A 76-year-old Japanese man presented with a chief complaint of general fatigue, as well as weight loss that began in July 2018. He visited a nearby clinic in October 2018 because of his general fatigue and was referred to our hospital because of severe renal dysfunction (serum creatinine: 12 mg/dL). The patient was previously healthy with no notable medical or family history, including no history of allergy. He had smoked 30 cigarettes/day for approximately 55 years and occasionally consumed alcohol.
Physical examination revealed a height of 157 cm, a weight of 44.6 kg, body mass index of 18.1 kg/m2, blood pressure of 162/77 mmHg, heart rate of 89 beats/min, and body temperature of 36.6 °C. The patient was lucid and had signs of anemia at the palpebral conjunctiva, but no signs of jaundice at the bulbar conjunctiva. Furthermore, we did not observe any significant findings during examinations of the oral cavity, cervical lymph nodes, cardiopulmonary sounds, abdomen, bilateral costovertebral angle, feet, joints, skin, or related neurological findings.
The blood and urine test results obtained on admission are shown in Table . The blood tests revealed severe renal dysfunction, anemia, and elevated levels of C-reactive protein and myeloperoxidase ANCA. The urinalysis revealed positivity for protein and occult blood. Computed tomography revealed evidence of interstitial pneumonia in the posterior segments of the bilateral lower lobes and mild bilateral kidney enlargement, suggesting acute kidney injury. Based on these findings, the patient was urgently admitted for treatment.
Hemodialysis was started for acute kidney injury on day 1 using heparin as an anticoagulant. Renal biopsy was performed on day 7, which revealed that 3 of 15 glomeruli were completely hyalinized, and the remaining 12 glomeruli were mostly hyalinized, with crescent formation and transitioning to fibrous crescents, as well as collapsed and destroyed glomerular loops (Fig. ). Lymphocyte infiltration was observed in the tubulointerstitium, and 60–70 % of all renal tubules were atrophied. Immunostaining revealed a pauci-immune pattern, and these findings fulfilled the diagnostic criteria for MPA. Thus, the patient was diagnosed with RPGN related to acute kidney injury caused by AAV.
The Birmingham Vasculitis Activity Score was 18, and no alveolar hemorrhage or neurological symptoms were observed. The patient was treated using three sessions of steroid pulse therapy (methylprednisolone at 1,000 mg/day), one session of intermittent intravenous cyclophosphamide pulse (IVCY) therapy (because we considered avoiding aggressive immunosuppression since the kidney biopsy results showed more chronic changes and fibrosis/atrophy than the active disease), and oral steroid therapy (prednisolone at 50 mg/day) (Fig. ). However, the patient’s renal function did not improve, and maintenance dialysis was started.
On day 15, clotting was observed in the hemodialysis catheter. Complete blood count with biochemical parameters was performed as a follow-up to assess anemia and the state of AAV after steroid pulse therapy revealed a drastic drop in the patient’s platelet count to 47,000/µL without elevated levels of C-reactive protein. HIT related to hemodialysis using heparin was strongly suspected, and D-Dimer with other coagulation parameters were evaluated to assess diseases causing thrombocytopenia. The D-dimer concentration had increased acutely to 22.7 µg/mL up from 4.1 µg/mL on admission despite the negative level of C-reactive protein after AAV treatment suggesting improvement of AAV. Because type II HIT can potentially cause critical thrombosis, physical and image examinations were performed based on a suspicion of thrombosis.
The patient was lucid after hemodialysis initiation, symptoms were absent, and vital signs were as follows: blood pressure of 133/68 mmHg, heart rate of 67 beats/min, body temperature of 36.2 °C, and oxygen saturation of 99 %. Regarding physical findings, no findings of vision loss, restricted visual field, abnormal cardiopulmonary sounds, abdominal pain, and livedo reticularis were observed. The pulse of the bilateral radial arteries and the bilateral dorsalis pedis artery were normal. There were no findings of motor paralysis, sensory disorders, gait disturbance, dysarthria, aphasia, and unilateral spatial neglect. No significant neurological findings were observed, and no findings of thromboembolism were observed in the trunk or limbs. However, we performed head magnetic resonance imaging and computed tomography of the trunk to establish differential diagnoses of thrombosis, inflammatory disease, and chronic diseases related to acute thrombocytopenia with an increase in D-dimer concentration and clotting in the hemodialysis catheter. This is because we consider that AAV is often accompanied by thrombosis and is rarely accompanied by cerebral aneurysm or arterial stenosis resulting from vasculitis. Moreover, thrombosis could similarly be caused by type II HIT.
Consequently, acute asymptomatic cerebral infarction was observed in the left occipital lobe without findings of vasculitis in cerebral arteries during head magnetic resonance imaging (Fig. ). In contrast, computed tomography of the trunk revealed no findings of thrombosis, inflammatory disease, and chronic diseases. Thus, HIT was suspected based on the decreased platelet count after starting heparin treatment and the development of asymptomatic cerebral infarction, as well as clotting in the hemodialysis catheter. Disseminated intravascular coagulation was considered unlikely based on the absence of infection or malignant tumors, and thrombotic microangiopathy was considered unlikely based on the haptoglobin value being within the normal range. Furthermore, idiopathic thrombocytopenic purpura was considered unlikely based on the negative results for anti-platelet antibodies (Table ), and there was no atrial fibrillation. However, a high likelihood of HIT was judged based on the HIT scoring system (a 4Ts score of 6) [], and the presence of HIT antibodies on day 15 supported a diagnosis of asymptomatic cerebral infarction caused by type II HIT (Table ). Because there was no bleeding lesion in the brain, the patient was treated using aspirin (200 mg/day).
After thrombocytopenia was confirmed, the anticoagulant treatment during hemodialysis was changed from heparin to nafamostat on day 15, which we have commonly used for patients in whom heparin is contraindicated. However, the platelet count did not begin to recover until after the anticoagulant treatment was changed from nafamostat to argatroban on day 29. The platelet counts gradually improved, and the patient was discharged on day 51, with argatroban treatment during the subsequent hemodialysis. The patient did not experience any vascular events after the discharge, and a negative result was observed for a second HIT antibody test that was performed on day 622.


A 71-year-old African American man presented to the hospital with progressively worsening chest pain, shortness of breath, fatigue, and lightheadedness for one day. The chest pain was right-sided, non-radiating, and continuous with no exacerbating or relieving factors. He had a medical history of uncontrolled type 2 diabetes mellitus, morbid obesity, hypertension, obstructive sleep apnea (OSA), and tobacco abuse. He had undergone multiple joint replacement surgeries (the last one being three years before this presentation) and used crutches to ambulate. He was found to have blood pressure (BP) of 90/60 mmHg, heart rate (HR) of 110 beats per minute, respiratory rate (RR) of 35 breaths per minute, and SpO2 of 98% on room air. Physical exam revealed diaphoresis, respiratory distress, and decreased breath sounds in all lung fields. Labs revealed troponin of 0.91 ng/mL, brain natriuretic peptide (BNP) of 748 pg/ml, lactate of 5.0 mmol/L, creatinine of 1.5 mg/dl (baseline: 0.98), and D-dimer of >7,650 ng/mL; the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test was negative. Despite receiving fluid resuscitation, the patient remained persistently hypotensive and was transferred to the ICU due to a need for vasopressors.
A preliminary diagnosis of PE was made, but a CT pulmonary angiogram could not be performed due to an acute kidney injury. The patient had a bilateral lower extremity ultrasound, which showed acute right femoral deep vein thrombosis. An echo showed RV hypokinesis, flattened septum, and severe pulmonary hypertension. Thus, the diagnosis of SPE was confirmed, and systemic AC with a heparin drip was started. His blood pressure spontaneously improved within the same day, and he was transferred out of the ICU. However, over the next three days, his oxygen requirements went up again. SARS-CoV-2 test was repeated, which came back positive, raising the possibility of a false-negative test on admission versus hospital-acquired coronavirus disease 2019 (COVID-19) infection. At this point, he was transferred back to the ICU to administer high flow oxygen at 60 L and 100% FiO2, with a chest X-ray showing worsening bilateral infiltrates. His creatinine trended down from a peak of 2.6 mg/dl. A CT pulmonary angiogram was finally performed, which showed extensive bilateral PE with right and left lobar artery involvement and right heart strain. CDT with EKOS was carried out. However, the patient's FiO2 only minimally improved. A repeat CT pulmonary angiogram two days later showed a slight decrease in clot burden post EKOS with persistent right heart strain (Figure ).
A repeat EKOS procedure was considered, but the clot appeared more organized on the new CT scan. The patient received half-dose systemic thrombolytic with tPA-50 mg over one hour with simultaneous AC. Within 24 hours, his oxygen requirements came down, and he was discharged home two days later.


A 5-year-old girl with history of mackerel allergy, atopic dermatitis and chronic constipation, had a 3-month history of epigastralgia and vomiting, which occurred repeatedly, every 2 weeks. A pediatrician performed physical and laboratory examinations when she had no symptoms; however, no abnormal findings were recognized. Four months later, she was transferred to our institution for a detailed workup because of recurrent epigastralgia.
On abdominal examination, a small palpable mass was identified in the upper abdomen. A blood analysis revealed the following: white blood cell count, 10,100 /μl; hemoglobin, 13.2 g/dl; and C-reactive protein, 0.66 mg/dl. The patient’s liver enzyme levels were within the normal ranges. On abdominal ultrasonography with color Doppler imaging, an 11.8 × 13.6 mm nonvascular lesion with mixed echogenicity was detected near the round ligament of the liver (Fig. ). Enhanced computed tomography (CT) confirmed a 14 × 16 × 20 mm mass with low attenuation surrounded by a hyperdense line with disproportionate fat stranding on the right side of the round ligament of the liver (Fig. ). There was no ascites or hemorrhage in the abdominal cavity. These findings suggested an abscess of the round ligament of the liver. Her symptoms were improving; thus, we prescribed oral antibiotics and planned to perform elective laparoscopic exploration followed by resection. After her last admission to the hospital, she had no symptoms for approximately 2 months until she underwent surgery. The target lesion was small and was detected preoperatively. We therefore decided to perform two-site laparoscopic surgery [].
Under general anesthesia, the patient was placed in the broard base position. The umbilicus was opened through a 1.5 cm longitudinal incision, and a wound retractor (LAP PROTECTOR Mini-mini; Hakko Co. Ltd, Tokyo, Japan) was applied. Two 5-mm trocars (scope and operator’s right hand, respectively) were inserted through multichannel port device (E・Z access; Hakko Co. Ltd) to attach to the wound retractor and pneumoperitoneum was established (8 mm Hg, 5 L/min CO2 insufflation). In addition, a 3-mm trocar (operator’s left hand) was inserted at the right lateral abdomen under a laparoscopic view (30° rigid scope, KARLSTORZ, Tuttlingen, Germany). Observation of the abdominal cavity revealed adhesion between the omentum and the round ligament of the liver (Fig. a). Macroscopic observation revealed no apparent mass lesions. We performed adhesiolysis of the omentum from the round ligament of the liver using a vessel sealing system (LigaSure™ Maryland; Medtronic, Dublin, Ireland) (Fig. b). After ligation of the round ligament of the liver attached to the liver site using a loop suture (ENDOLOOP® Ligature; Johnson & Johnson, NJ, USA) (Fig. c), we resected the round ligament of the liver with the surrounding tissue using a vessel sealing system (Additional file : Video). The resected specimen was extracted through the umbilical wound. The postoperative course was uneventful. She was discharged from hospital 3 days after surgery and remained asymptomatic for approximately half a year.
The resected specimen is shown in Fig. a. Microscopically, 6 mm of granulomatous tissue was observed around the round ligament. The collection of multinucleated giant cells and histiocytes, hemosiderin deposition and an area of coagulative necrosis with lymphocyte infiltration were also detected (Fig. b). Necrotic liver tissue in the area of necrosis was detected by silver impregnation staining (Fig. c). We concluded that the resected tissue was an ALL with ischemic change.


