right mediastinum adjacent to the right atrial border. A follow-up CT scan revealed a large right-sided mass adjacent to the right atrium and extending into the right chest measuring 5.1 cm × 9 cm × 4.3 cm (). Her last imaging study was a fluoroscopy study 10 years ago that showed no indications for a mediastinal mass. An echocardiogram revealed a normal ejection fraction (55–59%), no wall motion abnormalities, and a cyst near the right atrium. The patient had continued pleuritic chest pain and difficulty breathing and the decision was made to perform video-assisted thoracoscopic surgery (VATS) for pericardial cyst removal. The patient underwent general anesthesia with a 37 French left-sided double-lumen tube. Standard ASA monitors were applied. Two large-bore peripheral IVs and an arterial line were placed for continuous blood pressure monitoring. Intraoperatively, a large cystic lesion was adherent to the pericardium (). There was no solid component and no obvious communication with the pericardium. Part of the cyst wall was left on the phrenic nerve to preserve it. The patient tolerated the procedure well, had no postoperative complications, and was discharged home on postoperative day number two. The final pathology report revealed benign, acute inflammatory pericardial cyst.


A 54-year-old male with a history of probable neurosarcoidosis, lymphocytic leptomeningitis, seizures, cirrhosis, and possible ethanol use disorder presented with encephalopathy, hypoxia, and several weeks of reported intermittent fevers. For the treatment of neurosarcoidosis, he was taking mycophenolate 1000 mg orally twice a day and last received an infliximab infusion the month prior to presentation.
Approximately seventeen months prior to presentation, the patient underwent extensive investigation for ataxia, near syncope, and encephalopathy, during which he received empiric treatment for encephalitis with corticosteroids, although herpes simplex virus studies were negative. Magnetic resonance imaging of the brain and spine from the cervical spinal cord to the lumbar spinal cord found leptomeningeal enhancement. Cerebral spinal fluid (CSF) found 24 white blood cells/mm3 (reference range 0–5 cells/mm3) with 83% lymphocytes (reference range 0–60%), 8 red blood cells/mm3 (reference range 0–0 cells/mm3), glucose of 35 mg/dL (reference range 40–70 mg/dL), protein of 247.6 mg/dL (reference range 15–45 mg/dL), and no oligoclonal bands. Biopsies of the brain and meninges found leptomeningeal fibrosis with prominent arachnoid cap cells. Chest imaging and fluorodeoxyglucose-positron emission tomography found nonspecific pulmonary nodules and hilar lymphadenopathy. Additional unremarkable studies included bone marrow biopsies, lung biopsies, and sinus biopsies. No infectious pathogens, including Histoplasma, or neoplastic processes were identified.
Eleven months prior to presentation, the patient presented with encephalopathy. He was thought to have lymphocytic leptomeningitis. Serum and CSF angiotensin-converting enzymes (ACE) were normal. CSF studies found 21 white blood cells/mm3 (no reference range) with 91% lymphocytes (no reference range), 1 red blood cell/mm3 (no reference range), glucose of 39 mg/dL (50–70 mg/dL), and protein of 188 mg/dL (15–45 mg/dL). Investigations for infectious pathogens, including serum and CSF fungal studies such as for histoplasmosis, and neoplastic processes were negative. He received intravenous immunoglobulins and corticosteroids for an unclear autoimmune disease. A month later, his neurology providers thought his symptoms and studies were consistent with probable neurosarcoidosis and proceeded with treatment using mycophenolate and infliximab. Six months prior to presentation, he developed keratitis and uveitis.
Vital signs at presentation were temperature of 36.4°C, blood pressure of 80 mmHg/52 mmHg, heart rate of 93 beats per minute, respiratory rate of 24 breaths per minute, and oxygen saturation of 91% on 10 liters per minute of supplemental oxygen. Conventional chest radiography () found a diffuse miliary pattern, which was also identified on subsequent computed tomography of the chest. CSF studies found 1 white blood cell/mm3 (no reference range) with 95% lymphocytes (no reference range), 1 red blood cell/mm3 (no reference range), glucose of 28 mg/dL (50–70 mg/dL), and protein of 53 mg/dL (15–45 mg/dL).
The patient received empiric vancomycin, piperacillin/tazobactam, and amphotericin for possible bacterial and fungal infections. He underwent endotracheal intubation for acute hypoxic respiratory failure and was extubated approximately one week later. Urine, serum, and CSF antigen studies were positive for histoplasmosis and blastomycosis, but the positive studies for blastomycosis were thought to be secondary to cross-reactivity. Respiratory culture obtained via bronchoscopy grew Histoplasma capsulatum. Fungal blood culture grew Histoplasma capsulatum. Bone marrow biopsy, obtained after the administration of antibacterial and antifungal agents, found hemophagocytosis that was thought to be consistent with the diagnosis of disseminated histoplasmosis, although the bone marrow culture had no growth of pathogens. For treatment of disseminated histoplasmosis, he completed a course of amphotericin, was briefly on itraconazole, and was transitioned to voriconazole, on which he was eventually discharged after a month-long hospitalization. Pneumocystis jirovecii polymerase chain reaction study of the bronchoalveolar lavage was positive for which he received a complete course of trimethoprim-sulfamethoxazole, although suspicion for pneumocystis pneumonia was low. The patient's hospital course was complicated by acute kidney injury, aspiration pneumonia, and Pseudomonas aeruginosa pneumonia.


A sixty-one-year old male, in otherwise good health, was referred to otorhinolaryngology emergency for a one-year history of progressive dysphagia and recent dysphonia and dyspnea.
Intraoral clinical examination revealed an enormous mass (80 × 55 mm in size) filling the oropharynx and surpassing the anterior pillars. The lesion was firm and tender and showed no fluctuation. Cervical lymph nodes were not palpable. The remaining clinical examination revealed pain in the right lower limb.
Upon arrival in the emergency room, a rescue tracheotomy was performed.
Magnetic resonance imaging (MRI) showed a voluminous process occupying and infiltrating the entire posterior tongue. The lesion was heterogeneous on T1 and T2 tissue signal. Imaging was enhanced after injection of GADO (measuring 75 × 55 × 39 mm along major axes). This process infiltrated the uvula and the tonsils (). No associated cervical lymph nodes were found.
Biopsy of the tongue showed a squamous mucosa whose chorion was massively infiltrated by tumoral proliferation with distinct plasmacytic differentiation. Immunohistochemistry showed positivity of CD138 and monoclonal expression of Lambda chains ().
To screen for other locations, we performed whole-body MRI which demonstrated a lesional process occupying the lower metaphysis of the right femur. The lesion was rounded with polylobed contours and had an intermediate signal in T1 with a central zone in hypersignal. It destroyed the inner cortical and measured 61 × 47 × 47 mm according to major axes (). Spine MRI did not demonstrate signal abnormalities of the vertebral bodies or the spinal cord.
Laboratory workup showed a 7.5 g/dl normocytic anemia and accelerated sedimentation rate. Calcemia and renal function were of normal range. There was no clear monoclonal peak in serum electrophoresis. The serum and urinary immunofixation revealed lambda chains confirmed with nephelemetric free light chains dosage. Beta2 microglobulin was slightly elevated.
Bone marrow aspiration showed 12% dystrophic plasma cell medullary infiltration, with presence of some plasma cells clusters (). Screening of prognostic genetic abnormalities by conventional cytogenetics and fluorescent in situ hybridisation (FISH) was negative.
The patient received VTD induction therapy according to local guidelines (bortezomib: 1.3 mg/m2 and dexamethasone: 40 mg both on days 1, 4, 8, and 11 and thalidomide 100 mg daily in a 21-day schedule).
After 4 courses, the patient was in complete remission (CR) according to International Myeloma Working Group (IMWG) criteria []. He then received autologous stem cell transplantation (ASCT) after conditioning with melphalan 200 mg/m2. Two additional VTD cycles were given posttransplant as consolidation. Patient then started maintenance treatment with bortezomib at a dose of 1.3 mg/m2 every 2 weeks for a planned total duration of 2 years.
Overall, treatment was well tolerated with no grade 3 or more side effects.
One year after ASCT, the patient is still on bortezomib maintenance, with good tolerance and no sign of relapse.


