A 74-year old man, hypertensive, diabetic for 30 years, with chronic smoking symptoms, was admitted to the cardiovascular surgery department of the Mohamed Vth military teaching Hospital of Rabat, for single bypass. Ten days after surgery, the patient had febrile peaks at 39 °C and purulent sternum discharge. Aerobic and anaerobic blood cultures were performed. The C-reactive protein was at 327 mg per liter and the leukocyte counts to 24*103 cells per microliter, predominantly neutrophils (92%). In immediate postoperative, the patient developed bronchitis with interstitial pictures on chest radiograph but without purulent secretions.
The scanner has objectified the presence of a hypodense mass in the anterior mediastinum.
Microbiological examination of deep pus drained during a revision surgery of surgical site showed the presence of two bacterial strains (Fig. ). The identification of bacterial colonies obtained on Chocolate-isovitalex agar, was on biochemical basis using NH API* strips and bacterial grow in presence of the X-factor and the V-factor on Muller-Hinton agar which allowed the isolation of Haemophilus influenzae and Aggregatibacter aphrophilus. Susceptibility analysis of the isolated strains was carried out with the disc diffusion methodology according to the CA-SFM*. It showed the same susceptibility profile for the 2 strains with a susceptibility to the aminopenicillins, cephalosporins third generation, tetracyclines, quinolones and fluoroquinolones, rifampicin and erythromycin, chloramphenicol and imipenem.
The minimum inhibitory concentration (MICs) of aminopenicillins obtained by E-test strip was 0.75 μg/ml and imipenem was 2 μg/ml (Fig. ).
Blood culture performed during the same episode objectified the presence of the same bacterial strains with the same susceptibility profile to antibiotics.
The patient was treated by empirical antibiotic therapy: ciprofloxacin (800 mg per day), cephalosporins third generation (2 g per day) and vancomycin (2 g per day). Treatment was adjusted to the result of susceptibility studies (Amoxicillin 2 g per day with fluoroquinolone for 3 weeks) with the installation of an irrigation-suction system using suction drains (VAC® therapy).
The evolution marked by the improvement of the patient on the clinical and biological way after 10 days of curative antibiotic therapy.


A 79-year-old male with a history of hypertension, hyperlipidemia, and polycythemia vera underwent PCI of the left anterior descending artery (LAD) 1 week prior to admission at an outside institution with overlapping 3.0 × 15 mm Integrity bare-metal stents (Medtronic) to the mid-LAD (Fig. A). He developed chest pain approximately 40 min prior to arrival in the ER where he was found to have anterior ST elevations with hemodynamics consistent with shock. He was taken emergently to the laboratory where angiography with a 6 Fr system was performed via the right radial approach demonstrated a 100% occlusion of the LAD with in-stent thrombosis (Fig. B). There was also angiographic underexpansion of the stents at the site of occlusion (Fig. C). In the interim from arrival, we were able to obtain his catheterization report from the other hospital, and it was reported that an attempt was made to postdilate the stents with a 3.0 and 3.25 noncompliant (NC) balloon without resolution of the “waste” in the midportion of the stent. Bivalirudin was administered, and a Runthrough wire (Terumo) was passed distally restoring antegrade TIMI 1 flow. We then advanced a 0.9 laser to the lesion (Fig. D). The catheter would not advance through the lesion. Given the recent issues encountered by the previous operator, we performed laser with contrast injections at a setting of 80/80 (fluency/rate) for approximately 1 min. We then did aggressive dilation with a 2.5 and then a 3.0 NC balloon with expansion of the stent (Fig. E). He stabilized hemodynamically at this point. We then performed intravascular ultrasound (IVUS) demonstrating severe concentric calcification and lumen diameter of about 3.75–4.0 mm. Postdilation was performed with a 4.0 × 12 Quantum balloon (Boston Scientific) with an excellent angiographic result (Fig. F). Final IVUS demonstrated good stent expansion; however, on pullback, there was evidence of significant distal left main and ostial LAD disease with heavy calcification; this was also appreciated in the LAO cranial views. After the patient was stabilized and recovered from his event (echo demonstrated a decline in the ejection fraction (EF) to approximately 25% with anterior wall motion abnormality compared with a previously reported normal EF), a heart team approach was used to determine the best revascularization option for the patient. Given the extent of calcification and anatomic concerns, he eventually underwent bypass and was discharged home on postoperative day five.


A 73-year-old male with history of hypertension, hyperlipidemia, and esophageal reflux presented to an outside hospital with a non-ST elevation myocardial infarction and underwent PCI of the LAD with overlapping 3.0 × 38 and 3.5 × 18 Resolute DES (Medtronic). There was a suboptimal stent expansion in the LAD, and he was discharged on dual antiplatelet (DAPT) therapy. He presented to the same institution 6 days later with acute ST elevation and stent thrombosis. They were able to pass a wire and did sequential balloon inflations sizing up to a 4.0 balloon. Antegrade flow was restored, but despite aggressive dilation, the lesion did not expand. He was transferred to our institution for bypass. The surgical team evaluated him, and it was felt PCI would be a better option if feasible rather than surgery in the acute situation. In the interim, the patient developed cardiogenic shock and chest pain and was taken emergently to the laboratory where an Impella CP (Abiomed) was placed to stabilize the patient. A decision was made to perform laser atherectomy of the stent to try and expand the stent. Right radial access was obtained with a 6/7 slender sheath (Terumo). Angiography revealed a patent LAD with TIMI 1 flow (Fig. A) and underexpansion of the stents at the overlap (Fig. B). A 0.9 ELCA catheter was easily advanced through the lesion (Fig. C). Laser atherectomy was performed with contrast at 80/80 (fluency and rate) for 2 min and then an attempt to dilate with a series of 2.5 and 3.0 NC balloons was performed. Despite high-pressure inflation at 26 atm, the lesion did not yield (Fig. D). Perhaps rupturing the balloon would have resulted in some plaque modification as well; however, this did not occur. It was felt that the 0.9 ELCA did not have enough contact with the underlying plaque given the preexisting channel (although underexpanded). Therefore, a 1.4 ELCA catheter was advanced to the lesion; however, it would not advance through the lesion. Atherectomy was performed at 60/40 for 1 min with contrast puffs during atherectomy (Fig. E) followed by attempted dilation with a 3.0 NC balloon without resolution of the lesion (Fig. F). It was decided to use an atherotomy balloon at this time to increase the radial force. A 3.0 × 10 Flextome was advanced with an initial inflation at 14 atm (Fig. G) without resolution. The lesion yielded at 24 atm (Fig. H). Postdilation was then performed with a 3.75 NC balloon with restoration of TIMI 3 flow (Fig. I and J). The patient was weaned off the Impella and had no acute issues postprocedure.


A 79-year-old Iranian man was admitted to Imam-Khomeini hospital with 6-month history of dyspnea, nonproductive cough, fatigue and weight loss. Previous clinical history and family history was unremarkable. He had no history of smoking or being passive smoker. He did not use alcohol or opium in the past, and his job is animal husbandry. Six month before recent admission, he had been admitted into another hospital, due to dyspnea. His spiral thoracic computed tomography scan revealed left massive pleural effusion with multiple cysts inside pleural effusion. The patient refused more investigation and discharged with his satisfaction. From first to second hospitalization, a little relief of his symptoms was seen. On February 2017, the patient was admitted again and his complaint was dyspnea and dry cough.
General physical examination revealed an oral temperature of 37°C, a heart rate of 90 beats per minute, a respiratory rate of 14 breaths per minute, and a blood pressure of 110/70 mm Hg and the oxygen saturation of 92% with room air. Aside from this, the clinical examination was unremarkable. Blood samples revealed an elevated CRP of 97 mg/L, leukocytosis (15400/microL) with a strong component of granulocytosis, but no eosinophilia. Physical chest examination showed decreased breath sound in left hemithorax. The remainder of the examination was normal.
The chest radiography showed left pleural effusion. Spiral thoracic computed tomography scan revealed left loculated pleural effusion (Figures and ). Echocardiography was normal and abdominal sonography revealed one cyst with 59 mm diameter and many wrinkle membranes in pleural space (Figure ). Thoracentesis obtained a milky fluid (Figure ) with the following biochemical values: 4800 leukocytes/mm3 with polymorphonuclear predominancy leukocytes/mm3; total protein 10.8 g/dL; lactate dehydrogenase (LDH) 5744 U/L; glucose 81 mg/dL; pH 7.34; Cholesterol 189 mg/dL triglycerides 68 mg/dL. A great number of cholesterol crystals were observed on microscopic examination. H & E stain of pleural fluid showed many scolices of hydatid cyst. Immunoglobin-G enzyme-linked immunosorbent assay for Echinococcus was positive, and then pseudochylothorax pleural effusion and spontaneously ruptured hydatid cyst was diagnosed.
The patient declined any surgical treatment; therefore he was prescribed antihelminthic treatment with albendazole 400 mg, two times daily. He was discharged with satisfaction. After 9 months follow up dyspnea was improved and the pleural effusion resolved gradually. After this time albendazole was discounted.


A 69-year-old man was referred to our Medical Imaging Department to undergo a virtual colonoscopy (VR). The patient had no specific abdominal complaint except mild chronic diarrhea worsened by metformin. He was referred to explain a positive fecal occult blood test. A conventional rectoscopy was normal, and a sigmoidoscopy was interrupted because of pain due to a spastic diverticular sigmoid. As he was taking clopidrogel (Plavix) for ischemic heart disease, there was a relative contraindication to perform a total optical colonoscopy (OC).
Almost immediately after starting the automated low-pressure colonic insufflation with carbon dioxide, the insufflator (with a maximal pressure set at 25 mm Hg) automatically stopped repeatedly, suggesting that there was a colonic stenosis or obstacle.
A complete cut off of the inflated colon was seen on a CT topogram at the level of the sigmoid and descending colonic junction (Figure ). The virtual colonoscopy was immediately converted into a conventional non-contrast-enhanced abdominal CT and completed by secondary contrast-enhanced acquisition.
A short contrast-enhancing “scar-like” intra- and extraparietal structure was found infiltrating the posterior colonic wall at the level of the sigmoid and descending colonic junction (Figure ). This curvilinear retractile “scar-like” tissue had developed multiple adherences with the retroperitoneum and the left iliac fossa and seemed to be stapling the colon on the retroperitoneum.
There was no obstruction, subocclusion, nor fecal stasis upstream, thereby suggesting a purely retrograde and unidirectional functional stenosis.
Additional ultrasound (Figure ) study showed a perfectly empty descending colon with a normal mucosal relief, but with a thickening of the muscle layer. At the junction of the sigmoid and descending colon, ultrasound demonstrated a centripetal retractile convergence of the muscle layers to an intraparietal very hyperechoic and very attenuating scar.
The complete retrograde and unidirectional stenosis was confirmed by classical colonic opacification obtained the next day after CT. Only a small amount of hydrosoluble contrast could pass through the stenosis.
Retrospective anamnesis of the patient revealed a very old history of a single acute colonic diverticulitis episode 19 years before.
After a discussion with the multidisciplinary staff, a celioscopic resection of the stenotic segment was proposed to protect the patient from a prograde occlusion. The celioscopic resection was difficult due to retroperitoneal and left ureteral adherences, so a classical laparotomy became necessary. The postoperative period was uneventful.
Gross anatomy (Figure ) of the resected colonic segment confirmed a short stricture constituted by corbelling fibrosis infiltrating the colonic wall of a diverticular segment. Histology showed typical fibrosis with discrete chronic inflammatory infiltrates and lymphoid clusters. Rare micro-abscesses related to chronic diverticulitis were also found.
Four months later, the patient was readdressed to the gastroenterologic staff to complete the study of the proximal colon which had not been studied. In the meantime, clopidrogel (Plavix) could be interrupted, and an optic colonoscopy was proposed to the patient. A small adenocarcinoma of the caecum was demonstrated – which was not visible on the CT – and a ceolioscopic right hemicolectomy was performed.