The patient was a 73-year-old female, with hypertension, grade C heart failure (HF), and congestive liver disease, who presented at the emergency room of a University Hospital complaining of nocturnal paroxysmal dyspnea and hemoptysis. Transthoracic echocardiogram showed a thickened mitral valve, with significant insufficiency, and reversed systolic flow in the left superior pulmonary vein; tricuspid valve closure was dysfunctional and there was important dilation of the right atrium (56 mm) and inferior vena cava (> 21 mm in diameter, with < 50% variability during respiration).
Physical examination at first presentation detected symmetrical edema of the lower limbs, large caliber varicose veins, discrete ochrodermatitis involving the distal third of the legs, although with no eczemas or ulcerations (CEAP clinical venous disease classification was 4a). There was a notable pulsating swelling in the left inguinal region.
Pursuing a hypothesis of femoral artery aneurysm concomitant with the varicosities, arterial Doppler ultrasonography of the left lower limb was requested. This showed triphasic flow in all segments investigated, with no significant parietal changes. Direct and indirect echographic signs of arteriovenous communication (fistula) were absent. During the venous study, alternating (bidirectional) flow was observed in the left common femoral vein and saphenofemoral junction. Supplementary venous studies of both limbs found no signs of deep venous thrombosis, but revealed an alternating spectral curve in the right deep venous axis, extending to both saphenofemoral junctions and great saphenous veins and also present in varicose dilatations in the thighs. On the left, in the territory of the inguinal swelling, large caliber varicose veins crossed anterior to the femoral artery, while the varicose tributaries that extended along the thigh and knee communicated with a perforating vein on the medial surface of the proximal third of the leg, and the perforator exhibited an alternating spectral curve with predominant blood flow in the direction of the deep vein system (, , ).
After the ultrasonographic diagnosis, an assessment in conjunction with the vascular surgery team was requested, and this physical examination revealed pulsatility along the entire superficial venous axis during, in addition to absence of thrill on palpation and slow filling of varicosities during the compression/decompression maneuver. Clinical treatment was chosen, with postural measures and elastic compression. Over the course of her stay, the patient exhibited significant clinical improvement of her heart disease and limb edema. Since this was oligosymptomatic varicose disease, with severe, recently compensated cardiac comorbidity in a patient of advanced age, the decision was taken to maintain ambulatory clinical treatment, with no invasive interventions. During the subsequent months, she suffered several additional episodes of decompensated HF and recurrent hospital admissions and died after 1 year of follow-up.


A 66-year-old Japanese man was referred to our medical center with leg edema. He had hypertension and dyslipidemia. His vital signs were unremarkable. Notable examination findings included moderate pitting edema in the lower extremities. Neurological and musculoskeletal examination findings were unremarkable. Laboratory test results (Table ) revealed a normal red blood cell count (440 × 104/μL [normal: 427-520 × 104/μL]), normal white blood cell count (4,400/μL [normal: 3,040-8,540/μL]), and normal platelet count (20.7 × 109/L [normal: 15.036.1 × 109/L]). Serum creatinine was 1.59 mg/dL, estimated glomerular filtration rate was 45 mL/min/1.73 m2, and serum albumin was 3.4 g/dL. Immunological analysis showed decreased immunoglobulins (IgG 291 mg/dL; IgA 16 mg/dL; IgM 21 mg/dL), and normal complement levels. The patient tested negative for antinuclear, double-stranded DNA, anti-Smith, antineutrophil cytoplasmic, and anti-glomerular basement membrane antibodies. The patient’s cryoglobulin test, as well as tests for hepatitis A, B, C, and HIV, was negative. Urinalysis showed profound proteinuria (7.5 g/day [normal: <0.02 g/day]) with mild hematuria (10-19 per high-power field [normal: <1 per high-power field]).
Since kidney atrophy (7 cm in length; 3.2 cm in width) was observed on ultrasonography, we performed a CT-guided percutaneous kidney biopsy (Figure ).
Light microscopy revealed 24 glomeruli with nodular glomerulosclerosis accompanied by mild mesangial hypercellularity (Figure ), and immunofluorescence microscopy revealed exclusive deposition of κ chain along the glomerular basement membrane (Figure ). Congo red staining was negative. Electron microscopy revealed continuous powdery electron-dense deposits in the subendothelial area (Figure ), which supported the diagnosis of LCDD.
Serum immunofixation revealed a monoclonal IgG κ band with a free light chain (FLC) ratio of 289 (κ chain, 3180 mg/dL: λ chain, 11 mg/dL). Bone marrow biopsy showed 19% plasma cell infiltration by CD138 immunostaining. Flow cytometry showed that 8% of monoclonal plasma cells were restricted to the κ chain and were positive for CD56 and negative for CD19. No cytogenetic abnormalities were detected using fluorescence in situ hybridization. The final diagnosis was LCDD caused by multiple myeloma. The patient’s serum N-terminal pro-B-type natriuretic peptide level was 54.2 pg/mL (normal: 0-125 pg/mL) and troponin I level was 2.9 pg/mL (normal: 0-26 pg/mL). Transthoracic echocardiography revealed that the patient’s interventricular septum thickness was 9.9 mm, suggesting a lack of cardiac involvement. A liver biopsy was not performed because the patient did not consent. The patient was deemed ineligible for autologous hematopoietic cell transplantation because of nephrotic-range proteinuria. Treatment with bortezomib, cyclophosphamide, and dexamethasone, followed by weekly daratumumab (16 mg/kg), was initiated. Acyclovir and trimethoprim-sulfamethoxazole were added for prophylaxis. After a one-year follow-up, proteinuria levels declined from 7.5 to 0.3 g/day, hematuria resolved, serum creatinine level decreased from 1.59 to 1.21 mg/dL, and the difference between involved FLC and uninvolved FLC (dFLC) decreased from 3169 to 200 mg/dL. At the time of reporting this study, the patient had been taking daratumumab, bortezomib, cyclophosphamide, and dexamethasone with a very good partial response. No treatment-related adverse effects, including infections, cytopenia, and peripheral neuropathy, have been observed to date. We performed a serum FLC assay and 24-hour urine protein measurement to monitor the treatment response during monthly outpatient visits. We also performed liver function tests and N-terminal pro-B-type natriuretic peptide measurements every three months to evaluate the emergence of cardiac and hepatic manifestations.


A 49-year-old female with a history of untreated mood disorder, hypertension, alcohol, and tobacco abuse; presented to the emergency department (ED) with a three-month history of generalized body weakness. She also had a history of confusion, inadequate food and water intake, and progressively worsening jaundice. Her boyfriend reported she had been lying on the couch for several weeks, and she crawled to the bathroom as she was unable to ambulate due to unsteadiness, dizziness, and lower limb weakness. He reported that the patient chews Cannabidiol gum (CBD) and drinks one liter of rum and two cans of beer daily.
Her vitals in the ED were heart rate 93 bpm, respiratory rate 17 cpm, temp 36.6 degree C, SPO2 94%, BP 101/74 mmHg. Significant physical examination findings were scleral icterus, 4+ bilateral pitting pedal edema, abdominal distention with demonstrable ascites by fluid wave, bilateral intention tremors, rotary nystagmus, power 3/5 in both lower extremities, 1+ bilateral knee jerk, and absent ankle jerk bilaterally. Significant laboratory findings include moderate hyponatremia, hypokalemia, deranged liver function test, leukocytosis, and elevated lipase levels and ammonia (Table ). Abdominal ultrasound showed mild hepatomegaly with diffuse heterogenicity. Non-contrast CT of the brain and cervical spine were unremarkable. She received 100 ml/hour of normal saline infusion for five hours; a repeat serum sodium dropped to 124 mmol/L. The normal saline infusion was continued for 16 hours with an improvement in serum sodium to 130 meq/l within 24 hours of presentation. This patient had drainage of ascitic fluid and was treated with thiamine, folic acid, prednisone, lactulose, rifaximin, furosemide, spironolactone, and ceftriaxone with improvement in clinical and laboratory abnormalities.
Her lower limb weakness at presentation was attributed to deconditioning and possible alcohol myopathy, but her weakness persisted despite three weeks of physical therapy, necessitating further neurologic workup. Non-contrast brain MRI showed areas of hyperintensity within the posterior pons consistent with osmotic demyelination (Figure ), Lumbar spine MRI showed chronic T12 compression deformity, mild spinal stenosis, multifactorial central and left lateral L3/L4 and L4/L5 spinal stenosis, high grade left lateral L4/L5 foraminal stenosis (Figure ). She declined electromyography (EMG) but had normal Thyroid-stimulating hormone, Creatine Kinase, and Vitamin B12 level. The lowest serum sodium during hospitalization was 124 mmol/L, and the maximum rate of correction was 6 units in 24 hours. Her hyponatremia was attributed to hypovolemic hypoosmolar hyponatremia from poor oral intake, with some contribution from chronic alcohol use. At the time of discharge to a rehabilitation facility, her serum sodium was 132 mmol/L, but her leg weakness persisted.