A 69-year-old female presented to our emergency department with chief complaint of neck swelling, sore throat and difficulty swallowing for the past two days. She also complained of fever and voice hoarseness. Flexion and extension of the neck made the pain worse. She denied difficulty breathing, nausea, vomiting, or chest pain. She reported a non-productive cough. She stated that her daughter and grandchildren were sick with a cough and cold. She took diphenhydramine, acetaminophen and some old amoxicillin at home. Her past medical history was significant for salivary gland cancer nine years prior that was treated with chemotherapy and radiation.
Her vital signs were: pulse 103, blood pressure 120/62 mmHg, temperature 37.6°C, respirations 18/min, and room air pulse oximetry 100%. Laboratory analyses revealed an elevated white blood cell count of 33 K/mm3, and an elevated procalcitonin level of 23.67 ng/mL. Radiograph of the soft tissues of the neck revealed an enlarged epiglottis and aryepiglottic folds, consistent with epiglottitis. In addition, subglottic narrowing of the airway is demonstrated (Figure ). The patient received intravenous ampicillin-sulbactam, methylprednisolone and diphenhydramine in the emergency department with some improvement. The patient was initially admitted to the intensive care unit and evaluated by the otolaryngology service using a flexible nasopharyngoscope. The patient was gradually weaned off of intravenous medications and discharged on hospital day three. Blood and throat cultures were negative.


A 75-year-old Caucasian woman with a past medical history significant for hypertension, dyslipidemia, and depression was admitted to our hospital for evaluation of an incidentally discovered left ventricular mass. The patient denied having a history of stroke, peripheral embolization, or myocardial infarction. The patient reported compliance with her medications and had been taking furosemide 20 mg, amlodipine/benazeprilat 5/20 mg, rosuvastatin 40 mg, aspirin 81 mg, sertraline 100 mg, zolpidem 5 mg, and omega-3 fatty acids/fish oil. The patient reported food allergies to bananas, pecans, and walnuts. The patient denied any significant surgical history. Her social history was significant for tobacco abuse in the past but denies current use of tobacco products, alcohol, and recreational drugs. Transthoracic echocardiography (TTE) was performed for shortness of air and revealed the left ventricular mass. The patient then underwent a transesophageal echocardiogram (TEE) for further evaluation, which localized the mass to the subchordal apparatus of the anterior mitral valve leaflet (Figures -).
The mass was globular and non-pedunculated and measured 1.9 cm within the chordae tendinae. The echo dense core differentiated the globular mass from vegetation or thrombus. The rest of the echocardiography findings showed normal left ventricular systolic function with a normal ejection fraction of 55% to 60%. The patient was then referred to cardiothoracic surgery, who wanted cardiac magnetic resonance imaging (CMR) for better identification and visualization of the mass. CMR revealed a 1.8 x 1.0 x 0.3-cm lesion on the anterior leaflet of the mitral valve (Figure ).
Consent was obtained, and the patient agreed to resection to decrease the risk of stroke, myocardial infarction, peripheral embolization, and sudden death. Prior to the surgical resection, the patient underwent coronary angiography to look for patency of the coronary vessels, which demonstrated a left dominant arterial supply system with no significant obstructive coronary artery disease and TIMI-3 flow in all the coronary vessels. Left ventricular end-diastolic pressure (LVEDP) was mildly elevated at 19 mm Hg, indicative of mild diastolic dysfunction. Preoperative electrocardiogram (EKG) was normal and showed that the patient was in normal sinus rhythm. During the surgery, gentle retraction of the aortic valve leaflets allowed visualization of the mass.
The mass was located within the left ventricle attached to the papillary muscle and chordae tendinae of the anterior leaflet of the mitral valve. The mass was shaved off without difficulty. The tumor was flushed in appearance, rubbery to spongy in texture, and 1.7 x 1.1 x 0.4 cm in size. No residual tumor was left behind. The tumor was thought to be a myxoma upon macroscopic inspection. No complications were encountered during the surgery. Histological examination of the mass from the pathology revealed narrow, elongated, and branching papillary fronds composed of central avascular collagen and variable elastic tissues surrounded by acid mucopolysaccharide and lined by hyperplastic endothelial cells (Figure ).
The surface lining cells were highlighted with CD-34, and the intermediate cells stained with vimentin and S-100 (Figure ). These findings confirmed the diagnosis of CPF.
Immediately post-op, the patient was confused, light-headed, and complained of dyspnea on exertion. These problems resolved by post-op day two. Following this, the patient’s post-operative course was uneventful. She was discharged to home on post-op day six with home health care.


An 18 year old woman was referred to our outpatient clinic of Endocrinology, University-Hospital of Naples Federico II because of hypothyroidism due to Hashimoto's thyroiditis. Blood samples showed high levels of thyroperoxidase and thyroglobulin antibodies and normal calcitonin serum levels. The patient was euthyroid with normal serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) during replacement therapy with L-T4. At physical examination, a palpable nodule of ~2 cm in size was detected in the isthmus of the thyroid. There were no palpable cervical lymph-nodes. An US evaluation confirmed an isolated lesion located in the isthmus, showing an isoechoic solid nodule with smooth margins; its size was 18 × 13 × 6 mm with intra and perilesional vascularity (Figure ). Therefore, a FNA was performed and cytological results revealed a TIR3A lesion. The cytological specimen showed an increased cellularity with some microfollicular structures in the background of scant colloid (Figure ). Thus, we assessed the risk factors associated with the isolated TIR 3A nodule of our patient. According to the ATA guidelines we repeated the FNA which confirmed the same result (TIR3A). The second US (after 6 months) showed that there were no clear signs suggesting malignancy such as microcalcifications or taller than wide-shaped nodules. However, we found a small hypoechoic cranial component in the nodule with blurred margins and elastography revealed an increased stiffness in this cranial component. No nodules were detected in the contralateral lobes by US; cervical lymph nodes were normal. Among the possible risk factors, our patient referred a familial history of thyroid cancer. Her mother was submitted to total thyroidectomy for a follicular variant of PTC twenty years ago; our subsequent evaluation showed that she was disease free at the moment.
On this basis, we decided that a surgical treatment was indicated for our patient and assessed the risk/benefit of total thyroidectomy vs. isthmusectomy.