A 78-year-old male presented with symptoms of chronic anemia. His physical examination showed bleeding per rectum. Blood investigations revealed iron deficiency anemia. The cause of anemia was fully investigated including CT abdomen/pelvis, upper and lower GI endoscopy. Gastrointestinal malignancy was excluded. Colonoscopy showed anal hemorrhoids. His anemia was secondary to chronic blood loss from anal hemorrhoids. Interestingly, esophagogastroduodenoscopy showed an incidental findings including yellow-white gastric lesion at the gastric fundus measuring 0.7 cm and a pedunculated gastric polyp at the antrum measuring 1.0 cm (Fig. a). Histological examination of the gastric biopsy specimens revealed an inflamed and hyperplastic polyp at the antrum (Fig. d and e). The fundus showed that the mucosal lamina propria contained chronic inflammatory infiltrate and clusters of oval shaped cells with abundant, foamy cytoplasm consistent with the diagnosis of GX (Fig. b and c). Biopsy from the surrounding area of the GX lesion showed a significant amount of acute on chronic inflammatory cells infiltration suggestive of severe gastritis with mucosal erosions and intestinal metaplasia (Fig. e) associated with a small number of H. pylori-like organisms. There was no evidence of glandular dysplasia or malignancy in the sections examined. The gastric lesions did not seem to be contributing to his anemia and therefore was not resected. The anemia was resolved after ligation of anal hemorrhoids and 3 months course of oral iron supplement.


A 42-year-old male was referred for left wrist drop, finger drop and a tingling sensation over the lateral dorsum of the left hand. The patient reported that he was well until 4 days prior when he was intoxicated and awoke with the symptoms. For 4 days, slight improvement of weakness occurred. He had no history of antecedent trauma, injury, infection, or mononeuropathy. Neurologic examination revealed weakness of the left wrist and finger extension (Medical Research Council grade II). Finger abduction appeared weak, but strength improved when the hand was passively extended to the neutral position. Wrist and finger flexion was intact. On sensory examination, there was a well-demarcated area of hypoesthesia and a tingling sensation over the lateral dorsum of the left hand between the thumb and index finger extending into the proximal phalanges of the 2nd finger. In addition, reddish skin color and slight edema were observed in the same area (Fig. ). There was no definite change in skin temperature and no pain. Reflexes were normal at the biceps and triceps brachii muscles, but the left brachioradialis reflex was absent. Routine blood analysis showed white blood cell count, C-reactive protein level and uric acid level were normal. According to the clinical information and neurologic examination, he was diagnosed with compressive radial neuropathy. After approximately two weeks of observation without specific treatment, the skin color recovered along with a marked improvement of the weakness and aberrant sensation. A nerve conduction study and electromyography were performed 2 weeks after the onset of the symptoms (Table ). On the affected left side, a normal radial compound motor action potential (CMAP) was recorded over the extensor indicis proprius muscle with the forearm and elbow stimulated. When stimulated above the spiral groove, the CMAP was reduced by 34% compared to that of distal stimulations. The contralateral radial motor nerve study and sensory nerve conduction were normal. Electromyography revealed that the left extensor indicis proprius, extensor digitorum communis, extensor carpi radialis and brachioradialis showed increased insertional activity, fibrillation potentials, and positive sharp waves and reduced recruitment pattern.


A 45-year-old male patient presented with a complaint of progressive pain and soreness in the lumbosacral region persisting for more than 3 months. The pain radiated to the left thigh and perineum but did not affect walking. Magnetic resonance imaging (MRI) and computed tomography (CT) scans with and without intravenous contrast showed a tumor mass adjacent to the left side of the fifth lumbar spinous process. The tumor was located in the lower left part of the erector spinae and extended onto the fifth lumbar vertebra, the first sacral vertebra, and the iliac wing. Positron emission tomography with CT (PET/CT) showed a hypermetabolic lesion in the erector spinae adjacent to the left side of the fifth lumbar spinous process. No sites of regional or distant metastases were found. A core biopsy of the tumor mass revealed spindle-shaped cells with infiltrating inflammatory cells. Together the morphological and immunohistochemical features indicated a low-grade inflammatory myofibroblastic tumor. The expression profile based on immunostaining was as follows: overall positive for vimentin, CD34, ALK (SP8), and p53; focally positive for smooth muscle actin (SMA); sporadically positive for S-100; partially positive for CD68; and negative for cytokeratin (CK) (AE1/AE3), desmin, and CD117. The Ki-67 nuclear labeling index was 10%.
The patient reported no other symptoms. Physical examinations revealed no neuro-pathological signs or symptoms. He denied smoking, alcohol, or illicit drug usage. He also denied recent radiation or toxin exposure. He had no history of unintentional weight loss, fever, or chills. He had no family history of malignant or other chronic diseases, with the exception of a sister who had breast cancer.
The treatment plan of the case was discussed by our multi-disciplinary team including experts from orthopedics, neurosurgery, chemotherapy, radiotherapy, pathology, and radiology. Considering that the boundary of the tumor was unclear and involved the sacrum, a complete resection would be difficult. Therefore, we administered neoadjuvant radiotherapy to the affected area at a dose of DT 5000 cGy in 25 fractions to the planning target volume (PTV). After shrinkage of the tumor volume, the patient underwent complete extensive resection at 1 month after radiotherapy. Postoperative pathology confirmed that resection of a lesion measuring 7.5 cm × 4 cm × 3.5 cm achieved negative histological margins and indicated a classification of the specimen as a mesenchymal-derived malignant tumor involving the sacrum. Histologic examination of the resected tumor revealed undifferentiated pleomorphic spindle cells surrounding an area of geographic necrosis with frequent atypical mitosis. Microscopically, the morphology conformed to that of a high-grade spindle cell sarcoma consistent with UPS. The result from MDM2 amplification using fluorescence in situ hybridization was negative, and thus, lipogenesis on histology could be excluded (Additional file ). The expression profile of the UPS tissue is described in Table , and representative images of staining tumor tissue are presented in Fig. .
A postsurgical MRI scan obtained 1 month after surgery showed postoperative changes and no obvious mass in the surgical area. The patient underwent adjuvant chemotherapy with liposomal doxorubicin and ifosfamide but had to discontinue chemotherapy after 2 cycles due to intolerance of grade 3 fatigue and grade 2 nausea. At 3 months after surgery, three new lesions were discovered in the bilateral pulmonary region on a routine follow-up CT scan (Fig. ). Further radiographic imaging with PET/CT showed hypermetabolic metastases involving the erector spinae of the left posterior sacral, fifth lumbar spine, sacrum, left ilium, and twelfth thoracic vertebra, accompanied by multiple lung lesions and a suspected metastasis adjacent to the spleen (Fig. ). At this stage, the patient refused further chemotherapy.
With the standard therapeutic options exhausted, primary tumor tissue was subjected to DNA sequencing via next-generation sequencing (NGS) with an ILLUMINA Nextseq 500 (3DMedicines, Inc.). The MasterView 381 cancer-gene panel covered 4557 exons of 365 cancer-related genes and 47 introns of 25 genes frequently rearranged in 381 cancer-related genes (Additional file ). The genomic DNA was extracted with the QIAamp DNA formalin-fixed paraffin-embedded tissue kit (Qiagen) following the manufacturer’s protocol and quantified with the Qubit™ dsDNA HS Assay kit (Invitrogen). Bioinformatics analyses involved analyzing the clipped reads, which can be extracted by the tag information of bam files, which mapped the individual reads to the reference human genome (hg19) with bwa aligner v0.7.12. Candidate reads that were discordant or aligned in the same direction were filtered. Read pairs with reads mapped to separate chromosomes or separated by a distance of over 2 kb on the same chromosome were kept for fusion detection at the probe level. Output rearrangements contained translocation, inversion, long deletion, etc. []. Through this profiling, a LMNA-NTRK1 gene fusion encoding exons 1–2 of lamin A/C and exons 11–17 of the NTRK1 gene was identified (Fig. ), and the other unlisted genes were all wild-type. The sequencing results for the LMNA-NTRK1 gene fusion are presented in Additional files and .
After extensive discussion and consultation with the patient and his family, we initiated crizotinib therapy per os at 450 mg per day on January 23, 2017. One month later, chest CT scanning showed that all lesions in the bilateral lungs had almost disappeared, and the patient had achieved a near-complete clinical response (CCR, Fig. ). PET/CT imaging was repeated after 4 months of treatment and continued to show the same response to crizotinib therapy. PET/CT revealed that local FDG metabolism was slightly increased at the lesions of the fifth lumbar spine, sacrum, left ilium and left paraspinal muscle. However, with crizotinib treatment, the FDG metabolism was significantly reduced in comparison with that seen in the first PET-CT examination. The bilateral pulmonary nodules had disappeared, and the twelfth vertebra, which had shown osteolytic bone destruction, now showed signs of healing, with an increased density and a lower FDG metabolism. The volume of the left front nodule of the spleen was significantly reduced after treatment (Fig. ). A timeline of the treatment course is presented in Fig. . As of July 2018, clinical assessments in this patient showed an ongoing near-CCR of 18 months. In general, the side effects of oral administration of crizotinib at 450 mg per day were tolerable for the patient. During the course of treatment, the patient experienced grade 3 myelosuppression and grade 2 weakness, but myelosuppression could be alleviated with granulocyte colony-stimulating factor (G-CSF)-based supportive treatment.


