A 60-year-old male, with a pre-existing diagnosis of Loeys-Dietz type 2, presented to the emergency room with left-sided chest pain for three weeks. He had a sudden onset of left-sided chest pain around 3 weeks ago, which was described as stabbing in nature and was 6/10 in intensity. It radiated to the back occasionally, was exaggerated by lying down, and did not increase upon exertion.
He was diagnosed with Loeys-Dietz syndrome in 2005. Genetic testing revealed a TGFBR2 mutation specifically R460H. In 2006, he underwent a prophylactic aortic root replacement for an aortic root aneurysm measuring 4.6 cm with a porcine bioprosthesis. On a routine two-year follow-up, a CT showed a left coronary artery pseudoaneurysm secondary to a left coronary artery dehiscence. He underwent another aortic root replacement and single coronary bypass with an aortosaphenous vein graft. Intraoperative findings revealed a left coronary artery sinus that had detached from the aortic graft, with increased the friable aortic tissue preventing a patch repair, necessitating an aortic replacement. In addition, other aneurysms included a right popliteal aneurysm measuring 4.4 cm, AAA measuring 3.5 cm, left internal carotid artery aneurysm measuring 9 mm, left subclavian artery aneurysm measuring 3.6 cm, and right ICA aneurysm measuring 6 mm.
On arrival to our emergency room, his vital signs were stable. Physical exam and electrocardiogram were unremarkable, serial cardiac enzymes were negative, and additional lab work-up was negative. Chest X-ray was obtained and was negative for any acute cardio pulmonary abnormalities. Keeping in mind his medical and surgical history, a cardiac CT scan with IV contrast was ordered which () revealed an aneurysm of the left subclavian artery, a sinus of Valsalva aneurysm arising from the right lateral aspect of the aorta measuring 2.4 × 3.8 × 4.0 cm and the right coronary artery arising from this aneurysm. A three-dimensional reconstruction of this pathology is shown in . This was compared to a CT scan done approximately 2 years ago which was within normal limits, showing an aortic root replacement with stable postoperative changes. He was transferred to a specialized facility for surgical repair of the aneurysm.
He underwent a redo sternotomy where the superior vena cava was cannulated, a vent was placed in the right superior pulmonary vein, the aorta was clamped, and the heart was arrested. A pseudoaneurysm was identified and recognized to be caused by dehiscence of the right coronary artery from a large defect in the old Freestyle graft. Patch and reimplantation of the right coronary artery were considered, but this was unsuccessful in prior operations. Replacement of the old prosthesis was decided upon.
The old Freestyle was excised, and the old saphenous vein interposition graft to the left coronary was detached from it. The annulus was then rimmed with mattress sutures which were passed through the base of a Valsalva graft then a magna pericardial valve. The valve and graft were lowered, and the sutures tied in and cut. The old vein graft to the left coronary could not be directly implanted, so a segment of autologous saphenous vein was interposed. The distal end of the Valsalva graft was grafted to the ascending aorta, and the right coronary artery was anastomosed to the Valsalva.
Though the heart was resuscitated, there was significant bleeding from the undersurface of the right coronary, which was not repairable. The heart had to be rearrested, and the right coronary anastomosis was taken down. The ostium of the right coronary artery had become quite macerated, so it was oversewn, opened longitudinally, and another segment of autologous saphenous vein was grafted onto it. The proximal end of that vein graft was joined to the Valsalva graft.
The aortic clamp was released again and the heart resuscitated. The patient was warmed and weaned from bypass. Hemostasis was achieved. The heart initially seemed to be functioning normally, but when LV function worsened, it introduced the possibility that the interposition vein graft to the left coronary graft was stenotic. Accordingly, the interposition graft was revised which successfully addressed the stenosis. The heart was resuscitated again, the patient was weaned from bypass uneventfully and hemostasis was achieved. The postoperative course was unremarkable. The patient received a predischarge CT scan which showed no residual pseudoaneurysm. Coronary reimplantation grafts to the RCA and left main were patent. Additionally, the left main graft had approximately 50% stenosis due to mild kinking. The patient was ultimately discharged in a stable condition.


A 79-year-old asymptomatic Caucasian male presented with progressive renal failure with abnormal serum creatinine (range of 1.82 to 2.18) in July 2012. Complete blood count (CBC) showed red blood cell count (RBC) of 3.36 x 108/uL, hemoglobin 10.9 g/dl, hematocrit 33.1%, mean corpuscular volume (MCV) 99 fL, mean corpuscular hemoglobin (MCH) 32.8 pg, mean corpuscular hemoglobin concentration (MCHC) 33.0%, red cell distribution width (RDW) 15.8% and white blood cell count (WBC) 4,000/uL, with differentials: neutrophils 50%, lymphocytes 37%, monocytes 8%, eosinophils 4%, basophils 1% and platelet count of 178,000/uL. Comprehensive metabolic profile (CMP) revealed: glucose 96 mg/dL, blood urea nitrogen 23 mg/dL, creatinine 2.18 mg/dL, sodium 140 mmol/L, potassium 4 mmol/L, chloride 107 mmol/L, carbon dioxide 25 mmol/L, albumin 4.4 g/dL, calcium 9.1 mg/dL, bilirubin (total) 0.8 mg/dL, phosphorus 3.3 mg/dL and magnesium 2.7 mg/dL. Computed tomography (CT)-guided needle biopsy of the left kidney showed severe lymphocytic inflammation mainly in the areas of tubular atrophy and interstitial fibrosis (Figure ).
Immunohistochemical staining showed atypical lymphocytes that were positive for CD20 and negative for CD5, CD10, CD19, CD22 and CD23. Molecular testing revealed an Ig heavy chain gene rearrangement; these findings were consistent with marginal zone B cell lymphoma. Furthermore, immunofluorescence (IF) microscopy demonstrated seven glomeruli with diffuse pseudo-linear staining of the glomerular capillary loops for albumin (1+). Glomerular staining for IgG, IgA, IgM, C3, C1q and kappa or lambda light chain was negative. Interstitium stained positive for fibrinogen, while protein casts were stained positive for IgA (3+), kappa light chain (3+) and lambda light chain (3+). By electron microscopy (EM), the glomerular basement membrane had a normal trilaminar structure, the mean thickness was within the normal range without electron-dense deposits or tubuloreticular inclusions and the majority of podocytes foot processes were intact (Figure ). No immune complexes were detected by IF or EM.
On serum protein electrophoresis (SPEP) and immunofixation, we found IgM kappa monoclonal gammopathy and serum M-protein level of 0.3 g/dL. Quantitative immunoglobulin testing was performed for IgG (699 mg/dL), IgA (51 mg/dL) and IgM (470 mg/dL). Serum free light chain (SFLC) showed kappa (37.9 mg/L), lambda (1.58 mg/L) and kappa/lambda ratio of 23.99. Urine protein electrophoresis (UPEP) showed a protein level of 91 mg/dL and M-spike of 18.1%. Bone marrow (BM) biopsy showed 30% BM involvement by clonal B cells, morphologically consistent with marginal zone B cell lymphoma. Positron emission tomography (PET) scan was found normal in 2012 and 2013. The patient was treated with five doses of weekly rituximab and one dose of rituximab-bendamustine combination, but renal function worsened and treatment was stopped in 2013. The patient was monitored closely without further treatment until 2017. PET scan (2017) showed a mild enlargement of the retroperitoneal lymph nodes (aortocaval from 1 x 0.8 to 1.4 x 1.2 cm, left periaortic from 1.4 x 0.5 to 1.3 x 1.0 cm) and a partially calcified subcarinal node from 3.1 x 1.1 to 3.5 x 1.5 cm (non-avid), and the spleen size increased from 12.2 to 14.2 cm in cubic centimeter dimension (Figure ). One dose of vincristine and prednisone was given at that time, but renal function declined further. The patient was offered bortezomib/dexamethasone or ibrutinib for further treatment consideration, which he declined.