We present a case of a 70-year old Caucasian gentleman who underwent a living donor renal transplant 10 years ago following a diagnosis of glomerulonephritis aged 34. More recently, he had developed acute heart failure manifested by bilateral leg oedema, facial oedema and difficulty in breathing together with severe and difficult to control hypertension with wide pulse pressures. Biochemistry at the time of presentation revealed Cr 190 mmol/L and eGFR 27–32.
The patient had past history of several transplant biopsies performed to investigate repeated rise in serum creatinine level over the last 10 years. Clinically, there was audible bruit over the right side of the lower abdomen. Ultrasound, CT angiography scan and subsequently catheter angiography demonstrated very high flow arterial venous fistula within the transplanted organ (Fig. ), likely to be the cause of the patients symptoms of decompensated heart failure. The main transplant artery and veins, as well as all intra renal branches were aneurysmal with extreme tortuosity, especially in the intra renal vessels. The maximum diameter of the main transplant artery was 12 mm with relative narrowing at the origin. Other salient findings were ectatic and tortuous iliac vessels (Fig. ). Given the decompensated heart failure being caused as a result of the high flow AVF, patient planned for super-selective embolisation of the arterio-venous communication under interventional radiology.
Informed consent was obtained and patient readmitted for elective super selective renal transplant embolization, to be performed under general anaesthesia in order to control the patient’s haemodynamic status. Given the knowledge of high flow through the AVM, plans were made to make both arterial and venous punctures. The contralateral left common femoral artery was punctured under ultrasound guidance and 6F sheath was inserted and positioned in the right common iliac artery. Through the sheath, the transplant artery was selected and 6mmx40mm angioplasty balloon was positioned and inflated at the origin of the transplant artery to reduce inflow and hence pressure into the AVM. The site of the AVM was approached via the venous side.
Since the arterial side has a tight, almost 360°, backward bend to AV communication site and the venous channel has shorter and straighter path, a 6F sheath was inserted into the right common femoral vein, aiming to deliver the embolic device. Multiple attempts at cannulating the fistula from the venous side failed due to the predicted factors previously described. The tortuosity of the vessels led to difficult in reaching the exact site of the AVM, whilst the high flow from the arterial side continually forced the guide wires and catheters out of the transplant vein and back up into the common iliac vein as the inflated balloon at the origin of the artery failed to reduce the flow.
Therefore, an additional 12F sheath and balloon (Medtronic ReliantM stent graft balloon catheter) were inserted into the venous ipsilateral side, coming from an insertion site just above the initial puncture. This balloon allowed transient occlusion of the common iliac vein (Fig. ), to ensure the guide wire remained in the transplant vein and not forced back into the host common iliac vein by the arterial pressure coming through the AVM. Once the wire was secured in situ, an occlusion plug (10mmx7mm) (AMPLATZER ™ Vascular Plug II, Abbott) was advanced through a 6F sheath and deployed across the fistula (Fig. ). This led to good embolic occlusive result with subsequent angiography showing no flow across the previous fistula (Fig. – (a) pre occlusion plug and (b&c) post occlusion plug).
Following successful embolisation of the fistula, patient’s haemodynamic status remained stable. There was a transient rise in serum creatinine immediately after the procedure due to contrast nephrotoxicity from the procedure itself. In the proceeding weeks, the blood pressure decreased to around 130/85 systolic and serum creatinine improved to 138 on latest bloods. Of most importance, the patient is clinically significantly improved and has reported complete resolution of breathlessness and oedema – suggesting his symptoms were a direct result of the AVF causing high flow cardiac failure.
USS of the transplanted kidney performed 1 week after intervention showed good perfusion and no evidence of a residual or recurrent AV fistula. Follow up CT Angiogram performed 2 months after procedure confirmed good perfusion of transplanted kidney, stable position of the occlusion device at AVF site and resolution of the previous AVF (Fig. ).


A 24-year-old woman from a Middle Eastern country presented to the Jefferson Pancreas, Biliary and Related Cancer Center for evaluation of a recurrent pancreatic mass. She complained of right upper quadrant fullness, and physical examination revealed a remote right subcostal incision. At the age of 12 years, she had first developed decreased appetite, weight loss, fatigue, pruritus, and subsequently became jaundiced. Medical records from that episode revealed that an endoscopic biliary stent was placed with surgical exploration through a right subcostal incision and partial resection/enucleation of a pancreatic mass. In the intervening 12 years, the mass had persisted and enlarged, although the patient was asymptomatic, having neither anorexia, pruritus, nor jaundice.
Routine hematology and basic chemistry panels were normal. The tumor marker cancer antigen 19-9 was mildly elevated at 89 U/mL (<35 U/mL). An abdominal computed tomography (CT) scan with contrast revealed an 8.2 × 7.6 cm heterogeneous-enhancing lesion, prominently involving the uncinate process of the pancreas (). The pancreatic head and neck were displaced and splayed around the anterior aspect of the tumor. The mass abutted the superior mesenteric vein (SMV) as well as the superior mesenteric artery (SMA). There was no evidence of main pancreatic ductal dilatation and the pancreatic neck, body, and tail were normal. Imaging showed no evidence of metastatic disease to the liver or regional lymph nodes. The mass was believed to be an SPT, based on the previous partial resection and the accompanying pathology report.
The patient underwent an open cholecystectomy and a difficult classic pancreaticoduodenectomy. The operative time was 12 h and the estimated intraoperative blood loss was 1500 mL. There was no evidence of metastasis, but the tumor had adhered extensively to the SMV and portal vein and surrounded the SMA. We were able to accomplish the separation of the tumor from the venous structures without incident; however, separating the tumor from the SMA proved challenging. At one point, the SMA was transected due to adherence of the tumor. The SMA was subsequently reapproximated in an end-to-end manner with good arterial Doppler signals distal to the anastomosis.
Pathological analysis of the surgical specimen revealed the tumor to be a solid pseudopapillary neoplasm (). All surgical margins were free of neoplasia and all harvested regional lymph nodes showed only follicular lymphoid hyperplasia, with no evidence of granulomas or neoplasia. Immunohistochemical stains of the specimen were positive for CD56, CD10, and vimentin, with the neoplastic cells showing strong diffuse nuclear and cytoplasmic staining for β-catenin and weak diffuse staining for synaptophysin. The neoplastic cells were negative for chromogranin A, trypsin, AE1/AE3, and E-cadherin. Molecular genetic analysis was negative for the MYB gene deletion.
On the first postoperative day, the patient had a small amount of bile visible in the operatively placed drains, she was fluid seeking, and her abdomen was somewhat distended. Due to the suspicion of a vascular insult related to the SMA reconstruction, an abdominal CT with intravenous contrast was obtained and revealed an intraluminal thrombus in the proximal SMA, ∼1.5 cm from its origin off the aorta, causing near complete occlusion of the SMA (). She was therefore returned to the operating room where the proximal jejunum appeared ischemic. We performed an SMA embolectomy and repaired a leak at her hepaticojejunostomy through reconstruction of the biliary-enteric anastomosis. She tolerated the reoperation well and improved nicely.
On the fourth postoperative day, an upper gastrointestinal series with water-soluble contrast instilled into the stomach through a nasogastric tube revealed no contrast extravasation, and both the afferent and efferent limbs of the duodenojejunostomy were grossly patent.
The patient and her family were instructed on the home management of the large abdominal incision and superficial wound infection. Healing occurred over the next 4 months. Telehealth monitoring was used by our nursing experts to communicate with the patient on a regular basis, with mobile phone images documenting the status of the wound.
She returned to Philadelphia for a follow-up visit after 6 months. At that time, the patient appeared well, her wound was completely healed, and an abdominal CT scan with contrast showed normal after pancreaticoduodenectomy anatomy, without any evidence of recurrent or persistent tumor.