A 14-year-old male with no chronic medical conditions presented in the Emergency Department with a five-day history of fever, fatigue, bilateral conjunctivitis, cervical lymphadenopathy, hand swelling, and a skin rash on his lateral parts of the body, groin, and both hands (Figures and ). Because the skin rashes were very prominent, the patient was at first admitted in the clinic of dermatology, and for seven days, he was treated with empirical antibiotics and corticosteroid therapy. He did not develop any significant lower respiratory symptoms. On the third day of being in hospital, his fever resolved and skin rashes began to resolute. On the seventh day of being in hospital, he developed right-side hemiplegia and aphasia. Brain MRI (Magnetic Resonance Imaging) and MRA (Magnetic Resonance Angiography) were conducted, showing brain ischemia on the terminal branches of the left medial cerebral artery (). As a result, the patient was admitted in our Clinic of Neurology for further evaluation and treatment.
His laboratory testing showed increased white blood cell count (WBC) 13 100/mm3 with increased granulocytes, normal hemoglobin and thrombocyte levels, elevated inflammatory markers (ESR 65 mm/min, CRP 85.1 mg/L), increased d-dimer (4.8 mcg FEU/ml), low albumin level (31.8 g/L), and normal transaminases, bilirubin, blood urea nitrogen, and creatinine level. The patient had mild pyuria (5–10 WBC/hpf), but there was no pathogen isolated in the urine culture. The lumbar puncture was performed showing slight increase of proteins (0.92 g/L) and no blood elements. A plain view chest radiograph showed no significant abnormalities. Electrocardiography showed normal sinus rhythm. Transthoracic echocardiography showed normal ejection fraction without coronary artery dilatation. Brain and neck Computed Tomography Angiography (CTA) was normal. However, on transcranial duplex ultrasound, a slight increase of the pulsatility index (PI = 1.18) was observed, suggesting distal resistance due to occlusion of the terminal arterial branches of the left medial cerebral artery (MCA). An autoimmunity panel screening was performed, and the results were negative.
Three weeks before symptom onset, the patients' mother had been confirmed with COVID-19 and displayed mild upper respiratory infection, but our patient was not tested at that time as he had not exhibited fever or any other symptoms of illness. After admission in our hospital, the nasopharyngeal SARS-CoV-2 PCR was negative but serological testing for COVID-19 showed increased IgG levels. Serological (IgM) screening for cytomegalovirus, toxoplasmosis, rubella, HIV, and herpes virus was negative.
KD was diagnosed when our patient met four out of five clinical criteria (generalized rash, peripheral extremity swelling, bilateral nonexudative conjunctivitis, and cervical lymphadenopathy) associated with more than five days of fever. Intravenous immunoglobulin (IVIG) (2 g/Kg) was administrated together with a low dose of aspirin therapy and methylprednisolone 40 mg twice daily. Within 48 hours, the patient improved significantly with near complete resolution of neurological symptoms, and he was able to speak and move, showing only discrete right-side hemiparesis (4/5 muscle strength). Prior to hospital discharge, two weeks later, complete blood count, coagulation profile, d-dimer, albumin level, and CRP were normalized. Also, ischemic changes on brain imaging were decreased (). On the follow-up visit, two weeks after hospital discharge, the patient continued to do well without recurring symptoms.


A 73-year-old male with a past medical history of metastatic uveal melanoma with liver metastasis, chronic kidney disease stage 3A, hypertension, type 2 diabetes, and hyperlipidemia presented with nausea, itchiness, and worsening confusion for three days. He had received his first dose of ipilimumab and nivolumab three weeks prior. He denied any chest pain, palpitations, abdominal pain, lightheadedness, anuria, and dysuria. The patient was seen at his nephrologist's clinic where laboratory data showed potassium of 8 mmol/L, creatinine of 2.7 mg/dl, glomerular filtration rate (GFR) of 2 mL/min/1.73 m, and ammonia level of 34 umol/L. Of note, the patient had a baseline creatinine of 3 gm/dl about one year prior to admission. He was directly admitted to the intensive care unit (ICU) for emergent dialysis. Urinalysis showed mild proteinuria of 200 mg/dl, urine glucose of 300 mg/dl, and was negative for nitrites, leukocyte esterase, and eosinophils. No urine casts were appreciated.
Upon admission to the intensive care unit (ICU), the patient’s vitals were stable, and he was started on appropriate hyperkalemic treatment consisting of calcium gluconate, polystyrene sulfonate, sodium bicarbonate, regular insulin, and dextrose. The nephrology service was consulted, and the patient was immediately started on oral prednisone 60 mg daily, as there was a strong suspicion of drug-induced nephropathy. A repeat basic metabolic panel (BMP) was repeated four hours later with no improvement. A triple lumen dialysis catheter was placed and the patient underwent emergent hemodialysis (HD).
A kidney biopsy was consistent with acute tubulointerstitial nephritis (ATIN) (Figure ). Throughout the rest of his hospitalization, he had received a total of six rounds of hemodialysis until his discharge one week later. His creatinine had decreased to 11.60 mg/dl and his eGFR improved mildly to 4 mL/min/1.73m2. He was instructed to complete a steroid taper, stop immunotherapy, and was recommended to continue indefinite HD by his nephrologist.


A 16-year-old male collapsed shortly after having refreshments and was taken to the Accident and Emergency department of the General Hospital, where cardiopulmonary resuscitation was instituted, but he died in spite of resuscitative attempts. He had no known medical condition or psychosocial problems. He attended secondary school, but because of the COVID-19 pandemic was tutoured at home via online video conferencing like all Secondary and Primary school children on the island. Neither he nor his family had been in contact with persons suffering with COVID-19.
An autopsy was compulsory.
The body was that of a well-nourished young male, 155 cm long, asthenic and of appearance consistent with the stated age. Lividity was on the back.
He had pink mucous membranes, was anicteric, and cyanosed at the nail beds. There was no edema, clubbing, lymphadenopathy, or abnormality of the skin and the musculoskeletal system.
The cranium was grossly unremarkable and also was the sagittal sinus. There were no extradural or subdural hematomas. There was vascular congestion of the meninges, and the vessels of the circle of Willis were structurally unremarkable. The brain weighed 1300 g (1440+/-30 g), was edematous and there was no other gross pathology of the brain even upon serial sectioning.
There were 30 mL of serous pericardial effusion. The coronaries were patent and originated from their respective ostia, and had no gross pathology. There was no thrombus of the atria. The heart valves circumferences were as follows: Mitral 9 cm (7.8+/-0.7 cm), Aortic 6.5 cm, (5.3+/- 0.4 cm), Tricuspid 10 cm, (9.9+/-0.9 cm) Pulmonary 5.4 cm (5.6+/-0.5cm). The left ventricle thickness was 1.0 cm, and the right ventricle 0.2 cm. There was no myocardial injury, present or remote. There was cardiomegaly 270 g (RR; 125-250 g).
The pulmonary arteries contained no thromboembolism. There were approximately 350 mL of serosanguinous pleural effusions in each pleural cavity. The larynx was structurally unremarkable, and there was hyperemia of the trachea. There was no foreign body within the tracheobronchial tree or tumor. The right lung weighed 770 g (455 g upper limit of normal), and the left lung 710 g (415 g upper limit of normal) and were markedly congested, edematous, and contained no area of consolidation.
There were no bite marks of the tongue; no chemical burns of the oropharynx, or esophagus. The stomach contained a clear, non-pungent fluid and there was no gastritis. The duodenum and the rest of the gastrointestinal tract were structurally unremarkable. There was free flow of bile. The liver weighed 1950 g (1523 g upper limit of normal), and had a focal area of sub-capsular hemorrhage, attributable to an injury obtained during resuscitative attempts. The rest of the liver was congested. The spleen weighed 200 g (RR; 150-200 g), was congested, and revealed no abnormality upon serial sectioning.
The kidneys each weighed 90 g (RR; right kidney 90-110 g, left kidney 98-112 g), had smooth cortical surfaces, and normal cortico-medullary junctions. The adrenals combined weight was 20 g (RR; 16-20 g), and were grossly unremarkable. The ureters and the urinary bladder were structurally unremarkable, with the latter containing 50 mL of amber-coloured urine.
The genitals were structurally unremarkable.
Nasopharyngeal swab testing for COVID 19 using PCR, performed after autopsy was positive.
Heart: There was idiopathic cardiomegaly with enlarged myocyte nuclei, some showing bizarre forms ().
Brain: The brain showed thrombotic microangiopathy (). In addition, medium sized vessels were thrombosed and showed a vasculitis with a moderate infiltrate of lymphocytes in the immediate perivascular region.
Lung: There was hyaline membrane, pulmonary edema, pulmonary hemorrhage and areas of interstitial pneumonia. Fibrin microthrombi were evident within alveoli capillaries, arterioles, and post capillary venules. In many areas, the fibrin thrombi were within the wall of capillaries, arterioles and venules in the sub-endothelial locations, but not within the lumen of these vessels (1D). Fibrin deposits were also observed in the adventitia of the large pulmonary vessels. These sites of fibrin deposition correspond with the locations of the pericytes in the vascular system.
Liver: There was a moderate infiltrate of lymphocytes within the portal triad ().
This COVID-19 case showed both the inflammatory and thrombotic responses to COVID-19 occurring in the lung and brain. This young male had idiopathic cardiomegaly and died in congestive cardiac failure, with superimposed COVID-19.


The deceased was an 84-year-old male with urinary retention due to benign prostatic hyperplasia and was managed with an indwelling Foley catheter. He had no other known medical illnesses. He was discovered dead at home in his bathroom. His family indicated that he was clinically well prior to his death. There was no history of diabetes mellitus, hypertension, recent travel, exposure to infectious persons, toxic agents, or any history of tobacco smoking or alcohol use. He dwelled in his home with his elderly wife and grandchildren.
A partial autopsy was performed.
The body was that of a well-preserved, elderly male, cyanosed at the nail beds, and with no external marks of violence or trauma. The mucous membranes were pale. A urinary catheter was in-situ.
The trachea and lower airways were hyperemic. There was no tumor or foreign bodies in the tracheobronchial tree. There were 50 mL and 30 mL of serous effusions in the right and left pleural cavities respectively. The left lung weighed 750 g (RR; 325-480 g) and the right lung, 860 g (RR; 360-570 g). They were congested and edematous. There was no hilar lymphadenopathy. There were areas of consolidation at the bases of all lobes of the right and left lungs. There was no evidence of pulmonary embolism.
The heart weighed 310 g (RR; 270-360 g). The valve circumferences and ventricular thicknesses were within normal limits.
The coronary arteries showed mild atherosclerotic disease with approximately 20% stenosis of the left anterior descending, circumflex and right coronary arteries.
The myocardium revealed no recent or old injuries.
The liver weighed 1100 g (RR; 1500-1800 g) and spleen 150 g (RR; 90+/-40 g), both appeared congested with no other macroscopic evidence of abnormality.
Both kidneys weighed 130 g respectively (RR; 313 g combined weight) and showed an ill definition of the cortico-medullary junctions and chronic pyelonephritis. The prostate was enlarged, with a prominent middle lobe, and the urinary bladder contained cloudy urine.
There was no injury to the scalp or the underlying skull bones. The brain was not examined.
COVID-19 Test on nasopharyngeal swab, done at autopsy using PCR was positive.
Lungs: This showed interstitial pneumonia. () Fibrin deposits were distributed throughout the alveoli microcirculation, within the subendothelial locations of capillaries, arterioles, venules, and the adventitia of large pulmonary vessels (344D).
Heart: This showed focal ischemic changes globally.
Kidney: There were microthrombi within glomerular tuft and interlobular arteries.
Liver: There was portal triaditis.
This elderly male died from COVID-19 with diffuse fibrin deposits within the alveolar microcirculation and the adventitia of the larger pulmonary vessels. The resultant hypoxia would have contributed to multiple organ failure.