A 51-year-old woman was admitted to our hospital complaining of chest tightness, palpitations and dyspnoea after activity. On admission, physical examination revealed a normal state of consciousness, an average heart rate of 76 beats per minute (bpm), and a blood pressure of 111/70 mmHg. Cardiac auscultation revealed variable first heart sound intensity and a diastolic murmur in the mitral stethoscope area. The other findings were unremarkable. The electrocardiogram showed atrial fibrillation. The echocardiogram performed by our hospital also showed rheumatic heart disease (severe mitral stenosis and regurgitation) with normal cardiac function and wall motion.
After the completion of the preoperative examination, the patient was sent to the operating room for mitral valve replacement. The operation was successful. After the aorta was reopened, ventricular fibrillation occurred. Sinus rhythm was not restored until 5 rounds of electrical defibrillation had been performed. Not long after returning to the intensive care unit (ICU), this patient developed heart failure with low blood pressure (70~85/45~50 mmHg) and tachycardia (125–135 bpm). Blood gas analysis showed progressive lactic acidosis, and blood lactate increased from 2.4 mmol/L to 15.3 mmol/L. Troponin T was slightly elevated compared to the preoperative level (1.960 ng/mL vs 0.019 ng/mL). N-terminal pro-brain natriuretic peptide levels increased markedly from 821.7 pg/mL to 21,025 pg/mL. Electrocardiogram (ECG) (Fig. ) showed that the V5–6 ST-segment depression was 0.1 mV. The bedside chest film showed a small amount of fluid in the left chest. Urgent bedside echocardiography demonstrated akinesis in the middle and apical segments of the left ventricle with depressed LV function (EF 36%),while basal segments’ movement were generally normal.
To determine the blood flow in the myocardium, myocardial contrast echocardiography (MCE) was performed immediately (Figs. a, b, and a). For the MCE examination, the ultrasound system was switched to the contrast mode, with a mechanical index of 0.1–0.5. MCE was performed using intravenous administration of 2.0 mL of SonoVue (Bracco, Milan, Italy). To achieve a balance among ultrasound intensity, penetration, and the duration of myocardial opacification, the contrast-specific imaging mode needed to be adjusted. Similar enhancement intensity was observed in the basal, middle and apical segments. Quantitative analysis also showed approximately equivalent maximum intensity values in these regions.
The diagnosis was considered TCM instead of myocardial infarction. The treatment mainly involved maintaining effective circulation and reducing the postcardiac load. After the administration of epinephrine and norepinephrine, the patient’s blood pressure was still low. Considered the patient’s condition as heart failure, an intra-aortic balloon pump was inserted. Although myocardial enzyme levels were elevated, the doctors did not perform treatment for coronary heart disease, considering the reason of tissue injury after heart surgery. The therapeutic regimen for this patient included ventilator-assisted ventilation, postoperative anticoagulation therapy, anti-infection treatment and other conservative treatments.
A week later, the patient underwent coronary angiography, and the results showed no significant narrowing of the coronary artery. This patient was extubated 13 days after surgery and was later weaned from epinephrine. Myocardial contrast echocardiography performed 2 weeks later (Figs. c, d, and b) showed that apical movement was significantly improved, with a slight decrease in interventricular septal motion. In addition, the perfusion of the myocardium was normal, with an EF (Simpson) of 52%.
The clinical evolution was favourable, and the patient was discharged 3 weeks later. Before discharge, echocardiography showed that the artificial mitral valve function and the segmental wall movement were normal, with an EF of 72%. One year later, the patient remained asymptomatic and showed normalization of ventricular wall motion in the apical segment.


A 29-year-old woman was found unresponsive near a snowy mountain trail in winter. On that day, the outside air temperature ranged from − 2.0 to 1.0 °C. When emergency medical services arrived on the scene, they found that the patient was in cardiac arrest and in asystole. It was noticed that she also had mandibular rigidity. On the way to the hospital, emergency medical service staff were unable to insert an oral airway device for ventilation because the mandibular rigidity prevented sufficient mouth opening. The chest was compressible. CPR was performed with manual chest compression and bag valve mask ventilation ratio of 30:2 during transportation. When she was admitted to the hospital, 52 min had passed since she was discovered. She remained in cardiac arrest with an asystolic cardiac rhythm. Her initial core temperature was 22 °C measured by bladder thermistor. Her mandibular rigidity remained, and neck mobility was also restricted. Both elbows and knees could be passively bent with resistance and the chest wall was not stiff. We were concerned that postmortem changes (i.e., rigor mortis) had begun. We tried to force open her mouth for intubation and found that it could be slightly opened. Although this was insufficient to visualize the vocal cords with a conventional laryngoscope because of the impossibility of controlling it, we were able to insert an “Airway scope™” video laryngoscope, which allowed successful intubation. Although the patient was in cardiac arrest due to severe accidental hypothermia, which indicated an enhanced possibility of successful resuscitation, the mandibular rigidity connected, along with the supposition of rigor mortis initiation made us believe that it would be difficult to resuscitate successfully. However, her initial blood gas analysis revealed that her serum potassium level was 5.4 mmol/L (Table ). We decided to use veno-arterial ECMO to generate effective systemic perfusion and to rewarm the patient. After ECMO initiated, her temperature transiently dropped to 20.9 °C, then little by little turned to rise. Although she initially remained in asystole after ECMO was introduced, low amplitude ventricular fibrillation gradually appeared as her temperature rose, and the amplitude of ventricular fibrillation progressively increased. At this time, she started breathing spontaneously and her mandibular rigidity disappeared. Once her temperature reached 28 °C, we used defibrillation to achieve sinus rhythm and restore her circulation. Her temperature reached 36 °C after 165 min of ECMO (Fig. ).
After admission to the intensive care unit, her hemodynamic status gradually improved, ECMO was stopped on day 2, and she was discharged from the intensive care unit on day 12. The content of the patient’s bag revealed empty packages of a sleeping drug and a half-finished bottle of alcohol. On regaining consciousness, the patient confessed that she consumed the sleeping drugs and alcohol in an effort to commit suicide.
She was moved to another ward for rehabilitation and showed no neurological impairments on day 42 after the cardiac arrest event.