A 65-year-old male attended the eye clinic with a past history of sudden reduction of vision in the right eye (RE) when he was 52 years old, followed a year later by sudden reduction of vision in the left eye (LE). Extensive investigation in a tertiary referral centre had identified elevated homocysteine levels resulting from a gene mutation for the enzyme methylenetetrahydrofolate reductase (MTHFR) and hypercholesterolaemia. In the absence of other findings a diagnosis of bilateral NAION was made.
When seen in our clinic he had LogMar visual acuity of 0.2 in the RE and 0.0 in the LE. Colour vision was reduced in the right eye. Three out of 17 Ishihara test plates were correctly identified in the RE and 16 in the LE. Visual field testing (Humphrey 24–2) showed absolute superior and inferior nasal scotomas in the RE, and superior and inferior altitudinal scotomas with preservation of the central 20 degrees in the LE (Fig. ). The optic nerves were pale with minimal cupping. In view of these unusual findings, further tests were arranged. A carotid ultrasound scan was normal as was an MRI scan of the optic nerves and brain. Referral to a clinical geneticist was arranged. The typical genetic mutations for Lebers herediary optic neuropathy and familial hypercholesterolaemia were not found, however a homozygous mutation in the GPIbα (VNTR B allele) was identified. The hyperlipidaemia and elevated homocysteine levels were managed by the endocrine team. Medication consisted of atorvastatin 40 mg ON, folic acid 400 mcg OD and clopidogrel 75 mg OD.


A 58-year-old Japanese man with an 8-year history of T2DM had a symptom of pain in his right lower leg and visited the emergency room in Kawasaki Medical School. Previously, he had felt the same pain in the same region when his blood glucose was very high and thereby he was diagnosed as having T2DM 8 years before.
He had acute osteomyelitis in his right lower leg when he was a baby. Except for this, he had no past history. He had no remarkable family history. He was a barber; he smoked tobacco (pack-years = 0.75 pack/day × 40 years) and he drank alcohol every day. After the episode of acute osteomyelitis when he was a baby, there was no problem in his legs until he had general fatigue and felt pain in his right lower leg at the age of 50. He visited the emergency room. His vital signs were as follows: heart rate 76 beats/minute, blood pressure 116/70 mmHg, and body temperature 36.4 °C. He had a symptom of slight local swelling and heat sensation in the same area with pain in his right lower leg, but there were no findings in physical and neurological examinations. In addition, there was no ulcer or injury on his skin surface. Laboratory data (Table ) were as follows: white blood cell count, 7400/μL (neutrophil 64.7%); C-reactive protein (CRP), 2.50 mg/dl; plasma glucose, 382 mg/dL; hemoglobin A1c (HbA1c), 11.7%. He was diagnosed as having T2DM, but he had no diabetic complications. Magnetic resonance imaging (MRI) of his lower limbs showed an abscess and inflammatory change in his right lower leg (Fig. ). An axial T1-weighted (T1W) image of his right lower leg showed a slightly lower intensity, and an axial T2-weighted (T2W) image showed a markedly higher intensity (Fig. , upper panels). Based on these findings, we made a diagnosis of acute exacerbation of chronic osteomyelitis and T2DM. We thought that it would be better to hospitalize him and start administering antibiotics via a drip, but he did not agree to the hospitalization. Therefore, as an alternative, we started 300 mg/day of cefcapene pivoxil hydrochloride hydrate and insulin therapy (18 units of aspart) on an out-patient basis. After starting insulin therapy, his blood glucose level gradually decreased, and his leg pain was also gradually mitigated. Finally, his leg pain disappeared 2 weeks later. His CRP became within normal range, and 3 months later the focus in his right lower leg was markedly reduced on MRI. In addition, the focus was not detected in ultrasonography of the right tibia site. Just in case, however, we continued antibiotics therapy for 4 months. Since his glycemic control was improved 2 months later, we stopped insulin therapy and started orally administered anti-diabetic drugs.
He was then followed up as an out-patient with T2DM for approximately 8 years. The medication at that time was 1000 mg/day of metformin, 25 mg/day of alogliptin, 15 mg/day of pioglitazone, and 50 mg/day of ipragliflozin. However, he did not take the medicine for approximately 8 months on his own judgement at the age of 58. After his interruption of therapy for 8 months, he felt the same pain in the same right lower leg again. He immediately visited our hospital. He had symptoms of slight local swelling and heat sensation together with pain in the same area in his right lower leg, but again there were no findings in physical and neurological examinations at this time. His vital signs were as follows: heart rate 99 beats/minute, blood pressure 130/70 mmHg, and body temperature 37.0 °C. He had a symptom of slight local swelling and heat sensation in the same area with pain in his right lower leg, but there was no ulcer or injury on his skin surface. Laboratory data were as follows: white blood cell count, 6680/μL (neutrophil 63.4%); CRP, 0.32 mg/dl; erythrocyte sedimentation rate (ESR), 31 mm/hour; plasma glucose, 652 mg/dL; HbA1c, 6.9%; glycoalbumin 46.1%. Other laboratory data were as follows: red blood cell, 476 × 104/μL; hemoglobin (Hb), 15.9 g/dL; platelet, 25.1/μL; total protein (TP), 7.6 g/dL; albumin (Alb), 4.4 g/dL. Liver and renal function were within normal range as follows: aspartate aminotransferase (AST), 39 U/L; alanine aminotransferase (ALT), 50 U/L; γ-glutamyl transpeptidase (γ-GTP), 51 U/L; lactate dehydrogenase (LDH), 172 U/L; creatinine (Cre), 0.54 mg/dL; blood urea nitrogen (BUN), 13 mg/dL; Na, 131 mEq/L; K, 4.4 mEq/L; Cl, 96 mEq/L. Pathogenic bacteria were not detected. He had no diabetic complications, probably because his glycemic control was relatively good before the interruption of therapy. His leg MRI showed a spreading of the abscess and inflammatory change in his right lower leg (Fig. , lower panels). We hospitalized him in our institution but he did not agree to undergo surgery for remission. Therefore, we started 3.0 g/day of sulbactam sodium/ampicillin sodium and insulin therapy (24 units of aspart and 20 units of glargine). After starting insulin therapy, his blood glucose level gradually decreased, and his leg pain was also gradually mitigated. Local swelling and heat sensation disappeared approximately 5 days later. Finally, his leg pain disappeared approximately 2 weeks later, and he was discharged from our hospital. Just in case, however, we continued antibiotics therapy (450 mg/day of rifampicin and 4 g/day of trimethoprim) for approximately 2 months. After a total of 3-month antibiotics therapy during hospitalization and after discharge, we stopped antibiotics therapy. He was then followed up for approximately 6 months, and his leg MRI showed a reduction of the abscess and inflammatory change in his right lower leg. He had no symptoms and/or problems, and his inflammation markers remained within normal levels for at least 6 months.