A 7.5-year-old boy presented with progressive gait disturbance and falls. History included a full-term birth with no pregnancy or delivery complications. Developmental milestones including sitting up without support, walking, and speech were all within the normal range. Family history was remarkable for tremors in grandfather. He was first seen by the pediatric neurologist for unsteady gait and toe walking at the age of 3.5 years with the gait unsteadiness commencing around the age of 2.5 years with frequent falls. Tremors in the hands were noted sometime previous to the clinic visit. Examination was notable for a well-developed child with a normal funduscopic exam, no cardiac murmur, and normal mental status including speech, normal cranial nerves, and strength. He had 1+ deep tendon reflexes (DTRs) in both upper and lower extremities with down going toes. Gait was wide based and unsteady. He had a tremor in both hands.
By the age of 6.5 years he had progressed to more falls and worsening handwriting. Examination revealed pes cavus, mild scoliosis, and absence of cardiac murmur. Neurological exam was notable for trace to absent DTRs, loss of position sense, positive Romberg, downgoing toes, slowed rapid alternating movements, tremor on finger to nose exam, and wide based unsteady gait.
By the age of 7 years he had more frequent falls and worsening handwriting. Examination showed progression with respect to ataxia in upper and lower limbs with wider based gait. DTRs were absent and a positive Babinski was noted.
At last exam around the age of 7.5 years he was falling more, and exam showed evidence of increased tone in lower extremities with foot drop and steppage gait in addition to decreased proprioception in the lower extremities and inconsistent responses in the upper extremities.
Magnetic resonance imaging of the brain was normal. Laboratory testing including quantitative immunoglobulins, alpha fetoprotein, thyroid profile, serum lactate, vitamin E levels, creatine kinase, serum amino acids, and serum acylcarnitine profile were all normal. Echocardiogram showed global hypertrophy of both ventricles. Ophthalmological examination did not show any evidence of optic atrophy.
Mutation analysis showed one allele with a GAA trinucleotide repeat expansion of approximately 1000. Since the index of suspicion was high, frataxin sequencing was done which demonstrated another allele harboring a c.464G>A nucleotide change. The nucleotide change predicted an amino acid substitution of tryptophan to a premature stop codon at residue 155 (W155X).


A healthy 3-year-old Chinese boy presented with multiple asymptomatic hypopigmented subcentimeter macules over his lower abdomen and suprapubic region (). There was no preceding trauma or inflammation. The rest of his skin examination was normal. There was no family history of similar lesions.
He was initially diagnosed with tinea versicolor. However, after a course of topical antifungal cream, the lesions remained unchanged in number, size, and appearance. Upon review by a dermatologist, he was diagnosed with clear cell papulosis. No further investigations or treatment were needed. His parents were reassured, and he was discharged from follow-up.


An 81-year old female with a history of coronary artery disease, hypertension, and thrombocytosis suffered a witnessed trip and fall onto a nightstand. The patient took 75 mg of clopidogrel daily in addition to an 81 mg aspirin tablet. She reported a mild headache however had no change from her baseline mentation per family members with no evidence of obvious injury aside from a small area of ecchymosis near a small forehead laceration. She remained up and ambulatory with no further complaints. Ten hours after her injury the patient presented to the Emergency Department with stridorous and agonal respirations with a profoundly decreased level of consciousness. She was noted to have developed extensive ecchymosis on the anterior portion of her neck and chest. Her symptoms had begun rapidly shortly prior to arrival while lying in bed. Family reported that she had been in the constant company of her husband with no further falls or injuries that had occurred since her fall. The patient was intubated upon hospital arrival due to respiratory extremis with obvious swelling and crepitus noted on neck examination. A noncontrast CT scan of head was unremarkable while there was demonstration of a large retropharyngeal hematoma measuring 3.6 cm by 5.3 cm by 20 cm on a CT of the cervical spine with no evidence of fracture. Her hemoglobin was 9.5 gm/dL and platelets were 1234 per deciliter, with an INR of 3 and a slightly below normal and activated partial thromboplastin time of 23.9 seconds (reference range 25-35 seconds). A CT angiogram of the neck was subsequently obtained demonstrating active bleeding from the anterior ligaments of the vertebral column that was not felt to be amenable to embolization (). Given the extent of the hematoma intraoral surgical evacuation was performed with bleeding from the anterior vertebral spine controlled with Bovie cauterization, placement of topical thrombin, and drain placement. No reaccumulation of hematoma was noted during her hospital course. The patient unfortunately expired 12 days from the date of admission from presumed aspiration pneumonia and multisystem organ failure.


A 61-year-old male, with a history of emphysema, obstructive sleep apnea, and hypertension, presented to the emergency room with worsening shortness of breath over a three-month period. The patient also complained of orthopnea, paroxysmal nocturnal dyspnea, and progressively worsening lower limb edema. On examination, the patient had jugular venous distension, bilateral lower extremity edema, and bibasilar crackles. The laboratory evaluation showed a B-natriuretic peptide level of 11,065 pg/ml and a troponin level of < 0.04 ng/ml. A transthoracic echocardiogram showed a reduced left ventricular ejection fraction (LVEF) of 20%-25% with prominent hyper-trabeculations noted in the left ventricle, most prominent in the lateral and apical walls. These findings were concerning for LVNC. Cardiac magnetic resonance imaging (CMRI) showed a non-compacted to compacted myocardium ratio of 5:1 at the left ventricular apex (Figure ), confirming the diagnosis of LVNC. The patient underwent left heart catheterization, which did not show obstructive coronary disease as an etiology for the cardiomyopathy. The patient was managed with guideline-directed therapy for heart failure, including carvedilol, losartan, furosemide, hydralazine, and isosorbide mononitrate. He was also started on warfarin due to the increased risk of thromboembolism associated with LVNC. He had episodes of non-sustained ventricular tachycardia during his admission and was subsequently evaluated by electrophysiology (EP). He was discharged home with a wearable cardioverter defibrillator with instructions to follow up with EP in three months for an evaluation of implantable cardioverter defibrillator (ICD) placement for primary prevention.


A 12-year-old male castrated domestic shorthair cat was referred to the
Virginia-Maryland College of Veterinary Medicine Veterinary Teaching Hospital (VTH)
for weight loss of 10 months’ duration and anemia of 3 weeks’ duration.
Abnormalities identified by the primary veterinarian 3 weeks prior to admission
included a thin body condition and a grade II/VI holosystolic heart murmur. Serum
biochemical profile and total thyroxine were within normal limits. Complete blood
count (CBC) revealed a normocytic, normochromic, regenerative anemia (hematocrit
[HCT] 17.2%, reference interval [RI] 30.3–52.3; 66,500 reticulocytes/μl, RI
3000–50,000) and thrombocytopenia (142,000 platelets/μl [RI 151,000–600,000]). A PCR
panel testing for Mycoplasma haemofelis (MH),
Candidatus Mycoplasma turicensis (CMt) and
Candidatus Mycoplasma haemomintum (CMh) was submitted. The cat
was administered orbifloxacin 3.4 mg/kg by mouth once daily pending results of the
PCR panel and oral vitamin B supplementation (unknown type and dose) in the
meantime.
The CBC 1 week later revealed improved normocytic and normochromic anemia and
reticulocytosis (21% HCT and 94,600 reticulocytes/μl, respectively) and resolved
thrombocytopenia (159,000 platelets/μl). The PCR panel was negative. The cat
continued to receive orbifloxacin and vitamin B supplementation due to clinical
improvement.
Over the following 2 weeks, the packed cell volume (PCV) ranged from 20.1–22.5% and
reticulocyte count from 58,000–80,600 reticulocytes/μl. The cat also tested positive
for feline immunodeficiency virus (FIV) and negative for feline leukemia virus
(FeLV) on a lateral flow ELISA test kit (SNAP FIV/FeLV Combo) during this period of
time. The cat was vaccinated for FIV 7 years prior to testing. One year prior to
vaccination, the cat had tested negative for FIV through unknown diagnostic
methods.
The cat presented to the VTH 1 week later. Abnormalities on physical examination
consisted of a body condition score of 4/9 and a grade II/VI systolic parasternal
heart murmur. CBC revealed a normocytic, normochromic, mildly regenerative moderate
anemia (19.5% [RI 33.7–47.5%]; 83,500 reticulocytes/μl [RI 13,100–71,600
reticulocytes/μl]), marked thrombocytopenia (34,000 platelets/μl with platelet
clumping; RI 149,000–532,000 platelets/μl), a neutrophilic left shift (185 bands/μl;
RI 0–0 bands/μl) and lymphopenia (739 lymphocytes/μl; RI 804–9240 lymphocytes/μl)
with reactive lymphocytes. Mild cardiomegaly was present on thoracic radiographs.
Abdominal ultrasound identified mild splenomegaly and hypoechoic splenic parenchyma.
Fine-needle aspirate cytology of the spleen demonstrated moderate macrophagic
infiltration with phagocytosis of erythrocytes and erythroid progenitors and
extramedullary hemato poiesis. Cytological evaluation of a bone marrow aspirate
showed similar findings with moderately increased macrophages and phagocytosis of
erythroid progenitors and erythrocytes. Erythroid hyperplasia was also noted. Rare
phagocytosis of myeloid progenitors and megakaryocytic hyperplasia was also noted.
The macrophages were similar in appearance to those observed in the spleen. The
macrophages did not exceed 20% of the population. A bone marrow core biopsy was also
collected, but a definitive diagnosis could not be obtained with the sample owing to
low cellularity. Primary differentials at this point were hemophagocytic syndrome
and hemophagocytic histiocytic sarcoma.
In 2 weeks, the cat’s heart murmur progressed to a grade IV/VI parasternal systolic
murmur. Splenomegaly was now identifiable on abdominal palpation. CBC revealed
progression of anemia (15.6% HCT; 46,200 reticulocytes/μl), leukopenia (3500 white
blood cells [WBCs]/μl; RI 4250–14,610 WBCs/μl) characterized by neutropenia (2065
neutrophils/μl; RI 2272–9639 neutrophils/μl) and a left shift (105 bands/μl) and
mild thrombocytopenia (90,000 platelets/μl with manual estimate of 130,000
platelets/μl). Echocardiogram identified moderate, irregular, left ventricular
hypertrophy with left atrial enlargement and left ventricular chamber enlargement,
right ventricular chamber enlargement and right atrial enlargement. Small-volume
pericardial effusion with pericardial thickening and pleural effusion were also
noted. Primary differentials for these findings included either infiltrative disease
of the heart secondary to infection, inflammatory disease or neoplasia, hypertension, or hypertrophic cardiomyopathy. Chronic anemia may also have played a role in the cat’s cardiomegaly as
anemia has been associated with increased cardiac troponin 1 concentration, which is
suggestive of cardiac myocyte damage. Blood pressure was not evaluated. Thoracic radiographs revealed progression
of cardiomegaly but no evidence of congestive heart failure. Tests for
Histoplasma species antigen in urine and serum IgM and IgG to
Toxoplasma gondii were negative. Whole blood was tested using
PCR for Anaplasma phagocytophilum, Bartonella henselae, Bartonella
clarridgeiae, Bartonella quintana, Ehrlichia species, MH, CMh, CMt,
Rickettsia rickettsii and Rickettsia felis,
and was negative. In order to further differentiate between hemophagocytic syndrome
and an underlying neoplastic condition, splenectomy was recommended.
Approximately 2 weeks later, splenectomy was performed without complication. The cat
received buprenorphine 0.02 mg/kg IV q8–12h as needed for analgesia after surgery.
Liver biopsies were collected at the time of surgery. Recheck echocardiogram prior
to anesthesia revealed similar findings with progression of pericardial effusion and
mild cardiac tamponade. Repeat thoracic radiographs did not reveal any evidence of
pleural effusion or pulmonary edema, making congestive heart failure unlikely. The
cat had type A blood and was given 20 ml blood-type-compatible packed red blood
cells prior to surgery, which resulted in an increase in PCV from 18% to 21.5%.
Postoperative PCV was stable at 23.5%. The cat was discharged and returned 1 week
later for a recheck. The cat appeared more lethargic and the PCV had decreased to
15%.
Histopathology of the spleen revealed multifocal aggregates of mononuclear cells with
moderate amounts of eosinophilic cytoplasm, occasional variably sized
intracytoplasmic vacuoles and distinct cell borders (). Occasionally, macrophages within
the aggregates were observed phagocytizing erythrocytes (). There were also large numbers of
megakaryocytes and both myeloid and erythroid precursors throughout the splenic
parenchyma. Increased numbers of metarubricytes and rubricytes resulted in a myeloid
to erythroid ratio of approximately 1:2. Multifocal regions of red pulp contained
distinct sinuses void of erythrocytes. The hemophagocytosis within the spleen,
paired with the extramedullary hematopoiesis, was suggestive of hemophagocytic
syndrome. The macrophages did not exhibit characteristics of malignancy, which
lowered the suspicion of hemophagocytic histiocytic sarcoma. The splenic
histopathology was reviewed by five anatomic pathologists, who agreed with a
diagnosis of non-neoplastic hemophagocytic histiocytosis. Histopathology of the
liver was consistent with mild, multifocal extramedullary hematopoiesis. A diagnosis
of hemophagocytic syndrome was made. PCR testing for FIV was performed on the
splenic tissue and was found to be negative.
After splenectomy, there was no improvement in the anemia over the next 4 weeks, with
PCV ranging from 15–17%. The cat was started on lomustine at 41.6 mg/ m2
orally every 3 weeks. The cat’s PCV fluctuated between 22% and 25% over the following 2 months.
Evaluation with echocardiogram after the second lomustine treatment indicated stable
cardiac disease. A grade 3 non-febrile neutropenia (864 neutrophils/μl) was
encountered after the third treatment, so the treatment interval was extended to every 4 weeks. Lomustine was
otherwise well tolerated.
Three months after initiating lomustine, disease progression characterized by
thrombocytopenia, worsening anemia, ascites, pleural effusion, severe left atrial
enlargement and static pericardial effusion was noted. There was concern that the
cat may be in congestive heart failure owing to the presence of severe left atrial
enlargement, pleural effusion and ascites. Abdominal fluid analysis was consistent
with a protein-poor transudate. The cat was treated with vincristine 0.5
mg/m2 IV once and furosemide 1.5 mg/kg PO q12h. Over the following 6
days, a 25% reduction in body weight was noted, attributed to fluid loss and muscle
wasting. The thrombocytopenia improved but the cat was considered too debilitated to
receive any further chemotherapy. Owing to poor response to treatment, the cat was
euthanized and no necropsy was performed.