A 14-year-old boy, who was initially examined for continuous coughing, was referred to our hospital owing to an anterior mediastinal mass identified on chest X-ray (). Systematic examination revealed a 20 × 10 cm sized mass at the right anterior mediastinum that involved the right pulmonary vein and elevated levels of alpha fetoprotein (AFP), a tumor marker, at 3825 ng/ml. Needle aspiration was performed, but only necrotic tissue could be collected. We did not analyze the karyotype since the symptoms suggesting the Klinefelter syndrome were not observed. Therefore, a clinical diagnosis of malignant teratoma was made, and three courses of cisplatin-based chemotherapy were administered because AFP levels continuously increased. After chemotherapy, AFP levels decreased, although the size of the tumor did not change, as evident in a computed tomography (CT) scan. Next, tumorectomy and total right lung extraction were performed. The pathological diagnosis of the extracted tumor was malignant teratoma with areas of yolk sac tumor (). No cancer cells were found at the edges of the area where the tumor was removed. Two courses of cisplatin-based postoperative chemotherapy were administered until AFP levels were normal.
After 3 months of follow-up, the patient experienced pain in his right hip joint while AFP was still normal. The 99mTc-methylene diphosphonate bone scan showed increased tracer uptake at the left forehead and right hip joint (). Head and pelvic MRI also revealed signs of metastasis at the left forehead and right hip joint. Abdominal CT showed a metastatic region in the liver. Bone biopsy was performed at the left forehead. The pathological diagnosis was metastatic malignant melanoma originating from an immature teratoma of mediastinum (). Large heteromorphic cells with melanin were found in the original mediastinal malignant teratoma by retrospective re-examination. This suggested that a section of the malignant melanoma in the original malignant teratoma, which was composed of various components, metastasized. Because of the very fast disease progression, after consultation with the family, aggressive treatment was discontinued, and palliative therapy was provided. He died 15 months after diagnosis of the original malignant teratoma.


A 40-year-old white man presented to an outside emergency department in June 2018 with sudden-onset right calf pain, swelling, and redness. He had a history of juvenile polyposis syndrome, for which he underwent a partial colectomy as a child, and alcohol use disorder (in remission). He received surveillance colonoscopies at recommended intervals due to his history of polyps, the most recent of which had been unremarkable. Upon presentation, a venous ultrasound revealed an acute, occluding thrombus of his right popliteal, tibial, and peroneal veins. There was no preceding history of trauma or immobilization. He was discharged on rivaroxaban 15 mg twice daily and advised to follow-up with his primary care provider.
One week later, he presented again to an outside emergency department with a 3-day history of melena. An initial laboratory workup was significant for hemoglobin of 5.3 and mean corpuscular volume (MCV) of 55.7, for which he received 3 units of transfused red blood cells. Following stabilization and cessation of rivaroxaban, an abdominal computed tomography (CT) scan revealed a mass-like transmural thickening of the gastric antral and pyloric walls with tumor protrusion into the duodenal bulb. Also visualized were multifocal bilateral segmental and subsegmental pulmonary emboli, as well as a non-occlusive thrombus extending from his right renal vein into his suprarenal inferior vena cava (IVC). He underwent placement of an IVC filter. Subsequent upper endoscopy revealed diffusely irregular, raised gastric mucosa across the entire gastric body, with the appearance of a soft carpeted mass (Fig. ). This finding was suggestive of malignancy. A biopsy specimen of the mass showed gastric mucosa with prominent foveolar hyperplasia, focal granulation tissue, ulceration, reactive glandular changes, and evidence of chronic active inflammation (Fig. ). However, despite the suspicious gross appearance, there was no evidence of dysplasia or malignancy. Immunostaining was negative for Helicobacter pylori. Based on these findings, a probable diagnosis of MND was established. He was discharged on high-dose orally administered pantoprazole and scheduled for repeat upper endoscopy in 1 month.
Approximately 3 weeks later, he once again presented to an outside emergency department with the chief complaint of lumbar and suprapubic pain. An abdominal CT scan again showed a non-occlusive thrombus of his right renal vein, which was now noted to extend slightly above the IVC filter. Also visualized were abdominal varices and cavernous transformation of his portal vein suggestive of previous portal vein thrombosis. Upon this finding, he was admitted to our institution as a direct transfer for symptomatic renal vein thrombosis. A low-dose heparin drip was initiated immediately. Following transfusion of 1 unit of packed red blood cells, his hemoglobin remained between 7.2 and 7.6, and he had no ongoing melena. A comprehensive metabolic panel was notable for serum albumin of 2.4. A serum gastrin level was also elevated to 244 (upper limit of normal, 150). During his admission, he developed painful bilateral lower extremity and scrotal edema, which was managed non-pharmacologically. An urgent repeat upper endoscopy was recommended, but he declined this procedure due to concerns about the risks of endoscopic mass removal. Further intervention was deferred to his primary gastroenterologist, although treatment with cetuximab was discussed as an eventual option. He was bridged to orally administered anticoagulation without incident and was discharged on apixaban 5 mg twice daily for an indefinite duration. During a several-hour window when he was not anticoagulated, further laboratory evaluation of his hypercoagulability was performed; the results are shown in Table .
At 1-month follow-up with his primary care physician, he was tolerating apixaban well, with no further gastrointestinal (GI) bleeding. He was adhering to a high-protein diet with subjective and objective improvement in his edema. His hemoglobin improved to 8.8 and his albumin to 3.2. There were no other significant changes in his laboratory results. He continued to decline repeat endoscopy or mass removal. However, he expressed plans to seek care from an out-of-state oncologist and/or gastroenterologist with expertise in treating MND.


A 49-year-old male presented to our hospital for severe pain in his right flank of 2 hours duration following Extracorporeal Shockwave Lithotripsy (ESWL) performed on the same day for a stone in his right kidney. His past medical history includes nephrolithiasis, for which he underwent ESWL 3 years prior to presentation. At presentation, the patient was afebrile and hemodynamically stable with normal vital signs. Examination revealed exquisite tenderness over the right costovertebral angle. Laboratory studies revealed a hemoglobin value of 14.9g/dL, a hematocrit of 43.9%, creatinine of 1.03 mg/dL, and BUN of 30 mg/dL. An abdominal CT with contrast revealed 17x13x11 cm right perinephric hematoma with evidence of active contrast extravasation in the arterial phase (). A decision was made to send the patient for emergent arteriography. Catheterization was performed with a 5F Cobra catheter and contrast injection revealed active extravasation arising from the small branches of the middle subsegmental posterior renal artery (). The subsegmental branches were cannulated using a 2.7F Cobra catheter, and contrast injection revealed two bleeding branches from the posterior capsule. Embolization with 0.018 microcoils was performed and subsequent contrast injection did not show evidence of extravasation (). The patient was admitted for monitoring and supportive care. Serial complete blood count revealed a steady decline of hemoglobin concentration to reach 9.3g/dl on the 3rd day of hospitalization. At the time, the patient had nausea, fatigue, pallor, and tachycardia. He was successfully managed with transfusion of 1 unit of packed red blood cells and IV hydration. A follow-up CT scan revealed a slight reduction in the size of the hematoma to measure 16x12x10cm. Throughout his hospitalization, the patient's renal function was intact as determined by a stable creatinine value of 0.8 mg/dL (estimated GFR = 105ml/min/1.73m2 as calculated by CKD-EPI). Following hemodynamic stabilization and symptom resolution, the patient was discharged after a 4-day hospitalization and was followed up on an outpatient basis.