A 62-year-old postmenopausal female, para 3, presented with a complaint of a mass coming out of the vaginal orifice for the last 10 years. Initially, there were no symptoms but recently in the last five months, the mass had become irreducible, and she developed dysuria. She had no history of any previous illness or allergy. There was no family history of malignancies. There was no significant family or psychosocial history.
The patient was weak and fragile. Her systemic examinations were unremarkable except for the mass coming out from the vaginal orifice (Figures -).
Her vitals were normal. A genital and vaginal examination revealed an irreducible uterovaginal prolapse with maggots, larvae, and eggs. Ulcers were seen over the prolapsed mass.
Further investigation of the patient revealed that her hemoglobin, total leucocyte count (TLC), platelet count, partial thromboplastin time (PTT), activated partial thromboplastin time, blood sugar levels, and urine analysis were in normal range. Hepatitis B and C profiles were negative.
The patient was treated with analgesic and broad-spectrum antibiotics. The treatment options were presented to the patient with proper counseling. Vaginal hysterectomy was selected and informed consent was obtained. There were no intraoperative and postoperative complications. The histopathology report excluded malignancy. The symptoms resolved completely after the surgery. The patient was discharged and went back to routine life.


A 48-year-old female patient with chronic alcoholic pancreatitis was admitted via the emergency department with a history of hematemesis. Initial tests revealed significantly elevated pancreatic enzymes, compatible with acute exacerbation of chronic pancreatitis. She underwent elective upper digestive endoscopy (UDE), which reveled a gastric swelling suggestive of extrinsic compression. The upper digestive hemorrhage recurred, causing hemodynamic instability. Initial volume resuscitation measures were successful and an urgent UDE showed the swelling covered with mucosa indicative of infiltrate, an oval-shaped erosion with a hematin background located on the large curvature of the distal stomach, and a large clot occupying the entire gastric fundus, with no signs of active bleeding.
Magnetic resonance imaging (MRI) revealed a saccular aneurysmal dilatation of the SA measuring around 2.0 x 1.6 cm. It was surrounded by an oval-shaped mass with thick/hematic content, suggesting a pseudoaneurysm of around 6.4 x 4.3 cm, in contact with the posterolateral wall of the gastric body (
 ).
Having been diagnosed with PASA, the patient was treated with percutaneous embolization via the right common femoral artery. The SA was accessed using a coaxial technique with a guide catheter over a Simmons 1 (SIM 1) angiographic catheter over a 0.035” x 260 cm hydrophilic guidewire (
 ). The decision was taken to embolize using controlled release microcoils via microcatheter, one 8 x 30 mm unit distal of the neck and two 6 x 30 mm units proximal to the neck ( ). Control angiography showed total occlusion of the pseudoaneurysm ( ).
The patient remained hemodynamically stable and there were no complications related to the embolization technique, except for mild pain in the left hypochondrium on the first day after the operation. She remained hemodynamically stable for the next 2 weeks, with no further episodes of bleeding. However, because of her severe clinical status, she died from pulmonary sepsis.


A 72-year-old female patient was referred to our institute due to chest discomfort. The radiologic investigations revealed a giant aneurysm of the ascending aorta, extending but confined to the proximal aortic arch and 7.5 cm in size (Fig. ).
We performed a median sternotomy with initial arterial cannulation of the right axillary artery using an 8 mm vascular graft and the right femoral artery for a second arterial line with a Y-limb preparing the circuit. The arm of the circuit going to the femoral artery was clamped. A two-stage venous cannula was inserted into the right atrium. The bypass was initiated via the right axillary arterial line and systemic cooling was applied to reach a bladder temperature of 32 °C. During cooling, vessel loops with tourniquets were placed around the completely freed innominate and left common carotid arteries (Fig. a). Once the vessel loop on the innominate artery was secured, a cross clamp was applied distal to the innominate artery in an oblique fashion (Fig. b), and then the arm of the circuit going to the femoral artery was unclamped. One pump circuit was used for the axillary and femoral artery, and the perfusion pressure was maintained at approximately 50~60 mmHg, as measured in the bilateral radial artery. Cerebral saturation was monitored using near-infrared spectroscopy (NIRO 300: Hamamatsu Phototonics, Hamamatsu, Japan). The anterior arch resection was performed via a long beveled incision, starting at the right side of the origin of the innominate artery and ending in the lesser curvature of the arch in front of the clamp. The distal hemiarch anastomosis was carried out by means of a continuous 3–0 polypropylene suture with interrupted U-shape pledget stitches, and the graft was cross-clamped proximally; the pump flow was then returned to the antegrade arterial inflow through the axillary arterial line, and the proximal end of the aortic graft was completed just up to the sinotubular junction (Fig. a). The postoperative course was uneventful. Postoperative computed tomography showed a well-reconstructed aorta (Fig. b). At the one-year follow-up, there was no sign of a thromboembolic event or renal or hepatic failure.


A 32y old woman was referred to Yas hospital due to severe low abdominal pain and vomiting on May 2017. Ultrasonographic examination of her pelvis revealed bilateral ovarian cysts. During the 5 days before the admission, she had experienced severe right lower abdominal pain and vomiting especially after a meal. She had a long history of dysmenorrhea and, one cesarean delivery 3 years before. She was taking no medication. Her physical examination report included the temperature of 37°C, systolic blood pressure of 100 mmHg and heart rate of 120 beats per minute. The right lower quadrant of her abdomen was tender along with hypoactive bowel sounds. Laboratory data reported leukocytosis (16×109/L) with neutrophilia, C-reactive protein of 20 mg/dl and erythrocyte sedimentation rate of 60 mm/hr. Abdominal erect X-ray showed dilatation of small bowel segments. Colonoscopy was requested by gastroenterologist for finding the cause and excluding colon neoplasm. Diagnostic colonoscopy showed one small ulcer (8 mm) with the pressure effect of mass like lesion at cecum and scope couldn’t find the ileocecal valve. It was thought that a mass like lesion had caused the ileum obstruction. Colonoscopic biopsies were taken and histopathological examination revealed endometriosis. Afterwards, the patient was taken to the operating room for excision of the mass. At the exploration of the abdominal cavity, adequate exposure was attained by a vertical incision across the midline of the abdomen with a transverse extension to the right. The ileocecal part was covered by the omentum and was adherent to the abdominal wall. The ileocolic intussusception was seen without ischemic changes. Reduction of the intussusception was performed at first. After reduction, a firm mass was recognized at cecum, located close to the ileocecal valve. Then, the ileocecal resection was performed (). Pathological examination confirmed endometriosis.
The postoperative period was uneventful and she was discharged on the third postoperative day. She was doing well at the 6 months follow up.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.