A 63-year-old male with a past medical history of hypertension, hyperlipidemia, and diabetes presented to our hospital with bradycardia, hypothermia, and hypotension. On presentation, his temperature was 85.4°C, blood pressure (BP) was 80/61 mm Hg, respiratory rate was 18 breaths/minute, heart rate (HR) was 40 beats minute, and saturation was 92% on 6 L nasal cannula. On physical examination, he was slow to respond, but arousable to voice, without clear orientation, and had a Glasgow coma scale of 12. An electrocardiogram (EKG) showed bradycardia, incomplete right bundle branch block, and prolonged QTc interval of 621 msec (corrected by Hodges method due to bradycardia), as shown in Figure . His presenting fasting blood sugar was 91 mg/dL. The chest X-ray was unremarkable. The patient was immediately started on aggressive fluid resuscitation along with a dopamine drip. Atropine was pushed intravenously with no response. Keeping a high index of suspicion for myxedema coma based on his clinical presentation, he was started on levothyroxine 200 mcg and a stress dose of hydrocortisone 100 mg every eight hours. Thyroid-stimulating hormone (TSH), free thyroxine (free T4), and cortisol level were emergently ordered. External warming with blankets was provided. Initial labs revealed TSH of 0.172 µIU/mL (reference range: 0.465-4.68 µIU/mL), free T4 of 0.41 ng/dL (reference range: 0.78-2.13 ng/dL), and cortisol of 4.5 ug/dL (reference range: 4.5 -22.7 ug/dL). Six hours after initiation of treatment, there was the resolution of bradycardia (Figure ), prolonged QTc, and hypotension with HR of 68 beats/minute, QTc of 464 msec, and BP of 104/62 mm Hg.
Considering secondary hypothyroidism and hypocortisolism, further investigations for the possible central etiology were performed. Magnetic resonance imaging (MRI) revealed suprasellar mass measuring 2.5 x 2.2 x 2.0 cm with prominent T1 hyperintensity, abutting and uplifting the optic chiasma, findings compatible with hemorrhagic pituitary microadenoma (Figure ). Further laboratory investigations revealed decreased follicular stimulating, luteinizing, and growth hormone levels.
Once more arousable, the patient was further evaluated neurologically and did not have a visual impairment. Conservative management for pituitary apoplexy was considered with close neurological observation. Three months follow-up MRI revealed a reduction in the size of tumor and pituitary bleed, measuring as 2.1 x 1.9 x 1.8 cm (Figure ).


A 46-year-old otherwise healthy female presented to the clinic with complaints of progressive breast enlargement and pain over the past 3 months. Specifically, she described a more pronounced acutely developing enlargement of the right breast when compared to the left, associated with worsening discomfort and pain. Of note, the patient underwent bilateral augmentation mammoplasty using PAAG injections in China 18 years ago. She denied other associated symptoms such as fevers, chills, shortness of breath, or nipple discharge, as well as any new palpable breast masses or previous trauma to the breasts.
On physical examination, she was afebrile and well-appearing with stable vital signs. The patient had significant breast asymmetry, with the right breast markedly larger than left, as well as associated tenderness to palpation, enlargement of nipple areolar complex and presence of dilated superficial veins (). The right breast was noted to be more erythematous and warmer to touch when compared to the left. There were no palpable breast masses, axillary lymphadenopathy or inversion of the nipples.
Diagnostic work up included mammography and magnetic resonance imaging (MRI) of bilateral breasts. Mammography demonstrated presence of breast implants with extensive fibrous capsule discontinuity, suspicious for foci of intracapsular rupture that were more pronounced on the right. There was an air-fluid level within the implant of the right breast, representative of an extracapsular rupture which likely accounted for the size discrepancy between the breasts. MRI demonstrated diffuse nodular thickening of both capsules surrounding the PAAG implants, which was associated with mural nodules with nonvascularized finger-like projections ranging in size from 3 mm to 1.4 cm. Although these findings were benign, the patients acute breast enlargement, pain and evidence of extracapsular rupture with extravasation warranted surgical management.
The decision was made to proceed with removal of polyacrylamide containing capsules followed by immediate breast reconstruction. Wide inframammary fold incisions were used for completion of nipple-sparing mastectomy and en bloc capsulectomy in order to remove PAAG containing breast capsules as completely as possible. Copious wound irrigation using pulse lavage was performed to minimize presence of polyacrylamide particles. Intraoperative findings demonstrated bilateral breast capsules that had extensive fibrotic scar tissue and were filled with large amounts of porridge-like PAAG with moderate, diffuse infiltration into breast tissue (). The capsules were subsequently sent for pathological analysis.
The patient underwent immediate breast reconstruction using prepectoral tissue expander placement utilizing two subcutaneous drains per breast. She had an uncomplicated postoperative course and was discharged home on postoperative Day 1.
Gross pathologic examination of breast specimens demonstrated presence of pink-tan colored membranous tissue, consistent with fibrotic capsular tissue intermixed with polymers of polyacrylamide. Microscopic examination demonstrated presence of benign breast tissue with fibrosis, foreign body giant cells and chronic inflammatory cells. There was extensive purple, gelatin-like material which represented the presence of polyacrylamide hydrogel ().


The patient is a 73-year-old man of Finnish ethnicity with onset of diabetes, considered T2D, at the age of 30. He has a mild sensory diabetic neuropathy and moderate bilateral retinopathy. At diagnosis, he was started on metformin and approximately 20 years later insulin was added. For unknown reasons, he was never on sulfonylureas.
Strikingly many relatives on the maternal side have/had diabetes of a type-2-like form, which resulted in the patient being diagnosed with hepatocyte nuclear factor 1-alpha (HNF1A)-MODY in 2016 and being referred from primary care to our hospital for specialist care. Also the patient's daughter is heterozygous for the pathogenic mutation HNF1A:c.872dupC,p. Gly292ARgfs*25, which is the same mutation the father carries.
The patient also has a well-controlled hypertension and a chronic normocytic anemia, and has stented a left-sided renal artery stenosis. His BMI was 27 kg/m2.
His medication consisted at first visit of NovoMix 30 in a dose of 25 U b.i.d. (0.62 U/kg), metformin 850 mg b.i.d., acetyl salicylic acid 75 mg q.d., doxazosin 4 mg q.d., metoprolol 50 mg b.i.d., felodipine 10 mg q.d., and losartan 100 mg q.d. The patient's HbA1c was 56 mmol/mol (7.3% DCCT), and—surprisingly—he had positive titers of IgG antibodies against the β-cell antigen GAD-65 (449 U/mL [ref. <5]) but not against the IA-2 antigen. The patient's endogenous insulin production was suboptimal as the level of C-peptide only increased from 0.22 to 0.33 nmol/L (0.66-1.0 ng/mL) after meal stimulation.
The autoimmunity was discovered more or less by chance; the junior resident at the hospital outpatient clinic ordering the laboratory work up being oblivious of the view that MODY patients by definition do not have diabetes-associated antibodies.
The patient was started on dulaglutide 1.5 mg q.w., an agonist for the glucagon-like peptide 1 (GLP-1) receptor with potent antidiabetic effects. Glucagon-like peptide 1 has also potentially trophic and antiapoptotic effects on β-cells (at least in animal models and in human β-cells ex vivo) and improves β-cell glucose sensitivity without risk of hypoglycemia or weight gain. Glucagon-like peptide 1-based therapy has been shown to work well in HNF1A-MODY., , The classic treatment of HNF1A-MODY, however, has for many years been sulfonylurea drugs, also with good results but with a risk of hypoglycemia and weight gain. The patient's insulin regimen was maintained because of his low C-peptide levels, while metformin was discontinued. Four months later, the patient's HbA1c, body weight, and insulin dose were largely unchanged. The combination tablet Synjardy (empagliflozin 5 mg + metformin 850 mg) b.i.d. was added to improve glycemia and 3 months later the HbA1c was 49 mmol/mol (6.6% DCCT).
The patient's daughter with HNF1A-MODY was, unlike her father, negative for autoantibodies to GAD-65, IA-2, ZnT8, ICA and insulin. The patient himself was not tested for autoantibodies to ZnT8, ICA and insulin.
Patients with HNF1A-MODY have an increased risk of adenomatosis of the liver. However, ultrasound examination of the liver showed no abnormality.


After a mass was detected in the gynecological examination of the 40-year-old female patient who had presented with bleeding after sexual intercourse, dyspareunia, and watery vaginal discharge, and who had a history of 3 healthy normal vaginal births, a specimen for biopsy was obtained from the mass. The pathology was reported as cervical squamous type nonkeratinizing carcinoma, and the patient was referred to our tertiary hospital for advanced tests and treatment. The patient had no complaints other than postcoital bleeding, dyspareunia, and watery vaginal discharge with a foul odor. The gynecological examination revealed a normal vulva and vagina consistent with age; however, speculum examination revealed a massive lesion approximately 2 cm in size with irregular borders and fragile bleeding outside the transformation zone on the upper pole of the uterine cervix. The uterus was normal on ultrasound examination, and the ovaries and tubas had normal anatomical structure bilaterally. However, transvaginal ultrasonography revealed a normal uterine canal and a massive lesion of approximately 16 × 17 mm with irregular borders on the anterior surface of the uterine cervix that did not extend into the endocervical canal. A colposcopic examination was performed to obtain biopsy samples. The biopsies that had been carried out from the uterine cervical mass in another center also underwent the consultation of our hospital's pathology department. As a result of the pathological examination, CD 20-positive high-grade B-cell lymphoma infiltration was determined. In the immunochemical examination of the preparations, the neoplastic cells were CD20, LCA and vimentin-positive, and CD3, CEA, P63, CD56, and Pan-CK negative (Figures and ). The positron emission tomography (PET-CT) performed while waiting for the patient's pathology results revealed a right inferior jugular hypermetabolic millimetric lymph node with intense FDG uptake, hypometabolic in the center with hypermetabolic surroundings in the middle of the cervix, multiple hypermetabolic areas in the corpus uteri, multiple hypermetabolic lymph nodes in the abdomen, increased FDG uptake in the lesions close to the antral region of the small curvature of the stomach wall and fundus, intense FDG uptake in the liver areas that appeared hypodense, focal increased FDG uptake in the areas of filling defects in the bowel loops of the abdomen, and increased FDG uptake in the lytic areas observed in the left acetabulum, left femoral head, and the anterior end of the left first rib. After the imaging and the pathology studies, the medical oncology department administered systemic rituximab, cyclophosphamide, vincristine, and prednisone (R-CHOP) chemotherapy and radiotherapy to the right humerus and the pelvic region. The control PET-CT performed 4 months later revealed low FDG uptake in the lytic area observed in the right humerus head and a nonmetabolic millimetric nodule in the superior of the left lung lower lobe, and this was reported as findings consistent with the response to treatment. In the comparative PET-CT repeated 6 months later, the lytic hypermetabolic area in the right humerus head remained unchanged, no pathological lymph node involvement was observed, and complete cure was seen to have been achieved after chemotherapy treatments. It was also observed that the cervix uteri lesion in the case had regressed and the complaints had resolved.