Patient No. 1 was a 30-year-old male with a history of good physical health; a diagnostic consultation did not identify any foci of infection or record of otitis media, sinusitis, or head trauma. His major complaints included 1 week of headache and 3 days of headache aggravation, accompanied by nausea and vomiting. The patient was hospitalized at our department with a body temperature of 36.0°C. The physical examination report conducted at the Department of Neurology showed that the patient had clear consciousness, was apathetic, had a Glasgow Coma Scale (GCS) score of 15, a soft neck, normal limb muscular strength, normal deep, and superficial sensations. After hospitalization, a complete blood count reported a white blood cell count of 8.4 × 109/L (Normal reference range: 4.0–10.0 × 10ˆ9/L), 70.4% (Normal reference range: 50–75%) neutrophils, 20.1% (Normal reference range: 20–40%) lymphocytes, and C-reactive protein (CRP) level of 9.0 mg/L (Normal reference range: 0–10 mg/L). A cardiac echo reminded the heart that everything was normal. Head magnetic resonance imaging (MRI), including a plain scan and an enhancement scan, showed the following: (i) irregularly circular, slightly long, aberrant T1 and T2 signal shadows with sheet-like, long T1 and T2 signals as well as apparently enhanced diffusion-weighted imaging (DWI) signals were observed in the right parietal lobe; (ii) an edge ring wall with a relatively even thickness presented as slightly short T1 and T2 signals; (iii) the ring wall manifested an apparent increase in signal intensity after enhancement; (iv) the lesion was surrounded by large patches of T1 and T2 oedema shadow; (v) the adjacent ventricles and parenchyma displayed compression-resulted deformation; (vi) the midline structures were slightly shifted toward the left (Figures –). The patient received resection of the space-occupying lesion in the right parietal lobe. During the operation, a dark yellow and intact capsule (abscess wall) with brittle texture was visible. Because of its high internal pressure, the yellow, viscous pus was first aspirated to relieve the pressure before the capsule was completely excised. Some residual tissues did not have a clear boundary with the normal brain tissue. A pathological examination showed the presence of inflammatory exudates, necrosis, and granulations (Figures ). After the operation, the patient was provided with an empiric regimen of 1 g meropenem q8h and 1 g vancomycin q12h. A pus culture indicated the presence of Viridans streptococci, and a drug sensitivity test showed that the bacterium was sensitive to vancomycin; thus, the patient was treated with vancomycin 1 g q12h. After the operation, the patient had a low-grade fever that fluctuated around 37.5°C. After 1 week of treatment, his body temperature returned to normal. The complete blood count revealed the following: leukocyte count of 7.1 × 109/L, 65.4% neutrophils, 24.5% lymphocytes, and CRP level of 8.2 mg/L. As such, the patient continued the vancomycin regimen for 2 additional weeks, after which he displayed a remission of the headache and showed normal limb strength. A head computed tomography (CT) scan showed that the space-occupying lesion in the right parietal lobe had disappeared, the surrounding area had large patches of low-density shadows with a blurred boundary, and the midline structures displayed local left-shift (Figure ). The patient was discharged. A physical examination showed that the patient had a normal body temperature, clear consciousness, good articulation, and normal limb muscular strength.
Patient No. 2 was a 45-year-old female with no clear history of recent infection or a past record of sinusitis or otitis media. The patient was hospitalized due to symptoms of headache and right limb weakness for 1 week. A head MRI, including plain and enhancement scans, showed the following: (i) an aberrant, circular space-occupying lesion with long T1 and long T2 signal shadows was observed in the left basal ganglia; (ii) a ring wall with a relatively even thickness presented as slightly short T1 and T2 signals; (iii) the shadow displayed apparent intensification after enhancement; (iv) large patches of long T1 and long T2 oedema shadows were present in the surrounding area of the lesion; (v) the left ventricle exhibited slight compression-resulted deformation; and (vi) the midline structures were shifted lightly toward the left (Figures –). The patient was suspected of glioma at the local hospital and was transferred to our hospital at 9:00 AM the following day. Upon admission, the patient had a body temperature of 36.3°C, severe headache, and apparent agitation. A physical examination at the Department of Neurology revealed dementia, apathy, a GCS score of 10, babbling, soft neck, a lack of resistance, level 3 right limb muscle strength, normal muscular tension, positive Babinski signs. A complete blood count revealed a leukocyte count of 7.5 × 109/L, 72.7% neutrophils, 19.6% lymphocytes, and CRP level of 18 mg/L. A cardiac echo reminded the heart that everything was normal. After hospitalization, the patient received an intravenous infusion of 20% mannitol 250 ml q8h and was prepared for relevant preoperative examinations. Twelve hours after hospitalization, the patient fell unconscious and had a GCS score of 6, enlargement of the left pupil, loss of light response, avoidance of the left limbs upon needling, and slight buckling of the right limbs upon needling. An emergency head CT showed a spheroid shadow of slightly low density present in the left basal ganglia, the surrounding area had large patches of low-density oedema shadows, the left ventricle displayed severe compression-resulted deformation, and the midline structures exhibited a prominent rightward shift (Figure ). The patient was suspected of developing cerebral palsy and thus underwent emergency surgery including lesion resection in the left basal ganglia, resection of the polus temporalis, and a decompressive craniotomy. During the operation, the intracranial pressure was relatively high. As such, the left side of the polus temporalis was first excised, which revealed yellow brain tissue surrounding the abscess and a dark yellow and brittle capsule. The lesion was excised completely after aspiration and decompression. A pathological examination revealed that peripheral lymphocytes infiltrated into the surrounding blood vessels and that some areas were necrotic and accompanied by abscess (Figures ). After the operation, the patient displayed persistent fever that fluctuated around 38.5°C. A complete blood count revealed a white blood cell count of 7.2 × 109/L, 84.8% neutrophils, 8.9% lymphocytes, and CRP level of 24 mg/L. Pus culture indicated group B Streptococcus. Based on a drug sensitivity test, the patient was treated with a regimen of 1 g vancomycin q12h for 3 weeks, after which her body temperature returned to normal, and therapy was continued for an additional 2 weeks. Head CT revealed that the left space-occupying lesion disappeared; large patches or stripes of low-density shadows with blurred boundary were present in the surrounding areas; the surrounding brain tissue displayed swelling; and the midline structures remained in the middle (Figure ). However, the patient remained unconscious and was therefore provided with rehabilitation therapy including hyperbaric oxygen treatment for 6 weeks, after which she gradually gained consciousness. Physical examination upon discharge revealed a normal body temperature, high level of consciousness, babbling, level 1 right limb muscle strength, and normal left limb muscle strength.