Our patient is a 5-year-old female who was referred for evaluation and management of recurrent episodes of cellulitis in the left scapular region. A small cystic lesion had first been noted at the age of 2 years. While this had initially been an asymptomatic, small lump that grew in size over time, it first became symptomatic when the patient was 4 years old. The lesion developed surrounding induration and erythema, as well as purulent drainage and tenderness. Over the next 1-year period, she went on to develop 3 such episodes of cellulitis. This was treated with a 10-day course of cephalexin by the patient's family physician, and it was due to these recurrent episodes of infection that we saw the patient in consultation.
Physical examination revealed a playful and well-appearing 5-year-old female, weighing 24.8 kg and measuring 114.5 cm in height. Review of systems and cardiorespiratory examinations were unremarkable. On inspection of the left scapular region, approximately 7 × 5 cm area of cellulitis was noted, with a small opening and associated purulent drainage. The surrounding skin was tender to palpation, but there was no appreciable fluctuance. Thus, the initial working diagnosis was infected epidermoid cyst. An ultrasound of the affected area showed a complex cystic mass measuring 3.9 × 2.9 × 3.7 cm within the subcutaneous fat (). Deeper margins of the mass were poorly demarcated due to the degree of inflammation, and the lesion appeared to abut the underlying musculature. Since these findings were nonspecific, an MRI was obtained to further characterize the lesion. The MRI revealed the presence of a subcutaneous cystic lesion just superior to the scapula measuring 1.6 × 3.5 × 2.8 cm. While the mass abutted underlying muscular fascia, there was no extension into the underlying trapezius muscle itself (Figures and ). Thus, the decision was made to pursue surgical excision of the lesion. This was performed under general anesthesia, which the patient tolerated well. Intraoperatively, we noted that the mass was quite soft, cystic, irregular in shape, and not well circumscribed. Nonetheless, we were able to excise the lesion in its entirety. Histopathology from this specimen revealed a benign cyst lined with ciliated columnar epithelium (). In addition, the cyst wall itself contained smooth muscle, small mucous glands, and clusters of lymphocytes. Thus, these findings were in keeping with a bronchogenic cyst and not an epidermoid cyst as was initially suspected. On 1-year postoperative follow-up, the patient is doing well, with no recurrence of infection or other symptoms.


A 51-year-old woman was found comatose and hypotonic in her home. The patient was resuscitated and intubated on site and admitted to an external hospital. An opiate antagonization, because of suspected opiate intoxication (she was on a treatment of for chronic pain syndrome with fentanyl patches), did not show any effect on the patient's consciousness. She had a past medical history of arterial hypertension, obesity, sleep apnea syndrome, and depression.
A blood sample-laboratory analysis revealed rhabdomyolysis. Subsequently, the patient developed acute kidney- and liver failure, which led to immediate transfer to the intensive care unit of our hospital.
On neurological examination, the patient presented with coma, but did not show any focal neurologic impairment. An unenhanced computed tomography (CT) of the head showed almost symmetrical bilateral hypointensities of the globus pallidus (Figure ). These changes were interpreted as of primarily hypoxic origin, possibly caused by carbon monoxide (CO) poisoning, although there were no anamnestic indications supporting this assumption. A spinal tap showed no pathological findings of the cerebrospinal fluid (CFS). Four days after the initial event, the patient clinically improved and was cleared for extubation. The neurological examination thereafter was discreet with no focal neurological deficits and her mental status returned to normal.
MRI of the brain 3 weeks after hospitalization confirmed the bilateral lesions of the globus pallidus seen on CT, characterized by restricted diffusion and FLAIR-hyperintense signal changes (Figure ). At this time no leukoencephalopathy could be detected. These findings were again interpreted as of post hypoxic origin.
Approximately 3 weeks after the initial event, the patient developed progressive neuropsychiatric symptoms. First, she attracted attention with odd behavior (e.g., urinating into the rubbish bin or other patients' beds) and phases of agitation. Within a few days, the disturbance in behavior turned into a clinical picture dominated by reduced psychomotor activity and apathy, finally progressing into mutism. In addition, a novel increase in muscle tone with generalized rigidity and spontaneous myoclonus was observed.
A follow-up MRI-scan of the brain 5 weeks after the initial event showed, in addition to the known changes of the basal ganglia, a symmetrical, extensive increased FLAIR-signal with correlating marked diffusion restrictions of the white matter, primarily in the fronto-parietal regions of both hemispheres (Figure ). The cortex remained spared from these changes. Neither the brain stem nor the cerebellum showed any pathological changes on MRI. In conjunction with the clinical course the changes were diagnosed as DPHL.
A supportive therapy followed. During the course of the inpatient stay, the patient's impairment remained unchanged and she was released into early neurological rehabilitation about 6 weeks after the initial event. A follow up MRI nine months later showed a marked regression of the leukoencephalopathy with a remaining faint hyperintensity predominantly in the parietal white matter of both hemispheres and a complete regression of the diffusion restriction. A slight symmetrical enlargement of the ventricles could be seen indicating a mild atrophy (Figure ).