A 56-year-old man weighing 102 kg and 188 cm tall (Figure ) was referred to our hospital because of an evident thickening around the neck. He had had the enlargement for the last 10 years and lately, the condition worsened. He was also a heavy alcohol drinker for the last 30 years and had 50 pack-years of smoking upon presentation. He was employed as a farmer and construction worker and had never demanded health care for his condition in the past.
More specifically, during the last 3 years, the enlargement became a collar-like mass around the neck and dyspnea crises with cough and upper airway excretions appeared, especially when bending the neck. He was relieved after some minutes of neck extension. The patient reported progressive difficulty sleeping due to extensive bulk of the mass, while he never had a problem of snoring, sleep deprivation, or other sleep apnea-associated symptoms. Additionally, he complained of weakness and chronic fatigue during these last years. The mass presented with cervical pain upon weight lifting, while he did not have any signs of neuropathy.
He referred a known history of hypertension with frequent hypertensive crises with systolic blood pressures of 220-230 mm Hg after heavy drinking, for which he used an angiotensin II receptor blocker (ARB) and hydrochlorothiazide and was usually referred to the local hospital. The cardiac assessment was normal. He had suffered from hypothyroidism for the last 15 years.
Upon examination, he had a circular mass of the neck, semi-hard on the anterior and hard on the posterior in a double oval-shaped configuration. The mass was not fixed to the overlying skin. His articulation was disturbed, and he had stridor while bending the head. Interestingly enough, we noticed that his legs and arms had lipohypertrophic along with lipoatrophic areas and that his supraclavicular regions were hypertrophic. The identification of the “pseudoathletic” type of Madelung's disease (type I), and hence, the diagnosis was delayed because the patient's physique was attributed to his occupation as a construction worker. Neurological examination was normal.
High values of uric acid, cholesterol, triglycerides, CPK, and LDH were reported. A slight elevation of SGOT along with a double γ-GT price was compatible with alcohol abuse.
A facial, cervical, and thoracic computed tomography (CT) showed a bilateral and symmetrical fat mass of the posterior and anterior region of the neck and of the upper trunk, without displacement or infiltration of the trachea (Figure ). Based on these findings, the diagnosis of Madelung's disease was made and we decided to treat the patient surgically.
Two different operations took place. In the first one, orotracheal intubation was impossible, so nasotracheal intubation was performed. A Gluck-Sorenson incision was performed, and fat tissue was excised in a similar fashion as in bilateral functional lymph node neck dissection with preservation of the accessory and marginal and cervical branches of the facial nerves. More specifically, we dissected levels I-V on the right side and levels I-VI on the left side. The dissection of the tissue in the carotid triangles was laborious (the fat tissue had septa that extended between the structures). The excised specimen's size was 27 × 12 × 18 cm, and its weight was 627 g (Figure ). A tracheostomy was performed before completion.
In the second operation, which took place 3 weeks later, the patient was placed in a prone position. The fat masses of the cervical, occipital, suboccipital, retro-auricular, and upper dorsal regions were removed surgically and with liposuction. The weight of the fat tissue was 114gram. We continued with removing the fat mass from the upper anterior cervical region. Part of the skin was removed because of its excess. The tracheostomy from the first operation remained and was finally removed 6 days after the second operation.
Histological examination after both the operations confirmed the initial diagnosis.
During the next 6 months, we suggested the use of a soft collar because we desired extra tension of the musculocutaneous tissue over the neck triangles for better healing. The patient did not follow our orders for alcohol abstinence.
In Figure , we can see the final result three months later.


A 70-year-old Chinese female non-smoker with no family history of cancer suffered from repeated coughing for more than 10 days in October 2018. Computed tomography (CT) of the chest revealed a 5.1 × 3.6 cm density mass in the dorsal segment of the lower left lung (). Magnetic resonance imaging (MRI) scans showed that there were no metastases in the brain (). The level of the serum tumor biomarker, carcinoembryonic antigen (CEA), was 16.27 ng/mL, which was much higher than the normal range of < 5.0 ng/mL (). Immunohistochemical analyses revealed that the tumor cells of the left lung were positive for thyroid transcription factor-1 (TTF-1) and Napsin A, whereas focal staining was positive for CK5/6 (data not shown). Based on those data, the patient was diagnosed with stage II lung adenocarcinoma (cT3N0M0 of TNM staging system), and was recommended surgical treatment according to the National Comprehensive Cancer Network Guidelines. However, the lung lesion was tightly connected to great vessels, and thus, could not be completely removed by surgery. To identify a more effective treatment, a left lung biopsy was subjected to genetic testing of fourteen lung cancer-related genes using next-generation sequencing (NGS). A rare EGFR exon 18 mutation (p.E709_T710delinsD) was identified with a mutant allele frequency (MAF) of 74.8%, and accompanied by EGFR amplification and a TP53 p.M246_T256del mutation ( and ).
In consideration of the patient’s age and physical condition, the patient and her family refused radiotherapy and chemotherapy. Rather, the second-generation EGFR TKI, afatinib, was administered as a once-daily oral dose of 30 mg in November 2018. One month post treatment, a partial response (PR) was achieved with lesion shrinkage in the left lung according to the RECIST response criteria, and the serum CEA level returned to normal (4.58 ng/mL, ). Seven months after afatinib treatment, the left lung tumor volume was further reduced, accompanied by a stable CEA level (6.87 ng/mL, ). The lung lesion was re-evaluated using CT scans in December 2019 and revealed an increased tumor size (). The serum CEA level (15.80 ng/mL) was also elevated at that time (). However, the patient exhibited a stable disease (SD) according to RECIST response criteria. In March 2020, CT scans revealed no marked enlargement of the lesion, while the CEA level was markedly elevated (32.05 ng/mL, ). In spite of the SD that was maintained during this period, the possibility of slow progress was not ruled out. In the case of remission and with no obvious adverse reactions, the patient continued to be treated with afatinib until September 2020. At that time, there was no metastasis in the brain, but the target lesion in the lower left lung increased with a concomitant increase in CEA levels (45.80 ng/mL), thus, indicating progressive disease (PD) ().
After the development of afatinib-resistance, another tumor biopsy was collected and subjected to NGS-based genetic testing of 425 cancer-related genes. The results revealed that the MAF of the EGFR E709_T710delinsD mutation increased from 74.8% to 87.4% (). The patient was then switched to a third-generation EGFR TKI, almonertinib, with a once-daily oral dose of 80 mg, as it was thought to impart fewer adverse effects than osimertinib. In January 2021, although the lesion in the left lung was slightly enlarged and serum CEA levels (49.81 ng/mL) were higher than those in September 2020 (), the patient was considered as SD under the RECIST response criteria. Until February 2021, the patient was still receiving almonertinib treatment.


In August 2017, a 38-year-old man, former smoker, with cervical pain irradiated to the thorax left side underwent a computerized tomography (CT) scan evaluation, showing bone metastases in multiple vertebras and left pleural effusion. Thorax and abdomen CT scan, brain Magnetic Resonance Imaging (MRI), and 18-fluorodeoxyglucose positron emission tomography (PET) demonstrated a 3 cm tumor of the left lung inferior lobe with metastatic lymph nodes of the pulmonary hilum and homolateral mediastinum. Metastases were present in liver (3 lesions), right adrenal gland, multiple bone locations and brain (multiple sites). A diagnosis of cT1cN2M1c, stage IVc lung adenocarcinoma was made.
The tumor was characterized by immunohistochemical (IHC) stain on cell-block from pleural effusion with anti-thyroid transcription factor (TTF-1) antibody (mouse monoclonal antibody; clone 8G7G3/1; Ventana Medical System - Roche, Monza, Italy), which showed a strong positive nuclear staining (). The evaluation of the mutational status of EGFR, KRAS proto-oncogene, GTPase (KRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and erb-b2 receptor tyrosine kinase 2 (HER2) genes was performed on the Sequenom MassArray platform using the Myriapod Lung Status kit (Diatech Pharmacogenetics, Jesi, Italy). Before DNA extraction and purification by the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany), tissue enrichment for cancer cells was performed by manual macrodissection. The expression of CD274 molecule (PD-L1) and ALK receptor tyrosine kinase (ALK) was determined by IHC on the Ventana Medical System (Roche). The monoclonal primary antibody SP263 clone and the monoclonal primary antibody D5F3 clone were used for PD-L1 and ALK, respectively. The presence of gene fusions involving ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) (Break Probe ROS1 (6q22) Kreatech - Leica Biosystems, Amsterdam, Netherlands) and ret proto-oncogene (RET) (Break Probe RET (10q11) Kreatech - Leica Biosystems) was evaluated by fluorescence in situ hybridization (FISH). FISH tests were executed also to analyze the amplification of MET proto-oncogene, receptor tyrosine kinase (MET) (Probes: LSI MET spectrum red and CEP7 spectrum green – Vysis - Abbott, Illinois, USA) and HER2 (Probes: LSI HER2/neu spectrum orange and CEP17 spectrum green – Vysis, Abbott).
The sensitive EGFR mutation L858R, within exon 21, was detected and 10% of cancer cells expressed PD-L1 (). No other gene alterations were identified.
In September 2017, erlotinib treatment was started (150 mg/die) with zoledronate (4 mg every 28 days). In October, the patient completed the palliative radiotherapy on vertebral metastases of D9-11 (20 Gy in 10 fractions). After 2 months of treatment a partial response (PR) was observed with reduction of all disease localizations. EGFR mutational status in circulating tumor DNA (ctDNA) was evaluated every 3 months (). ctDNA was purified from 3 ml of plasma by the QIAamp Circulating kit (Qiagen) and EGFR was analyzed by the digital droplet PCR (Bio-Rad, Hercules, California, USA) with the PrimePCR™ ddPCR™ Mutation Assay for human EGFR. In January 2018, erlotinib dosage was reduced to 100 mg because of a grade 3 skin rush of the face, truncus and extremities (National Cancer Institute – Common Terminology Criteria for Adverse Events). The CT scan confirmed the PR and the ctDNA analysis highlighted a decrease of L858R amount ( and ).
In May 2018, the patient presented with dyspnea and left hemithorax pain. A chest X-ray showed massive pleural effusion, an ultrasound-guided thoracentesis was performed. Tumor cells were not detected in the effusion, but ctDNA analysis revealed an increased L858R amount (). The radiological response was maintained until August 2018, when a CT scan documented a pleural metastasis enlargement with pleural effusion. MRI of liver metastasis and brain demonstrated an enlargement of the left prerolandic metastasis and disease meningeal diffusion. An ultrasound-guided thoracentesis was performed with a diagnosis of adenocarcinoma metastasis, TTF1 positive (). Cell-block from pleural effusion had a low percentage of tumor cells (<5%) and EGFR mutational status was evaluated by the same highly sensitive droplet PCR assay used for ctDNA analysis. On the pleural effusion only the L858R mutation was detected, whereas L858R sensitive and T790M resistance EGFR mutations were both detected on ctDNA. Therefore, in August 2018, the treatment was switched to osimertinib. However, the patient experienced thoracic pain and in October 2018 a CT scan demonstrated an oligoprogression of a sternal bone metastasis. A biopsy of the lesion showed a histological switch towards squamous cell carcinoma positive for tumor protein p63 (p40) (IHC was performed using a mouse monoclonal antibody, clone BC28, on the Ventana Medical System - Roche) and negative for TTF1, with PD-L1 expression observed in 60% of cancer cells (). MET amplification (MET/CEP7: 5,8 - cut-off<2; MET copy number: 16,6 – cut-off<5) and EGFR L858R mutation were detected on the squamous lesion (). The MRI showed the disappearance of brain metastases, and T790M mutation was no longer detectable in ctDNA, but the L858R amount increased. At the same time the ctDNA was analyzed also by Next Generation Sequencing (NGS) using the 56G Oncopanel (Diatech Pharmacogenetics) on a MiSeq platform (Illumina, San Diego, California, USA): the L858R mutation was confirmed (4.14 allele frequency) and a missense mutation, the S215R (4.73 allele frequency), within exon 6 of tumor protein p53 (TP53) gene was detected. The TP53 mutation was confirmed both on the first pleural effusion and on the squamous lesion specimens. The patient underwent radiotherapy for the sternal metastasis, he experienced a pulmonary embolism with type I respiratory failure, and he received low molecular weight heparin with progressive recovery of the respiratory failure. Osimertinib was continued with a stable disease until December 2018. The ctDNA analysis found an increased L858R amount, in January 2019 the patient expedited a severe headache with retro-orbital pain and a skull CT scan showed a large secondary cranio-facial lesion, treated with radiotherapy (30Gy, 5 fractions). In March 2019, the patient showed neurologic and clinical deterioration without radiologic evidence of encephalic disease progression. A CT scan demonstrated an increase of the sternal metastasis infiltrating the surrounding soft tissues and an enlargement of liver metastases. The patient discontinued osimertinib, and, being not eligible for a systemic chemotherapy, died in April 2019.