A 64-year-old woman with a complex past medical history presented to the emergency department via ambulance after being found poorly responsive by her husband. Her husband stated that when he attempted to wake her up from a nap earlier that day, she was less responsive than usual and complained that she was unable to move her lower extremities due to stiffness. Upon questioning the patient, she admitted to shortness of breath and muscle stiffness but denied nausea, vomiting, diarrhea, headache, abdominal pain, chest pain, or a cough. She denied any recent falls or injuries.
The patient had a past medical history of anxiety, depression, hypertension, hyperlipidemia, neuropathy, fibromyalgia, stage 3 chronic kidney disease, chronic pain syndrome, and pseudotumor cerebri status post-ventricular atrial shunt. She denied any history of stroke or myocardial infarction. Home medications included 0.5 milligrams (mg) of clonazepam once daily, 100 mg lamotrigine once daily, 600 mg gabapentin twice daily, oxycodone 10 mg once daily pen, 20 mg citalopram twice daily, and paroxetine 25 mg controlled release in the morning and 12.5 mg at bedtime. The patient denied any alcohol, tobacco, or illicit drug use.
Upon presentation to the emergency department, the patient had a temperature of 101.1 ºF, heart rate of 107 beats per minute, 27 respirations per minute, and a blood pressure of 171/73 mmHg. A cardiovascular exam revealed regular rhythm with a systolic murmur grade III/VI, no edema, and palpable peripheral pulses. Lungs were clear to auscultation bilaterally, and the chest was non-tender. Abdominal exam revealed a soft, non-tender abdomen with normal bowel sounds and no masses. An electrocardiogram (EKG) revealed left ventricular hypertrophy, left anterior fascicular block, and sinus tachycardia with no other changes since previous EKG (Figure ). Her lactic acid level was 5.0 mmol/L, and her influenza screen was negative. Her urinalysis was normal, and a chest radiograph revealed a right lower lobe infiltrate. The patient was then admitted to the hospital for a further work-up.
Until aspiration pneumonia could be ruled out, the patient was placed on a nothing-by-mouth (NPO) diet and was given intravenous (IV) antibiotics and fluids. Her home opioid medications were discontinued, with the exception of morphine as needed. A comprehensive neurological exam revealed disorientation and difficulties in attention, as well as hypertonia and hyperreflexia in the lower extremities with clonus bilaterally. A cranial computed tomography (CT) image showed an unchanged ventricular shunt and no acute process. Additionally, an electroencephalogram revealed generalized slowing and triphasic waves typically observed in neurodegenerative diseases or encephalopathy.
Despite adequate hydration, antibiotic use, and decreased administration of opioid medications, there were little improvements in her vitals or mental status. After a day in the hospital, her sodium level rose to 155 millimoles per liter and her creatine kinase level increased to 455 units per liter. She continued to have an alternating psychomotor agitation, lethargy, confusion, restlessness, stiffness, hyperreflexia, tachycardia, and uncontrolled hypertension.
The patient had been prescribed serotonergic and opioid medications for several years, but after the patient’s husband arrived, he was able to share a more extensive history and inform the care team that her psychiatrist had recently made significant changes to her drug regimen to address her increasing depression symptoms. According to the patient’s husband, a week prior to admission, the dosage of her SSRI, paroxetine, started to be tapered down, while the dosage of another SSRI, citalopram, was simultaneously being increased. Both medications were being prescribed concomitantly at high doses. Additionally, about one week prior to the hospital admission, her pain management specialist had discontinued her buprenorphine patch and started her on morphine. After learning about these recent medication changes, her care team discontinued her citalopram and paroxetine. Benzodiazepines were then prescribed for agitation.
Over the next 24-48 hours, the patient showed marked improvement in her mental status. The patient was noted to be more alert and oriented, conversing appropriately, with no agitation observed by her fifth day in the hospital. Her temperature, heart rate, blood pressure, and electrolytes simultaneously normalized. Education regarding the use of SSRIs, as well as other treatment options for depression and pain, were provided by the psychiatrist and medicine physician. After a few more days of monitoring, the patient was discharged to her home under her husband’s supervision with plans to begin psychotherapy, physical therapy, and occupational therapy.


Case 1 is a 26-year-old female with negative history of FMF in her family. The first presentation of this disease started at the age of 14 including: abdominal pain, fever, nausea, arthralgia in knee joints, and erythematous swelling of the limbs (erysipelas-like eruption). She usually had an attack every 2 weeks that would last for 1-2 days with a severity score of 10. Her MEFV gene mutation was: E148Q (heterozygous).
She started using colchicine 1 mg daily about 12 years ago but the results were not desirable enough, and she increased the dose to 2.5 mg daily, and then, the number of attacks was reduced to one attack every 20–30 days that would last 1 day with a severity of 5-6. We added dapsone 100 mg daily about 3.5 years ago, and since then, she did not have any similar attacks, except by discontinuation of the drug because of its unavailability in a short course period, her attacks recurred.
There have been no known side effects of colchicine or dapsone in this case.


Case 2 is a 40-year-old female with no history of FMF in her family. The onset of disease was from age 20 with abdominal pain, chills and fever, diarrhea, sweating, and arthralgia such as knee pain. She had an attack every 2 weeks that would last for 3-4 days with a high severity score near 10.
She started using colchicine 1 mg three times daily about 10 years ago, and then after the number of attacks was decreased to one episode every 2-3 months lasting for 1 day with a severity score of 7-8. Her MEFV gene mutations were M680I (G/C)/V726A (compound heterozygous).
From 9 months ago, we started using dapsone 50 mg daily, and since then, she was free of similar symptoms.
She suffers from occasional dizziness as known side effect of this drug.


Case 3 is a 38-year-old male with positive family history of FMF. He presented his first signs at the age of 14 but with delayed diagnosis until he was 30 years old. His symptoms were fever, arthralgia, body pain, and oral ulcer. The frequency of his attacks was variable, and each attack lasted for 3-4 days with a high severity score.
He started using colchicine 1 mg daily 8 years ago, and then after he suffered similar attacks with no response to colchicine although with high doses (2 mg). His MEFV gene mutations were C.1981G > T (D661Y), we submitted this as a new mutation in infevers.
From 9 months ago, we started dapsone 50 mg daily. Dapsone significantly controlled the attacks during this time. There have been no known side effects of this treatment in this case.


Case 4 is a 32-year-old male with negative family history of FMF. His first presentation was at the age of 23 years old with abdominal pain, vomiting, fever, chills, and limbs pain.
He was diagnosed with FMF at the age of 25, and his MEFV gene mutations were M680I (G/C) M680I (G/C) (homozygous). His attack intervals were almost 10 days, and it lasts for 3-4 days with a high severity score.
He started using colchicine 1 mg twice daily from 7 years ago, and since then, the number of attacks was decreased to one attack every month with similar pattern.
Seven months ago we added dapsone 50 mg daily, and since then, he was completely free of symptoms. There have been no known side effects of this therapy.


Case 5 is a 12-year-old female with negative family history. Her first signs presented at 3 years of age with: fever, abdominal pain, vomiting, chills, and sweating. She usually had an attack biweekly, lasting for 3-4 days with a high severity score. Her MEFV gene mutations were M694V/M680I (heterozygous).
She started using colchicine 1-2 mg daily from 6 years ago with unfavorable response. From 7 months ago, we added dapsone 50 mg daily, and since then, she has not have any attacks.


Case 6 is a 17-year-old female with negative family history. Her first sign was presented at one year of age with: fever and chills, nausea, and body pain with a high score. Her MEFV gene mutations were M694V (homozygous).
She started taking colchicine 0.25 mg daily 16 years ago then increased the dose to 2.5 mg daily; however, attacks persists to one episode every 1-2 months with similar severity.
From 7 months ago, we added dapsone 100 mg daily. Dapsone has reduced the frequency and severity of attacks (one attack in 5 months with a very low severity score). There have been no known side effects of this treatment in this case.
shows these patients' data and summarized their findings.


A 74 year-old man presented with visual acuity deterioration in the right eye (RE). He had history of treated systemic hypertension. Best-corrected visual acuity (BCVA) was 20/80 in the RE and 20/20 in the LE. Fundus examination revealed a subretinal haemorrhage in the RE. Multimodal retinal imaging of the RE showed a type 2 (predominantly classic) CNV complicated by a spontaneous retinal pigment epithelial (RPE) tear (Fig. ). Patient had not received any prior treatments. A course of 3 monthly intravitreal injections of Ranibizumab (0.5 mg × 0.05 mL) was administered. 4 weeks after the third injection OCT scan showed splitting and restoration of the hyperreflective line attributable to the RPE (Fig. ). 9 months after initiation of treatment patient had received six intravitreal injections of Ranibizumab and BCVA improved to 20/32 in the RE.