A 14-year-old Chinese Malaysian boy presented to University Malaya Medical Centre, Kuala Lumpur in September 2013 with history of recurrent pneumonia, poor growth and steatorrhoea since childhood. He had finger clubbing and bronchiectasis. Later, he was diagnosed with CF and Pseudomonas aeruginosa was isolated from his sputum. He received 3 weeks of intravenous ceftazidime (50 mg/kg/dose, QDS) and gentamicin (5 mg/kg/dose, OD). He was discharged with azithromycin (5 mg/kg EOD), nebulised gentamicin (80 mg BD) amongst other CF-related medications. In November 2013, he was readmitted with a pulmonary exacerbation and his sputum sample grew methicillin-resistant Staphylococcus aureus (MRSA) and he received intravenous vancomycin, oral rifampicin (300 mg BD) and sodium fusidate (500 mg TDS) with significant clinical improvement. During a follow-up visit in December 2013, he had a productive cough but was apyrexic. He was empirically treated with oral ciprofloxacin (750 mg BD) and the sputum sample later isolated B.pseudomallei. As he clinically improved, the treatment regimen remained unchanged. Subsequently, the repeat sputum samples were negative for B.pseudomallei and he continued to remain active with good exercise tolerance and relatively stable lung function. It is noteworthy that he had been residing in an urban area of non-endemicity for melioidosis and there were no other known risk factors identified.
In August 2014, he was admitted with another pulmonary exacerbation and his cultured sputum grew B.pseudomallei and Pseudomonas spp. His chest radiograph showed diffused interstitial changes with bronchiectasis throughout both lungs with minimal pleural effusions. He received 2 weeks of intravenous ceftazidime (2 g; 6hourly) and amikacin (720 mg; 15 mg/kg/OD). Upon completion of antibiotics, he remained afebrile and the chest auscultatory findings improved. He was discharged with 6 months of oral doxycycline, and co-trimoxazole to treat the B.pseudomallei and 3 months of nebulized amikacin for chronic P.aeruginosa. He still continued on his alternate day of azithromycin (250 mg).
A detailed travel history revealed that in June 2014, he visited recreational parks in Sabah, Malaysia. During the visit, he went jungle trekking, snorkeling and dipped in a hot-water spring. It is noteworthy that melioidosis is endemic in Sabah, one of the two East Malaysian states on the island of Borneo, where B.pseudomallei prominently occurs in soil and water. Later then, he was admitted 3 monthly for antibiotic tuning and his sputum culture had no specific bacterial growth.
In August 2015, there was a decline in his lung function tests with deterioriorating cough. A bronchoscopy was performed and Burkholderia cepacia was isolated from his bronchoalveoloar lavage specimen, while acid-fast bacillus (AFB) smear was weakly positive. Initially, the patient was treated with intravenous imipenem and ceftazidime for 3 weeks but had recurrence of fever. However, the sputum AFB smears remained positive although the suspected nontuberculous mycobacterium could not be isolated despite various culturing techniques. Therefore, the antibiotics were changed to intravenous meropenem, doxycycline, amikacin and oral clarithromycin to treat both the B.cepacia and the suspected nontuberculous mycobacterium.
Upon discharge, he had been continuing with amoxicillin-clavulanate and doxycycline for 6 months, which helped with weight gain and secretion reduction. Repeat AFB smear remained negative for the subsequent 5 months. However, in January 2016, further decline in his lung function was observed with worsening respiratory symptoms. A chest computed tomography showed worsening bronchiectasis, tree in bud appearance in the lung peripheries, patchy consolidation and several enlarged lymph nodes at the right paratracheal region (Fig. ). His sputum sample grew P.aeruginosa and was also strongly positive for AFB. Intravenous meropenem and ceftazidime (for P.aeruginosa) and combination therapy of rifampicin, ethambutol, azithromycin and nebulized amikacin (for nontuberculous mycobacterium) was started. He improved clinically and was discharged with the above oral medications for 6 months.
B.pseudomallei was isolated once again in April 2016 and he was treated with intravenous amoxicillin-clavulanate and ceftazidime for 3 weeks. He was then discharged with 6 months of oral amoxicillin-clavulanate. However, in May 2016, his antibiotics were changed to levofloxacin (750 mg) and clarithromycin (500 mg). Following that, for the next 8 months, his sputum sample continued to grow B.pseudomallei but was negative for AFB. Despite many admissions for intravenous antibiotics against B.pseudomallei, the patient passed away from end stage respiratory failure in February 2017. Bacteriological reports were reviewed, and over the 3 years, the patient had several infective exacerbations and his sputum samples grew Gram-negative organisms that were later identified to be B.pseudomallei, Pseudomonas spp., P.aeruginosa, or B.cepacia (Table ).
All the isolates were found to have different susceptibility patterns (resistant to co-trimoxazole; intermediate to doxycycline and susceptible to all other antibiotics). The B.pseudomallei isolated in 2013, 2014 and 2016 (UMC083, UMC 082 and UMC114, respectively), were also further confirmed as B.pseudomallei using API 20NE (Biomerieux, France), Ashdown agar and also an in-house polymerase chain reaction (PCR) using specific primers []. However, we were not able to obtain the B.pseudomallei isolated in 2017.
The isolates were characterized by multilocus sequence typing (MLST), a method of molecular subtyping that compares sequences of seven housekeeping genes [], and repetitive-element PCR (rep-PCR). It appeared that these isolates were of two different sequence type (ST); ST51 (UMC083 and UMC114), which is a common ST found widely in Malaysia, Thailand, Singapore, Hong Kong and China, and ST1644, (UMC082) a new ST. The STs were deposited in the B.pseudomallei MLST database ().


The blind and painful right eye of a 38-year-old man was eviscerated in September 2016. The patient stated that his right eye had been blind since early childhood due to a unilateral congenital anomaly complicated by secondary glaucoma. He received the diagnosis of SO in January 2017 after he experienced visual loss in his only seeing (left) eye. At the time of diagnosis, the patient was admitted to the hospital and meticulously investigated for possible infectious and noninfectious causes to rule out other uveitic entities, but without any positive findings. At that time, his best-corrected visual acuity was 6/10. Slit-lamp examination yielded some vitreous cells in the left eye. Fundoscopy showed a few scattered pigmented chorioretinal scars and discrete yellowish round choroidal lesions throughout the left fundus (). Fluorescein angiogram delineated the active lesions as early hypofluorescent () with late staining. Left macular contour was normal on optical coherence tomography (OCT) examination (). He was started on oral prednisolone (64 mg) for 2 weeks with gradual tapering of 8 mg per week. Despite initial visual improvement, he experienced another episode of visual decline while taking 32 mg of prednisolone. His best-corrected visual acuity decreased to 2/10 and he had grade 4 vitreous haze according to the Miami grading. Fundus examination showed marked yellowish-white discoloration of the macula with some evidence of intraretinal hemorrhage ( and ). He was hospitalized and treated with pulse methylprednisolone 1 g (250 mg 4 times daily) for 3 days. Following pulse therapy, 64 mg oral prednisolone and 150 mg (50 mg 3 times daily) azathioprine were co-administered. Two weeks after the completion of pulse therapy, his visual acuity was still 2/10 despite a significant reduction in vitreous haze. Fluorescein angiogram and OCT demonstrated type 2 choroidal neovascularization (). Five intravitreal 2 mg aflibercept injections were given within a period of 8 months. His final visual acuity was 6/10 with a stable-looking macula ( and ) and he was continued on a treatment regimen of 150 mg azathioprine and 8 mg prednisolone daily.


The patient is a 72-year-old man with histologically confirmed moderately differentiated intrahepatic cholangiocarcinoma (Fig. ). He was diagnosed in October 2015 with the following symptoms: moderate weight loss, pain in the right hypochondrium, loss of appetite and asthenia, with a Karnofsky scale index of 70%. MRI image at the time of diagnosis is shown on Fig. a. The tumor was not surgically removed because of advanced stage, multiple intrahepatic nodules and lung metastases.
Four courses of chemotherapy (2 courses Gemcitabine in combination with Capecitabine and subsequent 2 courses Gemcitabine in combination with Cisplatin) were administered till May 2016. The treatment was poorly effective, and the tumor increased in size according to MRI (Fig. b); additional metastatic nodules appeared in the left and the right lobes with the spread to the bile duct, holedoch and into the gallbladder. Serum gamma glutamyltranspeptidase (GGT) level, which is associated with poor prognosis and tumor aggressiveness [, ], was significantly increased, when compared to pre-treatment levels (Fig. ). Karnofsky scale index decreased to 60%. As the patient did not respond to the best clinical practice treatment, we decided to switch the medication and considered TKI inhibitors as further treatment option. Taking into account available data on differential response of CCA patients to TKIs we performed advanced molecular analysis of the tumor to support our choice and identify the most effective drug.
We profiled gene expression in formalin-fixed, paraffin-embedded (FFPE) patient’s tumor biopsy sample, obtained at the time of the first CCA diagnosis. Briefly total RNA was extracted using Ambion’s RecoverAll™ Total Nucleic Acid Isolation. Complete Whole Transcriptome Amplification WTA2 Kit (Sigma) was used for reverse transcription and library amplification. Hybridization was performed according to CustomArray ElectraSense™ Hybridization and Detection protocol. Hybridization efficiency was detected electrochemically using CustomArray ElectraSense™ Detection Kit and ElectraSense™ 4X2K/12K Reader.
We next used bioinformatical software Oncobox to analyze gene expression data and to identify molecular pathways differentially regulated in the patient’s tumor sample []. Based on the abundance of gene transcripts for the molecular targets of anticancer drugs, Oncobox also makes it possible to generate a rating of target drugs potentially effective for the individual patients [, ]. Particularly, this analysis revealed that the ERK and Ras molecular signaling pathways were highly activated in the CCA patient’s tumor biopsy (Fig. ), the predicted rating of the most effective target drugs is shown in Table . Regorafenib, a multi-tyrosine kinase inhibitor was on the top position of the rating. However, there were no published studies of Regorafenib efficacy and tolerability in CCA. At the same time, several case reports demonstrated efficiency of TKI target drug Sorafenib for CCA treatment [–]. We, therefore, decided to use Sorafenib as the next line therapy and it was prescribed to the patient (800 mg daily) in May 2016. Treatment with Sorafenib coincided with the decrease of serum GGT level. MRI analysis in October 2016 revealed moderate tumor growth, corresponding to disease stabilization (Fig. c). However, additional nodules occurred slightly below the xiphoid process in the diaphragm area. Therefore, disease progressed according to RECIST criteria. And, importantly, after Sorafenib treatment, the patient did not complain of pain in the right hypochondrium. Before Sorafenib treatment the patient received Tramadol (100 mg im once a day) and Fentanyl (75 µg/h, Duragesic transdermal tape). After 1 month of treatment with Sorafenib the pain medication was switched to Ketoral (30 mg im twice a day). Considering all the above-mentioned facts it was decided to continue Sorafenib treatment. MRI performed in January 2017 revealed progression of tumor growth and additional nodule in the left lung (Fig. d). In addition, the following side effects occurred: redness, swelling, pain on the palms of the hands and soles of the feet. GGT level increased up to 319 U/L in December 2016.
The treatment regimen was next changed to Pazopanib, another TKI drug recommended based on the Oncobox rating. Sunitinib was not chosen because we attempted to eliminate the hand-foot syndrome, which occurred during Sorafenib administration. In the previous studies, Sunitinib treatment of CCA patients induced hand-foot syndrome in 43% of patients []. On the other hand, recent clinical trial of Pazopanib in combination with Trametinib in CCA did not report hand-foot syndrome as a side effect []. Pazopanib administration (800 mg daily) started since January 2017. The control MRI in July 2017 revealed progression in the lung nodes and 20% increase in sum of diameters of target lesions, which is a borderline between stabilization and progression according to RECIST (Fig. e). However, the change of treatment regimen resulted in elimination of Sorafenib side effects and general improvement of life quality. In addition, start of Pazopanib treatment coincided with a start of a trend towards decrease of serum GGT level (Fig. ). As for October 2017 (2 years after initial diagnosis), the patient was alive and physically active, with Karnofsky scale 80%. Our patient passed away due to the liver failure in November 2017.