A 49-year-old female with no significant past medical history presented to her primary care physician with a chief complaint of a two-month history of an enlarging mass on her right buttock and discomfort with sitting. The patient denied additional symptoms, including weight loss, fever, and chills. Physical examination revealed a large mass on the right posterior buttock and hip that was mildly tender to palpation. Computed tomography (CT) scan of the right hip was subsequently obtained, which revealed an 8 × 8 × 10 cm3 necrotic mass involving the gluteus maximus with preserved fat planes. She was then referred to orthopedic oncology, which recommended magnetic resonance imaging (MRI) and open biopsy. The MRI two weeks after the initial CT scan revealed a large infiltrating soft tissue mass with central necrosis and thick peripheral rim enhancement within the right gluteus maximus, measuring approximately 10 × 10 × 8.5 cm3 with minimal preservation of fat planes (Figure ).
She then underwent open biopsy with pathology revealing high-grade malignancy composed of very atypical epithelioid and spindle cells. The spindle cells were arranged in vague fascicles and showed significant nuclear pleomorphism. Epithelioid cells had clear to eosinophilic cytoplasm and were arranged in nests surrounded by thin capillaries. Neoplastic cells were positive for smooth muscle actin, MART1, EMA, and CD99 immunostains, while negative for WT1, desmin, AE1/3, p63, EMA, CD34, HMB45, GFAP, S100, and SOX10. ERG was patchy positive. Retained nuclear expression was also seen on the INT1 immunostains.
Staging positron emission tomography (PET)/CT scan revealed a small opacity in the left upper lobe of the lung, adjacent to the aortic arch, measuring 8 mm with a max SUV 2.6. There was also a note of the primary tumor in the right gluteus maximus was highly 18F-fluorodeoxyglucose (FDG)-avid with a maximum SUV 17.3. The PET interpretation suggested possible inflammatory findings in the lung and treatment proceeded for the primary disease site.
Due to concern for margin status and proximity of the tumor to the sacral nerve, the patient was treated with neoadjuvant external beam radiation therapy of the primary tumor with 50 Gy delivered in 25 fractions (Figure ).
Three weeks after completion of pre-operative radiation therapy, MRI demonstrated T1 hyperintensity with internal debris/septations likely representing internal hemorrhage. The lesion mildly protruded through the sciatic foramen with mass effect, without invasion of the sciatic nerve, adductors, and proximal hamstring musculature without evidence of invasion or nerve enhancement. No adjacent osseous erosion or enhancement was identified. Overall, the mass was noted to have slightly increased in size, measuring 10.6 × 9.6 × 11.1 cm3.
She underwent uncomplicated surgical resection with radical resection of the soft tissue mass four weeks following the completion of radiation. The final pathology was consistent with the pre-operative pathology from the open biopsy and confirmed malignant perivascular epithelioid cell tumor (PEComa), measuring 11.7 cm. Histologically, the tumor was comprised of areas with nested cells with pleomorphic round nuclei without prominent nucleoli and clear to finely granular pink cytoplasm as well as larger areas showing markedly pleomorphic nuclei with abundant mitoses. Perivascular growth is present in the original biopsy. Necrosis was present over approximately 50% of the biopsy specimen. Immunohistochemical stains showed the tumor to be positive for the melanocytic marker MART-1, HMB45, and a smooth muscle marker (smooth muscle actin), while negative for other melanocytic markers, including SOX-10 and S100, and a muscle marker (desmin). Overall, it was determined to be a poorly differentiated high-grade pleomorphic sarcoma, but the combination of myomelanocytic immunohistochemical markers as well as the morphology in the lower grade areas confirmed a diagnosis of malignant PEComa, and the findings were consistent with Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 3 disease.
The margins were negative, with the lateral margin (at femur) closest at 1 mm and the deep margin (at sciatic nerve) 2 mm. The proximal margin was 4 mm with all remaining margins >1 cm. She recovered well post-operatively with only mild paresthesia in the area of the surgery.
Repeat imaging with CT chest/abdomen/pelvis two weeks post-operatively revealed enlargement of the previously seen left upper lobe nodule with interval development of multiple diffuse bilateral lung nodules. There was further progression on an outside CT angiogram performed a month later when she presented with increasing dyspnea and hemoptysis. She was seen by hematology/oncology, which recommended systemic chemotherapy with the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus due to metastatic disease, which was initiated once she recovered from a prolonged hospitalization.
Interval surveillance imaging revealed mixed response with substantial improvement in the intrathoracic disease burden, but the progression of disease elsewhere with new evidence of hepatic and osseous metastases with disease located in the T10 vertebral body and in the right sacrum. Outpatient MRI was ordered; however, prior to being performed, she was presented to the emergency department with acute onset of pain in the sacrum after bending down. MRI of the spine revealed new compression fractures at T10 and L4. She underwent corpectomy and kyphoplasty at L4 with radiofrequency tumor ablation and T9-T11 laminectomy with tumor resection.
After recovery from her surgery, she was recommended to undergo postoperative radiotherapy to the two sites in her spine and change therapy to Gemcitabine/Docetaxel; however, she sought an opinion at an outside institution, at which it was recommended to continue the mTOR inhibitor without postoperative radiation. Two months later, she developed severe back pain, and an MRI of the thoracic and lumbar spine revealed recurrent disease at T10 and L5 with the overall progression of the disease. The patient decided to continue seeking care at an outside institution and was therefore lost to follow-up.


A 36-year-old Cantonese-speaking female presented to our institute with a history of intermittent palpitations and dizziness for two days. Her ECG showed prolonged QTc (481 ms) with symmetric T wave inversions in the right precordial leads (V1-V3) (Figure ). Troponin level was positive at 0.054 ng/mL. She had a similar episode of sudden-onset spontaneous palpitations, which were presumed to be associated with fear and anxiety a month earlier. At that time, she was evaluated in the psychiatry emergency room for generalized anxiety disorder and discharged. There was no known family history of sudden cardiac deaths or strokes. She started to self-monitor using her apple smartwatch (Series 3). However, she could not find anything abnormal whenever she felt palpitations. She then started to use a pulse oximeter at home to monitor her symptoms. Her pulse oximeter showed a heart rate (HR) of more than 200 beats/min during an episode of palpitations and uneasiness in her chest. She went to the hospital with a video showing an HR of more than 200 beats/min (Video ).
Telemetry monitoring showed no abnormalities. Her transthoracic echocardiogram showed dilated and reduced systolic function of the right ventricle (RV) with an apical echogenic tissue and abnormal RV free wall motion. We scheduled her for cardiac magnetic resonance imaging (CMRI) and discharged her with an ambulatory 30-day event monitor. Two days after her discharge, she presented again to the emergency room with shortness of breath and palpitations that started while bending to lift a heavy object. She denied excess caffeine intake, syncope, chest pain, or recreational drug usage. Her ECG showed wide complex VT with a rate of more than 200 beats/min (Figure ). Labs were notable for positive troponin 0.016 ng/mL, pro B-type natriuretic peptide 143 pg/mL, lactate of 2.8 mmol/L, Mg 1.7 mEq/L, and Hg 11.2 g/dL (mean corpuscular volume 82 fL). Her rhythm converted to normal sinus rhythm with 50 mg of oral metoprolol and 2 g of intravenous magnesium. Her CMRI showed dilatation of RV with moderately decreased systolic function and multiple areas of thinning and severe hypokinesis of RV with extensive fibrosis and fibro-fatty infiltration, which were consistent with ARVD (Figures , ). Some areas of fibrosis in the left ventricle wall were also noted. Ejection of RV was 34%. Due to multiple episodes of non-sustained VT on 30-day cardiac event monitoring, metoprolol was discontinued, and the patient was started on sotalol. An electrophysiology consult was requested for the placement of an automatic implantable cardioverter defibrillator (AICD).
The patient was monitored with telemetry for two days after placing AICD. Telemetry revealed predominantly normal sinus rhythm with occasional premature ventricular contractions of two dominant morphologies and multiple runs of non-sustained VT. Genetic testing showed missense mutations in DSG2 and SCN5A genes associated with the autosomal-dominant version of ARVD.