A CVID-diagnosed, 25-year-old, non-smoker woman was admitted to our center with LIP progression: CVID diagnosis was consistent with ESID criteria. The restrictive, granulomatous lung disease developed: open lung biopsy and histological examination showed lymphocytic infiltration of interstitial tissue: LIP diagnosis was confirmed by the histologic examination as well as T and B cells repertoire analysis as described previously (). Before the therapy spleen extended to the iliac crest (27 cm, see Figure bottom panel): subileus was observed due to the pressure on intestines.
Progressive LPD was observed with hyperviscosity, paraproteinemia, high β2M and IgM level (Figure upper panel). Respiratory functional study showed: reduced forced vital capacity (FVC-60% of the predicted volume, i.e., 23 dl) () and low diffusion capacity (for carbon monoxide DLCO-5,18 mmol/min/Kpa, i.e., 49%). BAL, blood, urine, bone marrow, sputum cultures, and MALDI analyses were all free of bacteria, mycobacteria, actinobacteria, and fungi. Analysis of fluid obtained by BAL showed an increase in the total cell count, predominantly in neutrophils and lymphocytes but without significant predominance of NKT cells as observed in hypersensitivity pneumonitis or pulmonary sarcoidosis (; ) (data not shown). Initial immunoparameters and cytometric analysis are shown in the first column of Table .
Contrary to previous data (), after intravenous immunoglobulin (IVIG) dosage adjustment (from 0.3 to 0.5 g/kg every 21 days, accordingly to the decrease of IgG before replacement) was ineffective as well as glucocorticoids (topical, then systemic with high-dose methylprednisolone up to 50 mg/daily) (Figure ).
Due to serum sickness with high IgM-paraproteinemia and high risk opportunistic infections, especially EBV reactivation (see pentamer analysis in Table ) lower rituximab dose (150 mg/m2 every week) was used. The patient did not receive other concomitant medication. The sixth dose (Figures , ) was delayed due to spontaneously resolved temporary neurological sign.
After temporary (6-month) remission and relapse the standard dose (375 mg/m2) infusion every 21 days) was used with the same remission interval (about 6 months). Such optimal schedule for RTx dosage every 3 weeks was described elsewhere (). In the third course patients could not receive regular regimen because of the increased incidence of infectious processes (especially pneumococcal, herpes zoster reactivation).
Relevant data from episode of care is shown as a timeline (Figure ) and in Table .
Unexpectedly, after rituximab therapy the LPD was stopped (Figure , as shown in PET). Restrictive pulmonary disease and FVC systematically improved and finally normalized (Figure ). The decrease of spleen size and leading biochemical and serological parameters were observed (i.e., β2M and IgM level, see Figures , ) in line with LIP regression and FVC increase. Fortunately, rituximab therapy was a glaring alternative for IVIG escalation: It also reduced IgG requirements by up to 40% of adjustment dose (Figure ). The serological and clinical effectiveness (IgM, FVC and PET finding) of both schedules were comparable, but more significant reduction of β2M was observed after 150 mg/m2 of rituximab (Figure ).
Parallel cytometric lymphocyte analysis is organized as a timeline (Figure ). A low dose does not affect the incidence of infections, but surprisingly it shows more pleiotropic immunomodulatory effects. There was observed high increase in low absolute number of CD16+56+ NK cells. Interestingly, T cell (CD4 and CD8) level also decreased, but it increased after the standard dose without the considerable increase of very low level of regulatory FoxP3 positive T lymphocytes (Treg) (Table ). Absolute number of natural killer T cells (NKT, CD3+56+) increased temporarily after low and standard dose (Figure ). Therefore, initial NK/NKT ratio (2.7) decreased during LPD progression, but it increased after the initial low dose of rituximab (Table ). Rituximab therapy shows a significant inhibitory effect on CMV-specific CD8+ cytotoxic T lymphocyte (CTL) levels and interferon gamma release, but RTx-induced CD38 expression on T cells was higher after the low dose (Table ). Interestingly, a low dose causes increase of post-mitogenic (PHA) interferon release.


A 63-year-old male patient with large anterior mediastinal mass was referred to our hospital for treatment. The patient was pathologically diagnosed as cervical schwannoma and underwent surgical resection twelve years ago. He had re-operation because of the recurrent neck tumor four years ago. No specific neural, cardiovascular and respiratory disfunction and neoplasms his history contained as well as his family history. The patient suffered from chest oppression and shortness of breath for four months, and these symptoms gradually became worse. The Preoperative CT confirmed that the patient was diagnosed as TM and large anterior mediastinal mass (Fig. ) Due to occasion of severe airway overreaction during the process of his endoscopy, fiber bronchoscopy was not finished.
Consideration of potential risk from serious TM, the patient was intubated with guidance of fibreoptic bronchoscopy in the supine position, then underwent median sternotomy and tumor resection followed by tracheal suspension. The prime procedures of this surgery were briefly depicted by hand drawings (Fig. a: tumor site exposure; Fig. b: further sculpture of removed autogenous rib cartilage; Fig. c: anchoring malacial tracheal rings and membrane by fresh graft) and details of surgical procedure were as follows:
Step 1: Tumorectomy. After medisection of sternum followed by opening pretracheal fascia, upper principal bronchus and frontage of cervical schwannoma were revealed. Along the line between the tumor and its adjacent tissue,the tumor was underwent entire resected.
Step 2: Fabrication of scaffold. Partial autogenous rib cartilage was removed from 5th rib, and its top and bottom parts were penetrated with flexible steel needle to form two channels available for thread, which could manufactured a scaffold to anchor the extensive malacial tracheal rings and membrane (Fig. ).
Step 3: Tracheal suspension. Free rib cartilage graft, fixed with bilateral tracheal rings, were deposited in front of malacial trachea by silk thread across the channels to cover the collapsed tracheal wall, so the malactic tracheal rings and membrane were elevated and pulled for enlarging the diameter of cartilaginous ring (Fig. a).
After living a short period of mechanical ventilation with positive airway pressure, the patient was successfully extubated within 12 h after surgery. During his hospital stay, major postoperative complications didn’t occur, but mild pneumonia happened. The patient was discharged on the 16th day postoperatively. In the follow-up,the images showed that either cross section of intraluminal stenosis or collapsed segment of airway was remarkably relieved, and scaffold made by autogenous rib cartilage clinged to extratrachea stably. It was surprising that the graft finally integrated with tracheal wall (Fig. b).