A 19-year-old male of Caucasian origin was admitted to our center as a polytrauma after a road traffic accident. He was previously fit and well, a nonsmoker with an alcohol intake of approximately 10 units per month. The accident, in which his motorcycle collided with an oncoming vehicle, caused him to sustain multiple significant injuries including unstable pelvic fractures and femoral fractures. He had bilateral pneumothoraces, extensive pulmonary contusion, and a splenic hemorrhage. He presented in extremis with signs of hypovolemic shock. He was intubated and resuscitated using local major hemorrhage protocols to achieve a blood pressure of 159/93, receiving ten units of packed red cells and four units of fresh frozen plasma in the emergency department.
He underwent an emergency laparotomy and splenectomy and was subsequently transferred to the intensive care unit, where he became increasingly hypoxic with features of adult respiratory distress syndrome (ARDS). This culminated in him receiving veno-venous extracorporeal membrane oxygenation (ECMO) from day 15 of his admission for 21 days. He returned to theater on day 21 for a massive haemothorax which required an emergency thoracotomy. After being decannulated from the ECMO circuit, he was stepped down to the general intensive care unit on day 36 and was transferred to the ward on day 55 before being discharged after a 4-month admission including a prolonged rehabilitation and recovery period.
After presentation and commencement of ECMO, there was a relatively modest change in liver function tests. Alkaline phosphatase (ALP) increased from 55 to 143 IU/L between day 1 and day 6 of hospital admission and no persistent alanine transaminase (ALT) rise until after decannulation. Proceeding decannulation, there was a sequential increase in ALP peaking at 2335 IU/L on day 113. ALT rose to a lesser extent, peaking at 781 IU/L on day 52. The bilirubin did not rise above 57 μmol/L. The pattern of liver function tests is summarized in Figure . Autoantibody screen, immunoglobulins, and viral hepatitis serology were negative.
Serial ultrasound, computerized tomography (CT), and magnetic resonance imaging excluded biliary stones and sludge. The liver on CT at day 1 showed normal liver and biliary structure (Figure ), and it was not until 10 months after the admission, the repeat magnetic resonance cholangiopancreatography (MRCP) demonstrated a multistenotic pattern of disease within the intrahepatic ducts (Figure ).
In the absence of significant casts within the biliary tree and no evidence to suggest biliary sepsis, endoscopic retrograde cholangiopancreatography (ERCP) was felt not to be helpful. A conservative management approach was taken, and the patient was instigated on ursodeoxycholic acid to help improve cholestasis. With bilirubin improving, the patient was closely monitored as an outpatient upon discharge for progressive liver disease and dysfunction. Repeat imaging and noninvasive fibrosis assessments were undertaken. Despite having evidence of SSC, the synthetic liver function has remained excellent, cholestasis markers have improved, and there have been no episodes of cholangitis or biliary sepsis for over 1 year.


A 64-year-old Caucasian woman with a history of acquired FX deficiency from Amyloid light-chain (AL) amyloidosis, PAF, metastatic lung adenocarcinoma on erlotinib, hypertrophic cardiomyopathy (HCM), hypertension, and type 2 diabetes mellitus was seen in the hematology clinic for routine follow-up.
In 2013, she presented to the hematology clinic for self-limiting epistaxis and easy bruising. Initial outpatient laboratory tests were significant for abnormal coagulation profile (prothrombin time (PT) of 12.4 seconds, INR of 1.2, and activated partial thromboplastin time (aPTT) of 38 seconds), elevated alkaline phosphatase (160 U/L), and creatinine (1.16 mg/dL) levels. Further investigations revealed proteinuria (882 mg/24 h), and abdominal ultrasound demonstrated hepatomegaly with the right lobe measuring 21 cm in craniocaudal dimension. Serum and urine electrophoreses were remarkable for the presence of a paraprotein (immunoglobulin G-lambda). Abdominal fat pad biopsy was unrevealing, and liver biopsy (Figure ) showed extensive amyloid deposition. Immunohistochemical staining of the liver tissue revealed the presence of lambda light chain. A bone marrow core biopsy demonstrated extensive amyloid deposition (Figure ), and it was positive for Congo red staining with classical apple-green birefringence under polarized light. Fluorescence in situ hybridization assay was positive for lambda light chains. Further work-up of the abnormal coagulation study revealed a decreased FX coagulation activity of 45% (reference 70%-150%). Screening for inhibitor to FX was negative. Hence, a diagnosis of acquired FX deficiency secondary to AL amyloidosis was made. In view of her recurrent lung adenocarcinoma, she was deemed a poor candidate for autologous stem cell transplantation and she was started on melphalan and dexamethasone chemotherapy.
In 2015, she developed an episode of symptomatic PAF. Her coagulation profile showed PT of 16.3 seconds, aPTT of 33 seconds, and FX activity of 34%. As she has HCM, her CHA2DS2-VASc score was 4 with a significant risk for thromboembolism. Hence, she was started on apixaban 5 mg twice daily with close outpatient follow-up.
Three months later, she was found to have progression of her lung adenocarcinoma as she sustained a left pathologic subtrochanteric fracture requiring an urgent surgical intervention. In view of the need for her to undergo an open reduction and internal fixation of the left hip, her apixaban was temporarily withheld for close to 30 hours prior to the surgery. Preoperatively, her laboratory values were as follows: hemoglobin of 9.7 g/dL, PT of 20.3 seconds, and aPTT of 36 seconds. She had an uneventful open reduction and internal fixation of her left hip requiring one unit of packed red blood cell transfusion. Postoperatively, her laboratory values were as follows: hemoglobin of 8.1-8.4 g/dL, PT of 20.9 seconds, aPTT of 33 seconds, mixing studies showed correction (indicated underlying factor deficiency), fibrinogen level of 466 mg/dL, and FX coagulation activity of 37%. She was started on enoxaparin 30 mg subcutaneously every 12 hours for deep vein thrombosis prophylaxis. Two weeks later, she was restarted on her usual dose of apixaban for her paroxysmal AF. Her recovery was uneventful. A summary of her laboratory data is shown in Table .


Here, we present a case of a 55-year-old Caucasian female with a history of substance use disorder and a comorbid bipolar disorder, who presented to the local general hospital with a history of the fragmentation of a single personality into different personalities under emotional stress and under the influence of a drug. Multiple aspects of her personalities were reported, including the following: a personality of a seven-year-old child, a personality that would behave as a teenager, and another that acted like a male person in addition to her normal 55-year-old personality. She reported that she had been constantly dominated by her alternate personalities and became aware of their existence when people around her informed her, usually after a situation ended. She reported that stressful situations and substance abuse could aggravate the fragmentation of her personality. This was found to be mostly an involuntary phenomenon with seldom memory of the event.
While transitioning between these personalities, she was found to be violent even to people who were close to her. This could range from being suicidal to homicidal for which she was arrested twice in the past. She had to be isolated and restrained by being locked in a room and calling the police. As a result, she was hospitalized in a mental institution for a significant period at least two to three times in the past. Under the influence of stress or substances like marijuana or cocaine, her personality would split into various personalities. These states were very different from one another in terms of age or gender.
One of her alternate personalities behaved as a seven-year-old child and would show the same interests and choices that included becoming moody or a self-arrogant personality. While in these states, she could hurt herself or had weeping spells if her wants were not met.
Another personality acted as a teenager with some sharp choices and dressing. Increase in substance abuse, alcohol use, and smoking would lead to multiple cases of fights or homicidal attacks, with some incidents of self-harming events. Multiple scars were found on the dorsal side of her right hand. Her speech was found to be pressured and she would repeat the same words/ conversations.
The next personality was diagnosed to be a temporary transition to the opposite gender (a male). There was a change in voice and behavior. This included male dressing, language, a perception of male body parts, choices of friends, and attraction towards females, including sexual behavior.
The normal state of a 55-year aged female was the default personality that made her feel most comfortable. She reported that she had anxiety during a personality state transition, as it could occur at any time, and involuntarily, but mostly in stressful situations and during substance abuse. More violent and harmful events were reported when someone tried to meet the patient alone rather than in a group.
The treatment included psychotherapy with cognitive behavioral therapy addressing stress and substance use disorder. The psychotherapeutic treatment lasted for at least six months. The dual treatment of drug therapy was also involved to calm her down. The patient was prescribed escitalopram to reduce her anxiety symptoms. She believed that the anxiety pills were really helpful. After six months, the patient's condition was not drastically different. However, she believed her stress was getting better. The patient was further followed up for the next one year and the treatment continues to date.


A 16 year old girl presented with severe headache and visual loss, upon further questioning she also had primary amenorrhoea and galactorrhoea. An MRI [Fig. ] identified an apoplectic suprasellar tumour with a prolactin of 10,919 miU/L. After a week of treatment with cabergoline her vision had not improved so endoscopic trans-sphenoidal surgery (ETSS) was performed. Post-operatively, her vision returned to normal and she had no further galactorrhoea. 6 years later she has had no recurrence and has a normal prolactin. Histology confirmed pituitary apoplexy with expression of prolactin in a diffuse pattern. The Ki67 proliferation index was low.


A 14 year old boy was admitted with headaches and weight gain. At presentation he had only perception of light in his left eye and hand movements in the right eye. His MRI showed a pituitary tumour extending suprasellarly to compress the chiasm with features of apoplexy. The initial prolactin was 10,626 miU/L. Given his very poor visual function, he underwent emergency ETSS. Post-operatively his vision improved but he remains with significant visual impairment. Histology confirmed a prolactinoma with a moderate Ki67 (5%) and some mitotic activity. He remains on cabergoline although his subsequent MR imaging shows minimal residual disease.


A 15 year old boy was admitted with severe headache, reduced visual acuity and a sixth nerve palsy. Following an MRI he was diagnosed with a large pituitary macroadenoma with features of apoplexy. His prolactin was raised at 47,173 miU/L and he was commenced on cabergoline. His acuity had some improvement, however his sixth nerve palsy remained. Given his on-going visual symptoms, he underwent ETSS 6 weeks later. Post-operatively, his vision returned to normal with no ophthalmoplegia. Histology confirmed a prolactinoma with a low Ki67 and no up-regulation of p53.