The patient was a 52-year-old woman who complained of a pulmonary infection caused by M. simiae infection that lasted for the past two years. After treatment with clarithromycin, ethambutol, and ciprofloxacin, the patient successfully was recovered, and the symptoms of pulmonary infection were disappeared, and the results of the computed tomographic (CT) scan were normal.
For two days, she had close contact with a COVID-19 patient, and the symptoms, such as fever, dry cough, headache, tiredness, diarrhea, and loss of taste or smell, appeared after one week. The oxygen saturation was 96% in ambient air, and the COVID-19 real-time PCR test using nasopharyngeal swab was positive with normal CT scan. The patient was sent home and treated conservatively. After 20 days, all her symptoms were improved, and the result of real-time PCR for COVID-19 was negative.
After 25 days of COVID-19 recovery, she complained of pulmonary infection. The physician assumed the recurrence of COVID-19 infection, but the real-time PCR was negative for COVID-19 infection. The CT scan indicated bronchiectasis, consolidation, nodular lesions, and infiltration in the left lung with a degree of atelectatic changes. All clinical parameters were normal, except erythrocyte sedimentation rate (ESR) (82 mm/h) and C-reactive protein (CRP) rate (85.1 mg/L). Her symptoms were fever, sputum, night sweats, productive cough, weight loss, and dyspnea.
The three sputum samples were sent to the Pasteur Institute of Iran in October 2020 to evaluate the presence of mycobacterial infection. The smear test indicated acid-fast bacilli (AFB) in all three sputum samples. The results of culture after five weeks revealed slowly-growing mycobacteria with smooth, small, and non-pigmented colonies, when exposed to light, turned into yellow colonies.
The multilocus sequence analysis was also performed using full 16S rRNA gene and partial rpoB/hsp65 genes, as described previously , . The results of gene sequencing showed 100% homology to M. simiae.
The susceptibility testing was performed according to the Clinical & Laboratory Standards Institute (CLSI) guidelines for clarithromycin, amikacin, ethambutol, moxifloxacin, ciprofloxacin, trimethoprim/sulfamethoxazole (TMP/SMX), streptomycin, isoniazid, ethambutol, levofloxacin, rifampin, rifabutin, and linezolid . The results indicated that the isolate was extremely susceptible to amikacin, levofloxacin, and clarithromycin. Based on the susceptibility data, the patient was treating of levofloxacin, clarithromycin, and amikacin. After three month of treatment, the rate of CRP and ESR were normal and the general condition of the patient is very good and the symptoms of the disease almost improved.


A 73-year-old female with no significant medical history presented to the pulmonary clinic for dyspnea on exertion, gradually worsening over one year. She endorsed generalized weakness and frequent falls. She denied cough, fever, night sweats, or weight loss. On physical examination, she was afebrile with a heart rate of 81 beats/minute, blood pressure 141/86 mmHg, respiratory rate of 16 breaths/minute. Oxygen saturation was 99% on room air. Lung sounds were clear to auscultation. Mild bilateral upper extremity weakness and ataxic gait were noted. Reflexes were brisk in the upper and lower extremities, and the Romberg test was positive.
An extensive cardiac workup was nondiagnostic before referral to the pulmonary clinic, including echocardiography with preserved ejection fraction and normal stress test.
Pulmonary function test (PFT) (Figure ) revealed a severe restrictive pattern and mildly reduced diffusing capacity of the lungs for carbon monoxide (DLCO).
CT scan of the chest showed no evidence of parenchymal lung disease. The workup for connective tissue disease and hypersensitivity pneumonitis was unremarkable. The remarkable laboratory results are summarized in Table .
Serology was positive for myasthenia gravis (MG). Electromyography and nerve conduction velocity showed a decrement in repetitive stimulation, but it was not detected until 10 minutes post-exercise. The patient was started on pyridostigmine, azathioprine, and prednisone to manage seropositive MG. Her MG medication doses were increased over three months, but her symptoms, especially dyspnea and generalized weakness, did not improve. Intravenous immunoglobulin therapy was started, and fortunately patient had a dramatic response with the first session. The patient reported relief from shortness of breath and weakness. She is currently co-managed by the neurology and pulmonology clinic.


A 17-year-old female presented with a history of pain in the left upper limb, headache, and New York Heart Association (NYHA) grade 2 breathlessness for 1 year. On examination, the left radial and brachial pulses were feeble. Blood pressure in the left upper limb was 150/90 mmHg and in the right upper limb was 170/100 mmHg. Cardiac auscultation was unremarkable. The patient underwent a CTA which showed left subclavian stenosis in the proximal and mid regions with dissection, as well as stenosis of the suprarenal abdominal aorta. Serum erythrocyte sedimentation rate (ESR) was 82 mm/hour (Westergren’s method). The patient had two positive major criteria of classical symptoms and left mid subclavian CTA lesion, thus satisfying the criteria for diagnosis of TA proposed by Sharma et al. []. On transthoracic echocardiography, the left ventricle (LV) was normal-sized with normal wall thickness. There was mild global LV hypokinesia. The LV ejection fraction (EF) was 43% by Simpson’s biplane method (Figure ). This was correlated with the motion-mode method and visually (Figure , Video ). On examination in the suprasternal window using color Doppler, turbulence and double barrel appearance were noted in the left subclavian artery just distal to its origin from the aortic arch with a peak systolic velocity of 2.2 m/s and a peak gradient of 22 mmHg (Figure , Video ). On examination in the subcostal window on color Doppler, narrowing and turbulence were noted in the suprarenal abdominal aorta with a peak gradient of 54 mmHg (Figures , , Video ). These findings were suggestive of subclavian stenosis with dissection and stenosis of the abdominal aorta.


A 38-year-old female presented with palpitations and NYHA grade 2 breathlessness for three weeks. On cardiac auscultation, a loud end-diastolic murmur with a tambour-like quality was heard in the third left interspace. Blood pressure in both upper limbs was about 180/100 mmHg. The LV apex was hyperkinetic and present in the fifth intercostal space near the mid-clavicular line. The patient underwent a CTA which showed dilation of the ascending aorta with a dissection flap. Further, there was stenosis in the suprarenal abdominal aorta. The ESR was 42 mm/hour (Westergren’s method). The patient had one positive major criterion of classical symptoms and four positive minor criteria of high ESR, aortic regurgitation, abdominal aorta lesion, and hypertension. These satisfied the conditions for the diagnosis of TA as per the criteria by Sharma et al. []. On transthoracic echocardiography, the LV was normal-sized, with normal EF and mild pericardial effusion (Figure , Video ). Based on the values of LV cavity and wall dimensions from two dimensions and motion mode, the calculated LV mass was 220 g. Further, correcting for body surface area, the LV mass index (LVMI) was 142 g/m2 (reference value for females as per the American Society of Echocardiography guidelines is 43-95 g/m2), suggesting concentric LV hypertrophy (Figure ) []. The ascending aorta was mildly dilated (40 mm maximum diameter) with suspicion of a dissection flap (Figure ). The patient had a grade III/IV aortic regurgitation with a jet occupying around 50% of the LV outflow tract diameter (Videos , , Figure ). There was diastolic flow reversal evident in the descending thoracic aorta (Figure ). On examination in the subcostal window by color Doppler, turbulence was noted in the abdominal aorta suggesting stenosis (Video ). In view of the absence of significant LV dilation, suspicious dissection flap, and a tambour-like murmur quality, consideration was given to the fact that aortic regurgitation was probably of acute onset.


In May 2017, a 51-year-old man presented with epigastric discomfort for the previous several days. He had a history of untreated chronic hepatitis B virus infection for >29 years. He reported no other underlying diseases. At presentation, his body mass index was 22.0 kg/m2 (weight, 60 kg; height, 165.0 cm). He underwent further diagnostic investigations. A computed tomography (CT) scan showed 1 target lesion located in the right hepatic lobe, measuring up to 7.94 × 5.83 cm (Fig. A), with the characteristic radiological appearance of HCC (hyperenhancement during the arterial phase and delayed washout in the venous phase); no extrahepatic metastases and no portal vein invasion were detected. Laboratory tests results showed unusually elevated basal serum alpha-fetoprotein levels (>1210 μg/L). The patient had no ascites or hepatic encephalopathy. Laboratory tests showed that his total bilirubin <34 umol/L, albumin >35 g/ L. His coagulation function was normal. The Child-Pugh score was 5 (level A). Based on the performance status (Eastern Cooperative Oncology Group scale, 1), tumor status, and liver function, he was classified as having Barcelona Clinic Liver Cancer Stage C HCC. In addition, the patient underwent percutaneous liver biopsy for further diagnosis. Consequently, the patient was diagnosed with HCC clinically and pathologically.
According to the HCC guidelines, the patient was eligible for radical surgery.[ However, he adamantly refused the surgery and chose targeted therapy instead. Approximately 10 days after diagnosis, the patient began to take entecavir as antiviral treatment and donafenib (200 mg orally twice daily) as anti-tumor therapy (starting on May 26th, 2017). During the treatment, laboratory tests assessing liver function, coagulation, peripheral blood cells, and urine were performed every 4 weeks. Adverse effects were assessed using the Common Terminology Criteria for Adverse Events version 5.0. A CT scan was performed every 8 weeks.
After 8 weeks of treatment, the longest diameter of the target lesion decreased to 7.57 cm, and the alpha-fetoprotein level was stable. At 24 weeks of treatment, the longest diameter of the target lesion reached the lowest value (7.23 cm). The Response Evaluation Criteria in Solid Tumors Version 1.1 were used to determine the treatment efficacy and oncological response, which was stable disease (Fig. A–C). After 31 months of continuous therapy, the disease progressed (progression-free survival time was 31 months, from May 2017 to December 2019) (Fig. D). During the treatment period, the patient had persistent hand-foot syndrome (highest level 2), intermittent diarrhea (level 2), thrombocytopenia (level 2), hypertension (level 2–3), hypophosphatemia (level 2), and other adverse events. Except for hypophosphatemia, which was only kept under observation, all other adverse events gradually relieved after symptomatic treatment and dose adjustment of donafenib was not required. After disease progression in December 2019, the patient underwent radical surgery. A recent postoperative CT scan from June 2020 (Fig. E) showed that he remained cancer-free.


A 62-year-old woman suffered intermittent acid regurgitation and heartburn for 3 years. She occasionally had dull pain in the upper abdomen but no nausea, vomiting, melena or weight loss. She took omeprazole irregularly to reduce the symptoms. She had a history of chronic superficial gastritis and Helicobacter pylori infection, which was eradicated successfully 2 years ago. Her father died of pancreatic cancer and had no family history of gastric or colon cancer. There were no abnormalities during physical examination.
Gastroscopy revealed a type IIa lesion in the greater curvature of the upper gastric body, 4×6 mm in size, colorless change, that exhibited depression in its center and blood scab attachment. Close observation and FICE mode image enhancement showed that the demarcation line was positive and the surface pattern was slightly disordered (Fig. ). The pathology of the biopsy showed gastric adenoma with low-grade intraepithelial neoplasia. Immunohistochemical staining revealed MUC6 (+), MUC5ac (+), MUC2 (-), CD10 (-), Syn (+), CgA (+), p53 (mutant), Ki67 (+), Pep-I (-), and ATPase (-) (Fig. ).
The patient was treated with endoscopic submucosal dissection (ESD). The pathological results showed that resected mucosal tissue was 4×3.3 cm in size, and there was a superficial protuberant lesion (Type 0–IIa) on the surface of approximately 0.6×0.4 cm. The histological diagnosis was gastric adenoma of the pyloric type (with low-grade dysplasia), the lesion was limited to the mucosal layer, and the horizontal and vertical margins were negative. Immunohistochemistry staining showed MUC6 (partial +), MUC5AC (partial +), MUC2 (–), CD10 (–), Syn (–), p53 (wild type), Ki-67 (less than 5%), Pepsinogen-I (–), Pepsinogen-II (partial +), and ATPase (–).
The patient recovered well and was followed up for 6 months. At present, she has no abdominal discomfort. Gastroscopy was scheduled to be reexamined 12 months after the operation.