A 68-year-old white female presented to emergency department with complaints of
nausea, vomiting, and altered mental status.
One day prior, she presented to an outpatient clinic with left lower quadrant pain
and diagnosed with clinical diverticulosis. She was started on oral ciprofloxacin
and metronidazole from the clinic. She started taking these medications that
afternoon, both on an empty stomach. She began to have dizziness and vomiting since
4 am on the morning of presentation. She was brought by Emergency Medical
Service to the emergency department that afternoon.
The patient was afebrile (97.3°F) but had elevated blood pressure at presentation
(176/107 mm Hg). Physical examination revealed that she had dry oral mucosa, her
abdomen was soft, with no organomegaly, and she did not have any neurological
deficits. Laboratory findings on admission are shown in . Having nausea and vomiting,
physical examination with findings of dry mucus membranes and laboratory tests with
elevated blood urea nitrogen and creatinine suggested dehydration. She was also
noted to have hypercalcemia (). Hypercalcemia by itself could likely cause volume depletion,
since hypercalcemia leads to diuresis and vasoconstriction and contributes to acute
kidney injury. However, in this patient, given her recent history of vomiting, it
would be difficult to attribute volume depletion solely to hypercalcemia. There was
no history of primary HPT, thyroid disease, or thyroid cancer in her family. She was
treated with intravenous hydration with normal saline. Serum calcium reduced from
15.8 to 13.6 mg/dL with hydration alone. Prior to this hospitalization, she was on
over-the-counter calcium 600 mg, vitamin D3 800 IU, vitamin A 11 000 IU
daily, for history of macular degeneration, and valsartan/HCTZ 320 to 12.5 mg daily
for her hypertension; all medications had been taken for 3 years. These medications
were stopped during hospitalization.
She was subsequently referred for endocrinology evaluation. One week later,
laboratory findings in endocrinology clinic showed elevated serum calcium and
parathyroid hormone (PTH; ). 25-Hydroxy (25-OH) vitamin D; 1,25-OH vitamin D; and PTH-RP were
within normal limits. Serum immunofixation electrophoresis showed poorly defined
area of monoclonal protein. She underwent oncology evaluation to rule out multiple
myeloma.
Laboratory findings on oncology evaluation showed that urine Kappa light chains were
increased, as was the urine free Kappa/Lambda ratio, but no monoclonal spike was
detected in urine electrophoresis. On quantitative immunoglobulin (Ig) evaluation,
IgG (1327 mg/dL) and IgA (258 mg/dL) were normal, and IgM minimally elevated (289
mg/dL). Immunofixation revealed IgG Lambda monoclonal protein. She thus had
monoclonal gammopathy of undetermined significance but no myeloma; therefore,
myeloma was not contributing to hypercalcemia. Normal 1,25-dihydroxyvitamin D level
and angiotensin converting enzyme level ruled out the possibility of granulomatous
diseases like sarcoidosis and lymphoma.
She came for review in endocrinology clinic, a few weeks after her initial visit. She
had been off HCTZ for a few weeks at the time of this visit. Laboratory findings in
this visit ( and
) revealed elevated
calcium, with non-suppressed PTH, and normal 24-hour urine calcium. The diagnosis of
primary HPT was thus confirmed.
She was subsequently treated surgically for primary HPT. The right and left superior
parathyroid showed hypercellular parathyroid on pathology. The patient was
normocalcemic after surgery. The calcium on follow-up visit about a week after
surgery was 9.8 mg/dL (8.5-12.1).


A 61-year-old Caucasian female presented to a community hospital with a history of hyponatremia, arthritis, migraines, and bipolar disorder. She was admitted after coming to the emergency department (ED) on an emergency petition after her husband called the police. Her husband stated he called due to her manic symptoms and forgetting to turn the stove off. She was previously diagnosed with bipolar disorder in September 2017 for which she took divalproex 250 mg daily and quetiapine 50 mg at bedtime. At the time of the interview, the patient displayed hyperverbal pressured speech with rambling. Her thought process was goal oriented with bouts of loosening associations. She denied suicidal thoughts and use of alcohol, and she reported difficulty sleeping for which she used medical marijuana regularly. The patient appeared hypomanic, and her cognition and sensorium appeared clear.
At the time of admission, her sodium level was 129 mEq/L, with decreased hemoglobin and hematocrit. She was given olanzapine 5 mg orally at bedtime and was discharged two days later after her sodium levels and manic symptoms normalized from fluid restriction and oral sodium chloride.
Two days after discharge, the patient presented to the hospital with manic symptoms and was found to be hyponatremic. At admission, her sodium levels were 128 mEq/L. After treating her mania and restricting her fluids, her sodium level rose to 134 mEq/L. The patient had clear thoughts, speech, and cognition the following day. She stated that she was not drinking as many fluids, but, per the nurses, she was constantly requesting fluids.
On the third day of her admission, her sodium levels fell to 128 mg/L with a urine osmolarity of 268 mOsm/kg (reference range: 275 to 300 mOsm/kg), and a suspected increase in overnight fluid consumption was noted (Table ). She had a normal mental state, cognition, and sensorium, but was in distress about her constant fluctuating levels and wanted to leave the hospital. It appeared that she was having racing thoughts at this time and continued to discuss plans of divorcing her husband of 38 years and staying in a motel. SIADH and PPD were both considered at this time. She was further switched from divalproex and olanzapine to perphenazine and added sodium chloride tablets. She was discharged the following day.
A week following her third discharge, the patient was readmitted to the hospital with similar symptoms and hyponatremia. After nephrology consultation, she was diagnosed with reset osmostat (i.e., ADH shutting down due to low sodium levels). Her continuous cycles had shown that she was unable to control her fluid intake while at home and that she was at risk for continual admittance to the ED for hyponatremia with recurrent mania.


A 63-year old male presented with a history of lumbar laminectomy and fusion seven months prior to his initial presentation. He recalls that two days following his prone lumbar operation he began experiencing severe bilateral pain along the respective anterolateral thigh. Lumbar magnetic resonance imaging (MRI) ruled out spinal nerve root-related pathology as causative and a definitive diagnosis of bilateral MP, secondary to LFCN compression during the prone spinal surgery, was rendered. Conservative measures with oral analgesics were initially recommended given the typically self-limited course of this pathology. Despite an increasing regimen, including NSAIDs, narcotics, and anti-neuropathic pain medications, the pain persisted over the course of several months. Additionally, traditional anatomically-guided local anesthetic injections were attempted without improvement in his symptoms. Thus, the patient elected to proceed with operative decompression after eight months of failed conservative therapy and worsening quality of life.
The history of failed local anesthesia to even temporarily alleviate symptoms suggested a possible non-classic nerve location and prompted preoperative ultrasound to outline the superficial course of the LFCN. The ultrasound technique utilized has been previously described in the setting of percutaneous injection guidance (Figure ) [].
Skin markings in the inguinal region and upper thigh indicating the course of the LFCNs were made by the ultrasound technician prior to operative site preparation for surgery. Indeed, anatomically variant LFCNs were identified bilaterally on the preoperative ultrasound with neither nerve passing in a classic location medial to the anterior superior iliac spine (ASIS) (Figure ). On the right, the ultrasound identified the LFCN passing directly over the ASIS, while on the left, the nerve was localized lateral to the ASIS. Oblique incisions were made centered over the marked LFCN locations identified by ultrasound. Both LFCN anatomical variants observed on preoperative ultrasound were confirmed after intraoperative dissection. Fascia overlying the nerves was opened to effect decompression. The fascial opening was confirmed adequate by ensuring the absence of entrapment along its course out of the pelvis into the thigh (Figure ). The patient experienced immediate resolution of his preoperative pain and was discharged home on the same day without complication.