A 76-year old male presenting as a one-month history of dry cough and left chest pain was admitted to our hospital. The patient had a past history of aortic stenosis, abdominal aortic aneurysm, and chronic atrial fibrillation, and he had smoked one and a half pack of cigarettes per day for 27 years from the age of 20 to 47. CT scan of the chest showed left hilar lung mass, left pleural effusion, atelectasis of the left lower lobe and multiple lung nodules predominantly in the right lung (Fig. ). Cytological examination of the pleural effusion revealed adenocarcinoma cells and immunohistochemistry (IHC) analysis of pleural effusion cell block was performed to determine the primary organ from which the cancer developed. Malignant cells in the pleural effusion were positive for Cytokeratin 7 (CK7) and negative for cytokeratin 20 (CK20) (Fig. ). These cells were negative for two lung adenocarcinoma (LUAD) markers; TTF1 and Napsin A, and IHC analysis could not determine the primary organ of the tumor. Adenocarcinoma cells in the pleural effusion were also negative for LUAD specific oncogenic driver mutations: EGFR mutation and ALK translocation determined using the PCR-invader method [] and the intercalated antibody-enhanced polymer (iAEP) method (HISTOFINE ALK iAEP® kit, Nichirei Biosciences, Inc., Tokyo, Japan) [], respectively. The values of serum tumor markers were as follows: CEA 2.9 ng/ml (normal range, 0 to 5); CA19–92326 U/ml (normal range, 0 to 37); CYFRA 57.7 ng/ml (normal range, 0 to 3.5); pro-GRP 34.5 pg/ml (normal range, 0 to 80.9); PSA 0.96 ng/ml (normal range, 0 to 4). Although the primary organ was not clear, the patient was treated by the combination of carboplatin (AUC 5) and paclitaxel (200 mg/m2), which is one of the standard chemotherapy for both LUAD and CUP.
A tumor of the palate mucosa was noticed on physical examination of the oral cavity. The tumor of the palate mucosa was a small (major axis; 7 mm) and round mass with smooth surface. It located in the middle of his palate. Magnetic Resonance Imaging (MRI) showed this tumor in the palate; however, deep invasion was not observed (Fig. ). 18F-Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) indicated abnormal intake of FDG of the palate mucosa and both lungs, which were considered malignant lesions (Additional file : Figure S1). Multiple lymph node metastases, multiple bone metastasis, and pleural dissemination were also suspected.
A biopsy was performed for the tumor of the palate mucosa under the local anesthesia. The histology revealed an adenocarcinoma consisting of tubular or papillary proliferation of columnar-shaped tumor cells invading the subepithelial tissue (Fig. ). The tumor cells were positive for CK7 and negative for CK20, TTF-1 and Napsin A, which was consistent with the result of the pleural effusion. Whether the tumor of the palate mucosa was a metastatic or primary tumor remained inconclusive at this time.
Then, we evaluated the possibility of this tumor in the palate mucosa as a primary tumor. Most common malignant neoplasms of the palate mucosa are known to be MSGTs. Especially, SC is one of the common MSGT [], however mammaglobin and S-100 protein was immunohistochemically negative and ETV6-NTRK3 (EN) fusion was not observed in fluorescence in situ hybridization (FISH) analysis by using Vysis®LSI® ETV6 Break Apart Rearrangement Probe (Abbott Molecular/Vysis) (Additional file : Figure S2). Other MSGT such as AcCC, AdCC, PLGA, and MEC were also excluded as a diagnosis based on histological and immunohistochemical findings.
Because of the absence of EGFR mutation and ALK translocation, this case was registered to Lung Cancer Genomic Screening Project for Indivisualized Medicine in Japan (LC-SCRUM-Japan). The cancer genome screening of the fresh frozen tumor of the palate mucosa was performed using Oncomine® Cancer Research Panel (OCP, Thermo Fisher Scientific, MA, USA), which successfully identified an oncogenic KRAS mutation at codon 12 (p.G12D). Furthermore, presence or abscense of KRAS mutation in pleural effusion was examined. Genomic DNA was purified from formalin-fixed paraffin-embedded (FFPE) cells of pleural effusion using Deparaffinization Solution (QIAGEN) and QIAamp DNA FFPE Tissue Kit (QIAGEN). PCR was performed using 40 ng genomic DNA and the following primers; forward primer, 5′- AGGCCTGCTGAAAATGACTG -3′, and reverse primer, 5′- GGTCCTGCACCAGTAATATGCA -3′ (annealing temperature: 55 °C) []. As a result, KRAS mutation at codon 12 (p.G12D) was also identified in pleural effusion by direct sequencing (Fig. ). The KRAS mutation is known to exist in one third of the LUAD, but it is quite rare in MSGT [, ]. Although the KRAS mutation is also known to be one of the common abnormalities in pancreatic and colorectal cancers [], the possibility of metastasis from colorectal cancer is quite unlikely because gastrointestinal endoscopy did not show the presence of malignant lesions. The metastasis of pancreatic cancer is also unlikely from the results of CT scan and FDG-PET/CT. Together with the cytological similarities between tumor cells in the pleural effusion and those of the palate mucosa, we concluded that the tumor of the palate is a metastatic stage IV LUAD (cT3N3M1c according to the 8th edition of TNM staging of lung cancer). Adenocarcinoma, not otherwise specified (NOS), that shows glandular or ductal differentiation but lacks the prominent histomorphologic features was excluded as a diagnosis because the carcinoma in this study was characterized other, more specific types of carcinoma.
The disease progressed after two cycles of chemotherapy with carboplatin and paclitaxel. The patient received two cycles of immunotherapy with nivolumab as a second line therapy, but died due to disease progression four months after the first admission.


A 38-year-old female with no past medical history came to the hospital with complaints of episodic chest discomfort, mild dyspnea, and occasional non-productive cough. On physical examination, she was hemodynamically stable without any pathological finding. A chest x-ray was done and it showed mass-like opacities abutting the right heart (Figure ).
To have a better idea of the cause of opacity, a further assessment with computed tomography (CT) chest with contrast was ordered and it showed a large, well-circumscribed, heterogeneously enhancing mass of 10 cm with peripheral calcification in the right mediastinum. Also, there was a dilated vessel along the posteromedial and inferior of the mass (Figure ).
After the chest CT findings, the patient was admitted to the hospital for further evaluation and cardiac consult was called. In order to differentiate if the mass was due to some tumor or some anomaly of the coronary vessel, coronary CT angiography with contrast was ordered. A subsequent coronary CT angiography (CCTA) showed a 9.7 cm aneurysm and an anomalous vessel emanating from the left coronary artery and the proximal circumflex, fistulizing into the right atrial appendage. CCTA also showed a dilated right atrium likely due to fistula formation (Figures -).
When the right heart catheterization was performed, a rise in saturation was noted in the right side of the heart due to shunting of blood from the left side to the right side of the heart as a result of coronary cameral fistula formation between the right heart and the anomalous vessel originating from the left coronary artery and proximal circumflex artery. On transesophageal echocardiogram (TEE), an enlarged right atrial chamber was noted due to the fistulous tract draining into the right atrium. The cardiothoracic department then scheduled the patient for surgery. Sternotomy was performed to repair the coronary artery aneurysm with ligation and resection of the coronary cameral fistula and repair of the right atrium. Surgery went well and no intra-operative and postoperative complications were noted.