A 15 year old boy initially presented with visual deterioration, galactorrhoea and weight gain to another neurosurgical unit. MRI showed a large pituitary tumour. He had a prolactin of 67,000 miU/L and was managed conservatively with cabergoline. His follow-up showed evidence of tumour reduction and prolactin reduced to ~ 10,000 miU/L. He presented to our unit almost a year later with sudden onset severe frontal headache and significant bi-temporal hemianopia. His MRI showed an enlarged apoplectic pituitary tumour with considerable chiasmal compression. Given the severity of his visual deterioration he underwent emergency ETSS. Post operatively his vision improved but recovery was complicated by transient diabetes insipidus, which settled over a few days. Histology confirmed pituitary apoplexy within a prolactinoma. No mitotic activity was seen.


A 13 year old girl presented with a 6 month history of headache and right temporal hemianopia. Her family were also concerned that this previously very studious girl was struggling at school. Her MRI showed a suprasellar apoplectic tumour with a prolactin of 30,824 miU/L. She was started on a dopamine agonist and monitored as an outpatient. During this time her prolactin returned to normal and she was monitored with regular visual field testing and monitoring of her prolactin. After a year she presented again with deteriorating vision. MRI showed an enlarging apoplectic tumour despite a prolactin of 63 miU/L. She therefore underwent ETSS to prevent any further visual loss. Post-operatively, both her vision and her academic performance have returned to normal. Histology confirmed a prolactinoma with apoplexy. The Ki67 and p53 labelling were not elevated.


Α 54 year old Caucasian woman of Greek ancestry presented to the Retina Service of our Department complaining of metamophopsia and reduced visual acuity in both eyes, gradually worsening over the past four months. Her past medical history revealed that she suffers from beta thalassemia intermedia for which she receives blood transfusion biweekly and chelation therapy for the past 14 years. Her chelation therapy consists of DFO (50 mg/kg 5 times a week by an 8-hourly subcutaneous infusion), as well as deferiprone (50 mg/kg, per os, daily). Ferritin level was within normal limits. The remainder of her medical history included hypothyroidism treated with levothyroxine. No history of color and peripheral vision changes nor hearing impairment was reported. Her past ocular history was unremarkable.
On the initial examination, best corrected visual acuity (BCVA) was 20/25 in the right eye (OD) and 20/22 in the left eye (OS). Slit lamp biomicroscopy revealed no pathology from the anterior segment and intraocular pressure (IOP) measured by applanation tonometry was 14 mmHg in both eyes (OU). Dilated fundus examination showed a yellowish roundish macular lesion surrounded by RPE changes, as well as angioid streaks emanating from the optic disc sparing the macula in OU (Fig. ). The retinal vasculature appeared normal.
Spectral-Domain Optical Coherence Tomography (SD-OCT) revealed a subfoveal hyperreflective deposit above the level of the RPE corresponding to the lesion observed fundoscopically (Fig. ) while mild stippling was noticed in the macular area in fundus autofluorescence (FAF) (Fig. ). Finally, fluoroscein angiography revealed staining of the macular lesion in the late phases of the angiogram (Fig. ). To evaluate possible DFO retinopathy in this patient, electrophysiology testing, more specifically, full-field electroretinogram (ffERG) and pattern electroretinogram (PERG), was performed. Amplitudes and implicit times for each major waveform component were included. The responses were taken according to the International Society for Clinical Electrophysiology of Vision (ISCEV) []. The ERG revealed no abnormal rode and cone responses OU (Fig. ). Visual field examination, performed by automated perimetry (Humphrey 30–2 SITA-standard, Carl Zeiss Meditec, Dublin, CA) was also normal.
Taking into consideration the normal ffERG and after consultation with her hematologist, it was decided that the patient would remain on the prescribed chelation therapy, due to the severity of her systemic condition. The patient was followed up every 3 months in our department with SD-OCT for possible deterioration. Her BCVA remained stable for the next 2 years, with no anatomic change on OCT findings (Fig. ).


A 63 year old Caucasian woman of Greek ancestry presented to our Retina Service complaining of decreased central vision OU. She had a medical history of sickle beta thalassemia for which she was receiving regular blood transfusions. She was also receiving iron-chelation treatment with DFO (50 mg/kg 5 times a week by an 8-hourly subcutaneous infusion), for the past 25 years. The rest of her medical and her ocular history were unremarkable. The patient did not report any peripheral, night or color vision problems. There was no history of hearing loss. Her BCVA was 20/50 OU. Slit lamp biomicroscopy was normal and IOP was 15 mmHg in OD and 13 mmHg in OS. Dilated fundus examination revealed the presence of a yellow-brown macular lesion OU. The lesion consisted of yellow pigment lines expanding to the perimacular area in a tri-radiating pattern surrounded by areas of granular hyper-pigmented brown material. Fundus autofluorescence revealed hyperfluorescent areas in a butterfly shaped pattern corresponding to the pigment clumping areas seen in fundoscopy OU (Fig. ). Fluoroscein angiography demonstrated a large hypofluorescent, butterfly-shaped macular lesion surrounded by areas of focal hyperfluorescence OU (Fig. ). Spectral Domain-OCT demonstrated a subfoveal hyperreflective lesion at the level and above the RPE OU (Fig. ). Electroretinogram showed no abnormal cone and rod responses. Humphrey visual field perimetry using 30–2 SITA-Standard algorithm was within normal limits.
Haematologists were consulted regarding DFO discontinuation but they decided not to make any change in chelation therapy since the risks pertaining to the patient’s underlying disease outweighed the risk of possible visual loss. Therefore, it was decided to follow-up our patient closely every three months. During a 4 years follow-up period BCVA remained stable without any signs of anatomic change as it was demonstrated with repeated OCT examinations (Fig. , ).


A 5-month-old boy presented with psychomotor developmental retardation and was admitted to the pediatric neurodevelopmental unit of Bayi Children’s Hospital. He could not control his head, was prone to hypsokinesis, was unable to turn over or grasp, and had high muscle tension. The parents of the patient denied heredity history or consanguineous marriage.
A urine sample was prepared with urease pretreatment methods, according to the method in the reported literature []. Derivatization was performed with 100 μL bis-(trimethylsilyl) trifluoracetamide (BSTFA) + 1% trimethylchlorosilane at 90 °C for 40 min, the metabolites were analyzed by GC-MS after cooling. The final derivatized metabolites were injected into the GC-MS, using a split-less mode per microliter. The temperature of the injection port was set at 250 °C. The initial temperature of the column oven was 60 °C and held for 2 min, then increased with the speed of 10 °C/min until reaching the temperature of 220 °C, held for 3 min; then it was increased with the speed of 15 °C/min to the final temperature of 325 °C and held for 5 min. The temperature of the ion source and transfer line was 280 °C and 300 °C, respectively. The run time lasted for 33 min, and the scan range was programmed from m/z 50 to 550. Finally, qualitative analyses of the characteristic mass spectrogram of each flow peak and the ratio of the peak area of 2-HG to that of creatinine was used as the quantitative index [].
Following the manufacturer’s instructions, genomic DNA was isolated from the peripheral blood specimens of the three people (patient and his parents) with the RelaxGene Blood DNA System (TianGen, Beijing, China). PCR amplified the entire coding region sequences, covering all 10 exons and the exon-intron boundary sequences of L2HGDH with primers as described by Topcu []. The PCR products were sequenced directly on an ABI 3730 sequencer (Applied Biosystem, Foster City, USA). The results were analyzed with the Gene tool program and Chromas program. The naming of the mutations was on the basis of Human Genome Variation Society (HGVS) guidelines (), according to GenBank NCBI reference sequence NM_024884.2. We used three prediction software programs, SIFT, PloyPhen-2, and MutationTaster, to predict the potential pathogenicity of the sequence mutations. On structural analysis, the protein (Uniport ID: Q9H9P8) of L2HGDH for human was downloaded from Uniport (/). Then its three-dimensional structure was predicted using I-TASSER () with the default parameters and the model with the highest C-score was selected. We used the InterPro () to predict the domain of protein Q9H9P8. Finally, the predicted structure and the functional domains were visualized by PyMol 2.1 ().
Brain MRI revealed symmetrical, high-signal changes in the subcortical white matter, basal ganglia, and cerebellar dentate nuclei. The lateral ventricular wall showed multiple nodular gray matter heterotopia. The right side of the cerebellar hemisphere and vermis showed dysplasia (Fig. ).
GC-MS analysis showed visibly increased excretion of 2-HG (209.70 mmol/mol cre, normal range 0.00~ 19.85 mmol/mol cre) in the urine. The peak area ratio of 2-HG was 20.84, and the normal peak area ratio was 0.25, which was the 99.5 percentile of 500 newborns with normal metabolism. The retention time was 13.88. The characteristic ion used for quantification was m/z 349 (Fig. ).
We identified two novel mutations in exon 3 of the patient. One was a homozygous missense mutation (c.407 A > G, p.K136R). We used three prediction software programs, SIFT, PloyPhen-2, and MutationTaster, to predict the potential pathogenicity of the sequence mutations. The results were “damaging (0 score)”, “probably damaging (1 score)” and “disease causing (26 score)” respectively. This mutation was not present in the 1000 Genome Project, NHLBI GO Exome Sequencing Project and and InNormal Database (MyGenostics, number of 1000). The mutation site p.K136R of the protein was located in the pocket (shown in th black ellipse) of the FAD/NAD(P)-binding domain(Fig. ). The other mutation was a heterozygous deletion of one nucleotide (c.408delG, p.K136SfsX3), which would be expected to cause a premature stop codon at position 138 in the protein sequence. Further pedigree analysis of the healthy parents confirmed that the two novel mutations segregated with the disease in an autosomal recessive trait. His asymptomatic mother had the heterozygous missense mutation (c.407 A > G, p.K136R). His asymptomatic father showed both the heterozygous missense mutation (c.407 A > G, p.K136R) and the heterozygous delete mutation (c.408 del G, p.K136SfsX3) (Fig. ). Finally, we predicted the homozygous missense mutation (c.407 A > G, p.K136R) was the pathogenic mutation of the patient.