A 39-year-old woman underwent LDLT for primary biliary cholangitis (PBC) and autoimmune hepatitis. Azathioprine and prednisolone were previously administered to treat PBC and autoimmune hepatitis before LDLT. Owing to the underlying disease, her serum bilirubin level increased to 27 mg/dL, and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were 73 IU/L and 41 IU/L, respectively. She received an ABO-compatible, extended right lobe graft from her 51-year-old sister. The patient's preoperative model for end-stage liver disease score was 23 points, and the Child-Pugh score was 11 points with uncontrolled ascites, repeated spontaneous bacterial peritonitis, and esophageal varices.
The middle hepatic vein of the graft was lengthened using a polytetrafluoroethylene graft for convenient anastomosis to the recipient's middle and left hepatic veins. The liver graft had an 8-mm right inferior hepatic vein, which was anastomosed to the recipient's inferior vena cava. In terms of biliary anastomosis, there were 2 openings of hepatic ducts from the cut surface of the liver graft, which were anastomosed using separate hepaticojejunostomies for each hepatic duct opening with respective internal stents. The graft weight was 652 g, and the graft-to-recipient weight ratio was 1.15.
Following transplantation, the immunosuppressive regimen included tacrolimus and prednisolone. The patient's postoperative course was uneventful for 4 days. At that point, her serum bilirubin level declined to 7 mg/dL, and her AST and ALT levels were near normal at 38 IU/L and 72 IU/L, respectively. However, from postoperative day (POD) 5, serum bilirubin and hepatic transaminase levels were rapidly increasing: serum bilirubin, 13.9 mg/dL; AST, 152 IU/L; and ALT, 159 IU/L. The hepatic artery, as well as the portal and hepatic veins, were patent on Doppler ultrasonography. Abdominal computed tomography (CT) revealed a decreased size of the hepatic veins with low perivascular density. We provisionally diagnosed ACR on a clinical basis and started methylprednisolone pulse therapy (10 mg/kg for 3 days). Improvement of liver function tests was observed after this therapy: serum bilirubin, 10.6 mg/dL; AST, 85 IU/L; and ALT, 178 IU/L. However, serum bilirubin and hepatic transaminase levels subsequently increased, and the patient experienced right upper quadrant pain with increased ascites, pleural effusion, and weight gain of 6 kg. On POD 14, Doppler ultrasonography revealed normal flow of the hepatic artery and both portal and hepatic veins, without obstruction of the hepatic veins (Fig. A); however, abdominal CT revealed a decreased diameter of these veins with low perivascular density, heterogeneous enhancement of the liver graft, and increased amounts of ascites and pleural effusion (Fig. A). Therefore, we suspected VOD and simultaneously performed hepatic venography and transjugular liver biopsy. Hepatic venography showed no obstruction or stenosis of the hepatic veins (Fig. B). The histological results showed obliterative venulitis with perivenular inflammation, congestion, and hemorrhagic necrosis, and there was no evidence of ACR (Fig. ).
Clinical and pathological findings suggested VOD. We discontinued tacrolimus administration to avoid its negative effects on VOD and changed our immunosuppressive regimen to a combination of cyclosporine A and prednisolone. After this, the best conservative management for this patient using prostaglandin E1 (PGE1), antithrombin III (ATIII) concentrate, diuretics, and albumin was initiated. However, the patient's body weight or amount of ascites did not reduce.
On POD 23, intravenous defibrotide (25 mg/kg), divided into 4 doses over 21 days, was administered. During defibrotide administration, the patient's body weight decreased by 9.5 kg compared with the initial body weight (57 kg). Abdominal CT on POD 43 showed an increased size of the hepatic vein diameter and markedly decreased amounts of ascites and pleural effusion (Fig. B). Serum bilirubin decreased to 2.7 mg/dL, with AST and ALT being 33 IU/L and 31 IU/L, respectively. The patient was discharged on POD 59, and she is currently alive with normal liver function 25 months after LDLT. No unwanted effects of defibrotide were observed. The clinical course of the patients is summarized in Figure .


A 19-year-old male was transferred from a local district hospital to our centre for the management of traumatic chest injuries. The patient had been involved in an altercation and sustained three knife stab injuries. Two of these were superficial and affected the right upper and lower chest wall. The third was a deep penetrating injury to the left hemithorax.
Chest computed tomography (CT) performed at the local district hospital showed a large volume left sided haemothorax which was managed with a 24Fr intercostal drain (ICD). As a temporizing measure, the penetrating injury was packed with a ribbon gauze, and after the patient was stabilized, he was transferred to our regional level 1 trauma centre. The patient received 9 units of packed red blood cells, 2 units of fresh frozen plasma, and 2 units of platelets prior to transfer.
On examination, heart rate was regular at 93 beats/min, blood pressure of 106/55 mmHg, respiratory rate of 34 breaths/min, and oxygen saturation of 97% on 2 L/min supplemental oxygen. The ICD had drained 1800 mL of blood, and the blood test showed a haemoglobin of 140 g/L (normal 135-172 g/L), platelet of 263 × 109 (150-370 × 109), prothrombin time of 13.4 s (10.8-13.3 s), activated partial thromboplastin time of 24.7 s (28.2-36.6 s), and fibrinogen of 2.62 g/L (1.46-3.33 g/L). Renal and liver function tests were within normal limits. Chest CT demonstrated a slight reduction in the size of the left sided haemothorax and no evidence of active bleeding (). The ICD was up sized to a 32Fr to promote clot removal, and prophylactic intravenous co-amoxiclav was administered. No further blood products were required, and the patient was managed conservatively.
The ICD was removed three days later after 24 hours of minimal output and chest X-ray (CXR) showing a small volume of residual effusion. A day later, the patient developed a new fever and rising inflammatory markers. A repeat chest CT revealed a moderate volume haemothorax (). Thoracic ultrasound (TUS) identified an organized pleural space resembling haematoma with minimal pleural effusion. Given concerns over an evolving empyema in a retained haemothorax, co-amoxiclav was changed to piperacillin/tazobactam, and a 12Fr ICD was inserted under ultrasound guidance into the complex pleural effusion. This initially drained 300 mL of red-brown fluid (degraded haemoglobin) followed by a further 800 mL after a single dose of 10 mg intrapleural alteplase diluted in 10 mL of normal saline. CXR the following day showed an increased in the size of the pleural effusion. TUS however demonstrated a finely organized collection with minimal free flowing fluid. Together with a stable haemoglobin and minimal ICD output, it was felt that the changes were more likely due to an evolving empyema than recurrent pleural haemorrhage. A further two doses of intrapleural fibrinolytic therapy (10 mg alteplase and 5 mg dornase alfa) were administered resulting in a further drainage of 2000 mL of red-brown fluid. Subsequent chest CT showed a small residual basal collection and a thin pleural rind causing tapped lung (). Meanwhile, pleural fluid returned as an exudate with no evidence of infection on pH, microscopy, or culture. As the patient wanted to avoid surgery, an attempt to clear the pleural space and breakdown the pleural rind was made by inserting a second ICD into the basal collection, administering a further dose of 10 mg intrapleural alteplase, and placing the ICD on 4 kPa wall suction. Chest CT performed four days later showed significant improvement with minimal residual fluid and near-complete reexpansion of the trapped lung (). Both ICDs were removed, and the patient was discharged the next day. Haemoglobin remained stable throughout the admission, and no blood transfusions were required (). On follow-up two weeks later, the patient had made a full recovery with CXR demonstrating minimal blunting of the left costophrenic angle ().


A previously healthy 58-year-old male was found unconscious next to his bike in a pit excavated for sewer maintenance along the road (depth of approximately 1.5 m). On his initial assessment the ambulance service physician found a Glasgow Coma Scale score of 12 (E3M6V3), left frontal cephalohematoma, periorbital ecchymosis, and rhinorrhea. His pupils were 3 mm bilaterally with dubious light reflexes and intact corneal responses. The patient was sedated and intubated for safe transport and sequentially admitted to our Emergency Department (ED). Contrast-enhanced computed tomography (CT) scanning of his head and neck showed extensive traumatic subarachnoid hemorrhaging, a left-sided subdural hematoma, and an unusual course of the basilar artery with anterior deviation into the posterior aspect of the left sphenoid sinus that was filled with blood due to the extensive sinonasal fractures. (). Three-dimensional (3D) reconstructions revealed that the basilar artery herniation occurred through a longitudinal clival fracture (). Cranially, the basilar artery exited the left sphenoid sinus through the posterior wall and continued within the basal cisterns. In addition, there were extensive skull base fractures including the right carotid canal, hard palate, and pterygoid palates of the sphenoid bone. Moreover, there were fractures of the inferior walls of both orbits, left zygoma, and a small ventral pneumothorax.
After initial surgical stabilization according to the Advanced Trauma Life Support (ATLS) guidelines, the patient was transferred to the intensive care unit (ICU) for further supportive care and monitoring. Later on the day of admission, after withdrawal of sedatives, he was breathing spontaneously but appeared quadriplegic and anartric. The patient was able to respond adequately with vertical eye movements only and therefore was diagnosed with a locked-in syndrome. On hospital day 2, magnetic resonance imaging (MRI) of the brain confirmed the herniation of the basilar artery () and showed severe mesencephalic and pontine ischemia (). No antiplatelet or anticoagulant therapy was administered because of his intracranial and sinonasal hemorrhages. The patient remained respiratory and hemodynamically stable for 3 weeks in the ICU, without significant neurological improvement. A tracheostomy was performed and after 3 more weeks he became able to cough strongly and effectively, and reflexive swallowing was present. At the time of writing, 2 months after his head injury, the patient is in the medium care unit of the department of neurology, completely dependent for activities of daily living (ADL) and pending transfer to a neurorehabilitation center.


A 31-year-old female with history of hereditary angioedema (HAE) presented with acute abdominal pain with swelling and distension. The patient had a history of HAE and her exacerbations resulted in significant abdominal pain, swelling and, distension. On exam, she appeared in moderate distress. Vitals were significant for heart rate of 120. Abdominal exam revealed significant distension, hypoactive bowel sounds, tenderness to palpation, and guarding without any localization. Lungs were clear to auscultation. Electrocardiogram demonstrated sinus tachycardia with new T wave inversions in leads V1-V3, otherwise there were no acute findings suggestive of ischemia. Troponin obtained was elevated at 1.83 ng/mL. Chest X-ray showed no acute pathology. A transthoracic echocardiogram showed normal left ventricular function with ejection fraction of 65-70%, but the right ventricle was dilated and severely hypokinetic with moderate tricuspid regurgitation [Figure ].
Baseline echocardiogram completed one month prior to admission was normal. She underwent ventilation perfusion scan which was low probability for PE. Cardiology was consulted, acute coronary syndrome with RV infarct was thought to be unlikely, and thus cardiac catheterization was not pursued. Patient was managed supportively with volume resuscitation and symptomatically for her HAE exacerbation. Her abdominal swelling resolved and troponins continued to trend down and she was discharged home after three days. A follow-up echocardiogram done six months later showed normal RV function [Figure ].