This patient is a 29-year-old white woman from the USA with a medical history significant for severe IBS-D (diagnosed at age 12) and anxiety disorder. In July 2015, she presented with severe bleeding hemorrhoids secondary to IBS, which required hemorrhoidectomy and anal sphincterotomy in August 2015. The week before the surgery she developed pharyngitis and was treated with azithromycin, which resulted in mucousy diarrhea and abdominal discomfort. She tested negative for C. difficile antigen and toxins at that time.
A week after surgery, she developed a perirectal abscess that had formed at the site of the sphincterotomy and was prescribed orally administered ciprofloxacin. Despite moderate symptom improvement, in September 2015 she required an abscess incision and drainage procedure and Penrose drain insertion. Prior to the surgery she was given a single dose of clindamycin. An additional 2-week course of ciprofloxacin and metronidazole was then prescribed. In late September 2015 she was admitted to the hospital for two nights due to further complications related to the abscess and was then diagnosed as having a perianal fistula.
In November 2015, she was prescribed clindamycin for an episode of group C streptococcal-positive pharyngitis. In late November 2015, she was also diagnosed as having Ehlers–Danlos syndrome, which according to her medical record may partially explain the poor wound healing from the perirectal abscess. In December 2015, her fistula required an anus seton placement. She was treated with multiple courses of ciprofloxacin and metronidazole off and on from December 2015 to January 2016.
In January 2016, following up on her recurrent pharyngitis, she was diagnosed as having chronic tonsillitis which led to tonsillectomy. In February 2016, 2 weeks after the surgery she was prescribed clindamycin. At the beginning of March 2016, she was diagnosed as having bacterial vaginosis and was prescribed orally administered metronidazole. A week later she was diagnosed as having vaginal candidiasis and was prescribed orally administered fluconazole. In April 2016, she complained of dysuria and was prescribed ciprofloxacin. After 2 days, when urine analysis results came back negative, she was asked by her physician to stop the treatment.
In June 2016, she presented for follow-up with ongoing diarrhea and abdominal pain. She was diagnosed as having C. difficile diarrhea, her antigen and toxins laboratory results were indeterminate, and a toxigenic strain was confirmed by polymerase chain reaction (PCR). She was prescribed a 6-week course of orally administered vancomycin. After a week of treatment her symptoms worsened, and following discussion with her gastroenterologist her treatment was switched to a 2-week course of metronidazole. Hours later, she was admitted to the hospital for a 4-day period for colitis. Her C. difficile antigen and toxin test returned negative during her admission. She received intravenously administered metronidazole treatment during her hospitalization. Her symptoms improved during her hospital stay, with 1–2 soft bowel movements a day. At discharge her metronidazole course was stopped and she was again prescribed vancomycin, which she took for over a month. She continued to experience GI irregularity (3–5 bowel movements a day) beyond what she had experienced secondary to her IBS prior to her surgeries. In March 2017, she was prescribed rifaximin for 2 weeks to treat chronic diarrhea.
In November 2017, she was prescribed a series of clinical intestinal tests (SmartGut™, uBiome Inc., San Francisco, USA) with the instructions to administer the test at home whenever she was experiencing a noticeable change of GI symptoms, then follow-up with her health care provider to discuss the results. This sequencing-based test requires that patients use a sterile swab to transfer a small amount of fecal material from toilet paper into a vial containing a lysis and stabilization buffer that preserves the microbial DNA for transport by mail back to the laboratory for processing, which involves DNA extraction, 16S ribosomal RNA (rRNA) gene amplification, and sequencing []. She first used this test in November 2017, about a month after completing a 2-week course of rifaximin. The results revealed a number of microbial organisms that were outside the healthy reference ranges, but she was negative for all pathogenic organisms included in the test, including C. difficile (Fig. ).
Between November and December 2017, her GI symptoms worsened considerably; her daily bowel movements increased from 3–4 to 6–10, stool consistency became more mucous-like and gelatinous, and she was experiencing more pain with defecation. She re-tested with SmartGut™ test again in January 2018. Her results continued to reveal a number of microbial organisms outside the healthy range and, this time, her sample also indicated the presence of C. difficile (Fig. ). She immediately contacted her primary care provider, who re-tested her for C. difficile and confirmed indeterminate CDI by antigen and toxins A and B. Additional PCR testing at a regional laboratory confirmed the sample was positive for a toxigenic C. difficile strain. As a result of testing, her clinician started her on fidaxomicin; her symptoms improved rapidly. By April 2018, she had returned to her baseline in regard to her IBS-related GI symptoms with no blood in her stools.
In addition, the second SmartGut™ sample was tested for toxins A and B by sequencing at uBiome Inc. laboratory in San Francisco, USA, which resulted positive for both and confirmed the toxigenic nature of the C. difficile strain.


A 27-year-old female, para-3-live-1, with gestational hypertension and oligohydramnios presented to the gynecologic emergency at 34 weeks’ gestation in labor. Emergency lower segment cesarean section was perfomed in view of fetal distress. The child was born with a birth weight of 1.6 kg and was stable. There were no congenital anomalies in the child. The placenta was sent for histopathologic examination. On gross examination, the placenta was complete and measured 12´11´3 cm with the attached umbilical cord measuring 18 cm in length. The umbilical cord contained 5 blood vessels (). On microscopy, sections from the placenta revealed ≥10 capillaries each in ≥10 terminal villi in ≥10 non-infarcted areas examined in ≥3 low power (10´) fields of placenta (). Immunohistochemically, the capillary endothelial cells showed uniform positivity with CD34, demonstrating more capillaries than were easily discernible using hematoxylin-eosin staining (), and staining for smooth muscle actin (SMA) was negative (). There was no evidence of increased cellularity or fibrosis in the stroma. Sections from hemorrhagic areas showed ischemic necrosis (). Sections from the umbilical cord showed 5 blood vessels; 4 arteries and 1 vein () and an omphalomesenteric duct remnant (). Placental membranes were histopathologically unremarkable. A diagnosis of chorangiosis placenta with 5 blood vessels and omphalomesenteric duct remnant in the umbilical cord was given.