A 76-year-old man, former smoker (80 pack-years), with hypertension and hyperlipidaemia was referred to our hospital with a diagnosis of AE with IPF in 2013. After admission to our hospital, he was treated with steroid pulse therapy followed by systemic corticosteroid and cyclosporine therapy. His respiratory condition gradually improved, and corticosteroid dose was tapered. However, he needed 2 L/min of oxygen via a nasal cannula at the time of discharge. Corticosteroid dose was tapered gradually in the outpatient clinic. His forced vital capacity (FVC) declined by 8% in approximately 30 months after remission of AE. Nintedanib (300 mg/day) was administered in December 2015 because of the decline in FVC and a history of AE with IPF. A new small nodular lesion, measuring 13.5 mm × 11.7 mm (Fig. A), appeared adjacent to the honeycomb lung of the right lower lung lobe on a chest computed tomography (CT) scan before the initiation of nintedanib. Because of moderate deterioration of liver function after five months of nintedanib therapy, nintedanib was discontinued for two weeks and resumed after normalization of liver function at 200 mg/day.
The patient complained of right lower abdominal pain in September 2016. Acute gangrenous appendicitis was suspected on an abdominal CT scan. We observed neither deterioration of pulmonary function nor enlargement of the nodule (10.7 mm × 12.5 mm (Fig. B)) in the right lower lung lobe during nintedanib use. Nintedanib was discontinued, and his appendicitis improved with antibiotics.
In January 2017, four months after the discontinuation of nintedanib, the nodule in the right lower lobe increased in size from 10.7 mm × 12.5 mm to 20.8 mm × 22.0 mm (Fig. C). The patient underwent a resection of the nodule, which was diagnosed as squamous cell carcinoma (Fig. ).


A 40-year-old woman known for type 1 diabetes presented to the emergency room with back pain, diffuse myalgia, asthenia, and fever (38.5 °C). She had been taking nonsteroidal anti-inflammatory medication for 5 days following a trauma of the left ankle. Physical examination showed hypotension with arterial blood pressure of 70/30 mmHg. The patient remained hypotensive despite fluid resuscitation with crystalloids and required continuous norepinephrine infusion. At the time of admission, the patient complained of important pain in the left limb, although this was associated with a normal clinical examination. A small skin defect on the left ankle in relationship with the initial trauma was, however, noted. The gynecologic examination was normal. Laboratory tests on admission showed elevated plasma C-reactive protein and procalcitonin levels (320 mg/L and 23 μg/L, respectively), an estimated glomerular filtration rate of 15 mL/min/1.73 m2, an absolute neutrophil count of 1.4 G/L with increased band forms, thrombocytopenia (63 G/L), increased thromboplastin time, and very elevated creatine kinase levels (143,000 U/L). The patient was admitted to the intensive care unit (ICU) with the diagnosis of septic shock, and empiric antibiotic therapy was initiated with piperacillin/tazobactam plus clindamycin. A CT scan of the limb did not show radiologic signs of necrotizing fasciitis, but the patient subsequently rapidly developed signs of arthritis of both ankles plus the right elbow, which required surgical lavage. Synovial fluid and blood cultures came back positive with group A streptococcus (S. pyogenes), and the antibiotic therapy was deescalated for high-dose IV penicillin G. In spite of the initial acute renal failure and rhadomyolysis, the patient did not need renal support therapy during the ICU stay, could be transferred to the ward after 6 days, and recovered without sequelae. The final diagnosis was a toxic shock syndrome due to group A streptococcus with septic oligoarthritis, most probably originating from a skin lesion and a left ankle trauma, in young woman with type 1 diabetes.


Our patient was a 3-year-old Malay boy, who presented with fever of 2 days’ duration and an episode of generalized tonic-clonic seizure that lasted approximately 5 minutes. There was no up rolling of eye ball or drooling of saliva during the seizure. He had post-ictal drowsiness for 10 minutes. There were no other associated symptoms. Six weeks prior to the presentation he was brought to a general practitioner for fever and skin rashes over his face and upper limbs. He was treated with orally administered paracetamol and cefuroxime axetil. Subsequently, the fever resolved but the skin rashes persisted. On admission, he was diagnosed as having simple febrile seizure and eczema herpeticum. At 13 months of age he was diagnosed as having single gene deletion α-thalassemia trait (αα/−α4.2), and remained asymptomatic since diagnosis. His parents were non-consanguineous. His mother is 35-years old and has α-thalassemia trait. There was history of right ear infection a year before and that had resolved with treatment. He has history of allergy and intermittently was on orally administered desloratadine. There was no other significant past medical history, and he was not on any other medicine prior to the recent presentation. His immunization status was up to date, and developmentally he was normal. He lived with his parents who worked as police officers, and he has another healthy younger sibling of 5-months old. They lived in an apartment in a suburban area. He went to kindergarten when the parents worked.
On admission, a physical examination revealed Glasgow Coma Scale of 15/15, blood pressure 90/46 mmHg, pulse rate 120/minute, and temperature 37.9 °C. He was febrile, pale, with no jaundice, and he had “shotty” cervical lymph nodes. The results of examinations of his throat, tonsils, and ears were normal. Some maculopapular rashes with scaly and crusted areas were noted on his left cheek, both arms and knees, and trunk area. There was hepatosplenomegaly of 4 cm and 3 cm, respectively. There were no bleeding tendencies or neurologic deficit noted. Laboratory findings showed hypochromic microcytic anemia, thrombocytopenia, reticulocytosis, and raised serum LDH. A peripheral blood smear showed significant fragmented red cells, spherocytes, and polychromasia in keeping with MAHA (Fig. ). Serial investigation results showed persistent anemia and thrombocytopenia. His renal function test, liver function test, and coagulation profile were normal (Table ). Direct and indirect Coombs tests were negative (Table ). He was started on orally administered acyclovir for 10 days and received a course of cloxacillin for the rashes. TTP was suspected at this juncture. He was clinically asymptomatic, and was observed without any intervention prior to the results of ADAMTS13 assay. Subsequently, the ADAMTS13 assay results showed zero activities (0%) and markedly high level of ADAMTS13 inhibitor, 93.15 U/mL (negative < 12 U/mL; borderline 12–15 U/mL; positive > 15 U/mL) confirming the diagnosis of secondary TTP. Other laboratory investigations to identify specific secondary causes of TTP were negative: (i) viral studies on parvovirus, Epstein–Barr virus, and dengue virus; and (ii) blood culture and sensitivity. The screening for autoimmune disease showed anti-nuclear antibody positive and borderline double-stranded deoxyribonucleic acid (DNA), however, complement 3 and complement 4 levels were normal. He had no clinical findings to suggest connective tissue disease. He received fresh frozen plasma (FFP) transfusions (10–15 ml/kg per day) for 3 consecutive days. His hemoglobin (Hb) level was 8.1 g/dL and platelet count was 46 × 109/L prior to the transfusions. Subsequently, the counts recovered. He had a Hb level of 8.1 g/dL and platelet count of 168 × 109/L, a day after completed FFP transfusions. His reticulocytes count and LDH level reduced to 4.0% and 337 U/L, respectively. Six months later, the ADAMTS13 activity improved to 20.5%, and ADAMTS13 inhibitor reduced markedly to 14 U/mL. At 12 months, he remained in clinical remission, the ADAMTS13 activity had normalized to 48%; however, the ADAMTS13 inhibitor level was still detectable at 17.5 U/mL. He was given orally administered prednisolone 1 mg/kg per day for 6 weeks and it was tapered off 2 weeks later. A repeated ADAMTS13 activity at the end of the prednisolone course was > 114%. However, there was no result available about the inhibitor level. He is scheduled for follow-up every 3 months with surveillance of ADAMTS13 assay for 1 year. During clinic follow-up at 6 months after treatment, he remained in remission and his full blood counts were normal. A timeline for our patient is given in Fig. .


A 45-year-old, Caucasian male patient presented with right knee pain that started a year ago and aggravated eight months ago. He was an English teacher and denied a history of any trauma. The symptom sustained despite six months of conservative treatment at another clinic, including intermittent non-steroid anti-inflammatory drug medication, injection (the exact drug is unknown) or physical therapy. He had severe anterior knee pain during stair-climbing or squatting and had been aware of a cystic mass in the posterior aspect of the knee joint that had been progressively increasing in size. On physical examination, mild swelling and effusion of the right knee were seen without localized heat sense. Painful crepitation and moderate tenderness were present around the patellar tendon during knee motion and a large, non-tender cystic mass existed on the posterior aspect of the right knee joint. The crepitation also existed on his left knee, but he had no discomfort on the left side at all. Also, there was no cystic lesion on the left knee. The volume of the right infrapatellar region was greater than normal and felt firm to the touch. Passive full knee range of motion was possible but painful. There was no tenderness on the tibial tubercle or patella.
Plain radiographic examination of the right knee showed a large ossicle locating beneath the patellar tendon and inside the infrapatellar fat pad. A similar-sized ossicle was seen in the left knee, while it was partially fused to the hypertrophied tibial tuberosity (Figure ).
Right knee magnetic resonance images showed about 3.8 x 1.3 x 3.0 cm sized, well-circumscribed ossicle. Several smaller ossicles were also found near the tibial tubercle. Inflammatory changes in synovium, infrapatellar fat pad, and patellar tendon were also seen. A reactive bone marrow edema was found at the anterior aspect of the tibial condyle. Besides, a Baker’s cyst of 7.3 x 4.1 x 14.7 cm size was found (Figure ).
The patient chose to get surgery since the symptom continued after the prolonged conservative treatment. Since the lesion was benign in character and the patient requested to remove the Baker’s cyst simultaneously, arthroscopic surgery was planned to excise the ossicle and decompress the cyst. Right knee arthroscopy was performed through the standard anterolateral and anteromedial portals close to the patellar tendon. Anterior interval release of the hypertrophied fat pad was carefully performed with the mechanical shaver. Then the arthroscopy was inserted through a separate superolateral portal. The knee was held in a 45-degree flexed position and the outline of the ossicle was identified. The overlying fat and fibrous tissues were shaved, and the clear outline of the ossicle was visible (Figure ).
The ossicle was fragmented using an arthroscopic punch or a small osteotome and removed through the slightly extended anteromedial portal (Figure ).
An intraoperative fluoroscopic image was acquired to confirm the complete removal of the ossicle (Figure ).
The knee was held in a 15-degree flexed position and the inflamed retro-patellar tendon surface was debrided. Through the additional posteromedial portal, the Baker’s cyst was decompressed.
Postoperative recovery was uneventful. From the first postoperative day, the patient could walk with full weight-bearing and move his knee. Strengthening exercise for knee extensor muscles was encouraged as tolerable. The patient regained full knee range of motion and returned to his daily activities within two weeks after surgery. The excised tissue was subjected to a histopathological examination. The histology finding was consistent with OSD that mix of osseous and cartilaginous tissue was seen without evident cartilaginous cap (Figure ). At six months after the surgery, the patient’s right knee was normal without any clinical or radiographic sign of recurrence.