On May 3, 2017, a woman aged 65 years with no preexisting health conditions began
experiencing pain and paresthesia in her right arm while gardening. On May 6, the
patient sought care at an urgent care facility for the arm pain. She received a
diagnosis of carpal tunnel syndrome and was prescribed a nonsteroidal
anti-inflammatory drug and hydrocodone. On May 7, she was evaluated at hospital A
with shortness of breath, anxiety, insomnia, and difficulty swallowing water. The
patient expressed concern about exposure to a toxic substance. Diagnostic test
results including complete blood count, serum chemistry, D-dimer (to rule out
thromboembolism), troponin, magnesium, electrocardiogram, and chest radiographs were
unremarkable. She was given 0.75 mg of lorazepam for a presumed panic attack and
discharged. Upon entering the car, she experienced claustrophobia and shortness of
breath and immediately returned to hospital A’s emergency department (ED),
where she received an additional 0.25 mg of lorazepam and was again discharged.
On May 8, she was transported from her residence by ambulance to the ED of hospital B
with chest discomfort, shortness of breath, progressive paresthesia involving the
right shoulder and arm, and increased anxiety. On examination, she was agitated,
tachycardic, and intermittently tachypneic. Her neurologic exam was notable for
dysmetria (a type of ataxia). Laboratory results were notable for elevated cardiac
enzymes, a serum troponin I level of 1.05 ng/mL (normal <0.02 ng/mL), and a serum
lactate level of 8.8 mmol/L (normal, 0.7–2.1 mmol/L). Electrocardiogram
results suggested acute cardiac ischemia
with atypical chest pain. The patient underwent emergency cardiac catheterization,
which indicated normal coronary arteries.
On the evening of May 8, the patient became progressively agitated and combative and
was noted to be gasping for air when attempting to drink water. Hospital staff
members questioned family about animal exposures, and the patient’s husband
reported that she had been bitten on the right hand by a puppy approximately 6 weeks
before symptom onset while touring in India. According to the husband, the patient
cleaned the wound with the help of the tour operator but did not seek further
medical treatment. The patient had no record of a pretravel health screening, did
not receive rabies preexposure vaccination before the trip, nor had she ever been
vaccinated against rabies.
On the morning of May 9, the patient required endotracheal intubation and mechanical
ventilation for increasing somnolence, oral secretions, and oxygen desaturation;
peak axillary temperature was 100.6°F (38.1°C). Electroencephalography
demonstrated low-amplitude unreactive delta activity suggestive of severe
encephalopathy. In light of the concern for human rabies, the patient was sedated
with ketamine and midazolam, and the Virginia Department of Health was notified;
because rabies PEP is ineffective for treatment of rabies and not indicated after
the onset of symptoms, PEP was not administered. A lumbar puncture was performed.
Cerebrospinal fluid (CSF) lactate was elevated (2.6 mmol/L;
normal = 0.5–2.2 mmol/L), and CSF white blood cell count was 1
cell/μL (normal = 0–5
cells/μL) with 19% polymorphonuclear leukocytes and 81%
mononuclear leukocytes, consistent with encephalitis. CSF, serum, saliva, and nuchal
skin biopsy specimens were collected on May 9 and submitted to CDC for rabies
testing on May 10.
On May 11, rabies was confirmed by the detection of rabies virus RNA by real-time
reverse transcription polymerase–chain reaction (real-time RT-PCR) in saliva
and skin biopsy specimens, and rabies virus antigen by direct fluorescent antibody
testing of the skin biopsy (). No
antirabies virus antibodies were detected in serum or CSF. Sequencing of the virus
identified a canine rabies virus variant associated with dogs in India.
On May 13, the full Milwaukee protocol (an experimental protocol for persons with
rabies that has demonstrated inconsistent, rare success) () was implemented with the addition of
favipiravir (). On May 15,
the patient developed profuse oral secretions. On May 17, aggressive titering of
ketamine and midazolam was initiated to address increased agitation, and
dexmedetomidine was started to limit sympathetic responses during weaning. On May
18, repeat CSF studies continued to demonstrate no white blood cells, normal protein
level of 36.0 mg/dL, and a normalized lactate level of 2.2 mmol/L. Interferon beta
was started May 18 in the hope of stimulating an immune response; however, repeat
CSF analysis demonstrated no evidence of antirabies virus antibodies (). Rabies virus nucleic acid was again
detected in saliva by real-time RT-PCR on May 19. On May 21, the family decided to
withdraw advanced medical support, and the patient died shortly thereafter. Rabies
virus was isolated from brain tissue postmortem.


A 38-year-old woman with systemic lymphadenopathy and fever was admitted to a local hospital. Performance status was 2 according to the Eastern Cooperative Oncology Group criteria []. White blood cell count (WBC) was 21 × 109/L, with 91% of nucleated cells being small and mature lymphocytes. Mild anemia (hemoglobin, 10.8 g/dl) and moderate thrombocytopenia (platelet number, 46 × 109/L) were also observed (). Flow cytometric analysis revealed that the increased lymphocytes were positive for CD5, CD19, CD20, CD23, and IgGλ (). IgH/cyclinD1 translocation was negative in fluorescence in situ hybridization analysis. Cytogenetic analysis of bone marrow cells demonstrated the normal karyotype. She also demonstrated elevated levels of aspartate transaminase (156 IU/l; normal 13–30 U/l), alanine transaminase (139 IU/l; normal, 7–23 U/l), lactate dehydrogenase (595 IU/l; normal, 124–232 U/l), and total bilirubin (1.8 g/dl; normal, 0.4–1.5 mg/dl). Soluble interleukin-2 receptor was also markedly elevated (10,400 U/ml; normal, 190–650 U/ml; and ). Contrast computed tomography revealed multiple lymphadenopathy, hepatosplenomegaly, bilateral pleural effusion, and massive ascites. Bone marrow biopsy demonstrated a remarkable infiltration of small mature lymphocytes (57% of the total bone marrow cells). Immunophenotype of the major population was the same as that of peripheral blood lymphocytes. A small number of relatively large, blastic lymphocytes were diffusely observed in the bone marrow. Polymerase chain reaction (PCR) analysis demonstrated a single complementarity determining region (CDR-III) signal, indicating clonal B-cell proliferation. Taken together, she was diagnosed to have CLL (Rai stage IV and Binet stage C).
Because of her aggressive disease presentation and suspect of Richter syndrome, R-CHOP therapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, daunorubicin 50 mg/m2 for one day, and prednisolone 100 mg/body for 5 days) was chosen as an initial therapy. After the treatment, her lymphadenopathy, hepatosplenomegaly, pleural effusion, and ascites were improved and 8 courses of R-CHOP were given. Morphologic CLL cells disappeared in peripheral blood. However, flow cytometric analysis revealed that 0.17% of the total bone marrow cells were leukemic cells and that the same single CDR-III signal as the one detected at the diagnosis was confirmed by PCR. These observations suggested the presence of minimum residual diseases (MRD), even after additional three courses of rituximab monotherapy.
Because of young age, suspect of Richter syndrome, and remaining MRD, the patient was referred to the University of Tsukuba Hospital 21 months after the diagnosis for allo-HSCT. The graft was bone marrow from an unrelated female donor with one-allele mismatched HLA. Nonmyeloablative conditioning regimen was chosen containing fludarabine 30 mg/m2 for 3 days and 2-Gy total body irradiation. Tacrolimus and short-term methotrexate were used for graft-versus-host disease (GVHD) prophylaxis (). On day 14, neutrophil engraftment was achieved, and the MRD judged by PCR for CDR-III became undetectable with the bone marrow cells. Donor-cell chimerism in the bone marrow was 70.4%, when evaluated by short tandem repeat- (STR-) PCR analysis. However, a progressive neutropenia was observed from day 20, when peripheral blood cells showed decreased donor chimerism down to 14.2%. On day 24, STR-PCR of bone marrow cells revealed 100% recipient type, suggesting rejection of the donor graft. Favorably, however, the multilineage cytopenia was gradually improved, and single CDR-III signal was never detected after the transplant. On day 62, WBC was 34 × 109/L with 42.7% neutrophils and 41.8% lymphocytes. Hemoglobin was 10.2 g/dl, and the platelet number was 146 × 109/L. These observations suggested that autologous bone marrow recover with remission of CLL. No apparent acute GVHD was observed. Leukemic cells were never detected in the bone marrow or peripheral blood in flow cytometry even 10 years after the transplant. There were no chronic GVHD-like symptoms or signs. Cytogenetic studies were repeated 15 times over 10 years for the screening purpose to detect emergence of clonal cells. In total, 299 metaphase cells were analyzed, and abnormalities were found in 50 cells (16.7%, ). Abnormalities in 7q22 were found in four cells at 3 independent studies performed at 53 through 61 months after the transplant. However, the 7q22 abnormalities were detected only temporarily and were never found thereafter until 136 months after the transplant. All the other abnormalities were seen only one time. All this agrees with the concept of random chromosomal abnormalities (RCA) seen in automarrow recovery after receiving high-dose ionizing radiation exposure []. Despite the careful follow-up, the patient has been evaluated not to develop any clonal disorders such as myelodysplastic syndromes (MDS). Her blood cell counts and lymphocytes number were within the normal range at the last visit (140 months after the transplant), and there was no dysplastic changes in peripheral blood and bone marrow cells.