A 71-year-old Japanese man experienced dry cough for 2 weeks and visited the Department of Respiratory Medicine at our hospital in August 2007. Enhanced chest-abdomen computed tomography revealed a tumor with a 3-cm diameter in the left lower lobe and left pleural effusion (Fig. ). A 5-mm nodule, considered to be lung metastasis, was detected in the left upper lobe. Cytological analysis of the left pleural effusion by thoracic puncture led to the diagnosis of lung adenocarcinoma. Gadolinium-enhanced brain magnetic resonance imaging and bone scintigraphy did not reveal any other metastases. The tumor was classified as clinical T4N0M1, stage IV according to the TNM classification of the Union of International Cancer Control (UICC), 6th edition. According to the UICC 8th edition, it was classified as clinical T4N0M1a, stage IV A. The patient had a history of hypertension and was a past smoker (60 pack-years) and a company employee. The Eastern Cooperative Oncology Group performance status (ECOG-PS) at the time of admission was 1. The carcinoembryonic antigen (CEA) level was 97.4 ng/mL (normal, 0–5 ng/ml).
Beginning in August 2007, the patient received carboplatin (CBDCA) and docetaxel (DTX). After 4 cycles, the tumor was reduced to 1 cm in diameter. The 5-mm nodule and pleural effusion had also decreased. According to the Response Evaluation Criteria in Solid Tumors version 1.1, partial response was achieved, but he experienced progressive disease (PD) after 8 months. Six cycles of re-challenge chemotherapy (RC) using the same regimen were started in August 2008 and were effective. Thereafter, at each recurrence of PD, 4 to 6 cycles of RC were administered, and by 2013, 38 cycles had been completed over 6 years of treatment (Fig. A). However, we could no longer control disease activity using the same chemotherapy regimen. Moreover, primary tumor size evaluation became difficult owing to massive pleural effusion; although not standard, we estimated the effect of treatment using the increase and decrease of CEA as an index. CEA increased from a minimum of 4.6 ng/ml to 33.3 ng/ml in October 2013 during repeated cytotoxic chemotherapy. Although his EGFR mutation status was unknown, we initiated erlotinib administration and the CEA level decreased. After 8 weeks, the patient developed grade 3 acneiform rash, assessed using the Common Terminology Criteria for Adverse Events version 5.0, and erlotinib administration was discontinued for 6 weeks. Cycles of medication and treatment holiday were repeated, and the patient was carefully observed for skin rash. Dose reduction was attempted once, but it was not effective, because we noted an elevated CEA level and intolerable skin rash. For 3 years, 4-week erlotinib administration was repeated with 4–6-week treatment holiday intervals (Fig. B). CEA increased from a minimum of 3.1 ng/ml to 30.4 ng/ml in January 2017 during treatment with erlotinib. We performed EGFR mutation analysis using adenocarcinoma cells from the pleural effusion and detected exon 19 deletion and exon 20 T790 M mutation; therefore, osimertinib was substituted for erlotinib.
We continued monthly CEA measurements after beginning osimertinib administration and noted that the level continued to decrease. In August 2018, the CEA level was 12.1 ng/ml and the ECOG-PS was 1. As of the last follow-up, the patient has survived for >11 years since the diagnosis of lung cancer.


A 58-year-old man was admitted to our hospital with a two-month history of facial erythema and dry cough. He had no remarkable medical history except for essential hypertension five years ago. He was a current smoker with a smoking history of 37 pack-years. Although he initially seemed well and his vital signs were normal, a thorough physical examination revealed characteristic cutaneous manifestations of DM. He had a macular rash along with swelling on his forehead and upper eyelids (Fig. A), suggestive of a heliotrope rash. He also displayed a shawl sign characterized by a widespread, flat, reddened area on his upper back, shoulders, and posterior neck (Fig.B). Additionally, he had a flat, red rash on the back of the fingers and hands, indicating a Gottron’s sign (Fig. C). We observed a marked elevation of muscle enzymes in his serum, including aspartate transaminase (294 IU/L), creatine kinase (7833 IU/L), aldolase (50.3 U/L), and lactase dehydrogenase (606 IU/L) (Table ). Soon after admission, he felt muscle weakness, but not muscle pain, in his extremities. Manual muscle test detected reduced strength in his bilateral deltoid and hamstring muscles (grade 4/4), as well as iliopsoas muscles (grade 2/3), suggesting proximal muscle impairment. Based on the suspicion of idiopathic inflammatory myopathies, further analysis of auto-antibodies in patient’s serum revealed the presence of TIF1-γ auto-antibodies, but not that of anti-aminoacyl-tRNA synthetases (ARS), including anti-Jo-1, anti-PL7, anti-PL12, anti-EJ, anti-OJ, anti-KS, melanoma differentiation-associated gene 5, and anti-Mi-2 (Table ). Thus, the patient was tentatively diagnosed with possible DM and TIF1-γ positive myopathy. Fat suppressed T2-weighted magnetic resonance imaging coronal image demonstrated a high-intensity lesion in the bilateral rectus femoris, right vastus lateralis, vastus medialis, and bilateral obturator muscle. Needle electroneuromyography showed a myopathic pattern, with motor unit potentials diminished in amplitude as well as duration. Based on the DM diagnostic criteria recommended by Bohan & Peter and The Research Committee of the Japanese Ministry of Health and Welfare in 2015, we diagnosed the patient with TIF1-γ positive DM.
In addition, a routine chest X-ray (Fig. D) performed during admission showed a mass in the right middle lung field. Thoracic and abdominal contrast-enhanced computed tomography (CT) identified an inhomogeneously enhanced solitary mass (4 cm in size) in the right upper lobe (Fig. E), with ipsilateral hilar lymphadenopathy (Fig. F) as well as liver and left adrenal metastasis. Subsequent bronchoscopy and tumour biopsy confirmed lung adenocarcinoma. Thereby, the patient was diagnosed with cT2bN1M1b (stage IV) lung adenocarcinoma combined with TIF1-γ positive DM.
Following diagnosis, he was treated with 75 mg/day oral prednisolone for myopathy, which alleviated his muscle weakness, and improved his serum muscle enzymes and skin lesions within two weeks. At day 12 from admission, the patient was administered intravenous chemotherapy with cisplatin, pemetrexed sodium hydrate, and bevacizumab for lung adenocarcinoma. However, on day 19, he developed dysphagia, which was confirmed by a videofluoroscopic swallow study. He displayed hypopharyngeal muscle weakness, dysfunction of laryngeal closure, and ineffective oesophageal motility. Over the following one month, his posterior wall of the oesophagus at the level of the entrance considered to be ruptured due to emergence of oesophagus diverticulum on a repeated videofluoroscopic swallow study along with advent of both cervical subcutaneous emphysema on chest X-ray or the air in the cervical oesophageal wall on cervical CT. Thereafter, his general condition gradually deteriorated. Although the weakness in his extremities and his skin lesions were controlled, his oropharyngeal dysphagia persisted with conservative therapy, and his lung tumour was resistant to chemotherapy, resulting in his death due to respiratory failure six months later.


A 6-year-old boy, with a history of recurrent throat infections presented to Children's Memorial Hermann Hospital (CMHH) following 5 days of fever, sore throat, nasal congestion, and cough. Prior to presentation to CMHH, on day 1 of illness, he was diagnosed with influenza infection (clinical diagnosis) by his primary care physician (PCP) and prescribed oseltamivir which was discontinued on day 3 due to nausea and vomiting. Subsequently, on the 5th day of illness, he started to have abdominal and joint pain (left knee, right ankle, and right elbow). He was noted to be lethargic and had decreased oral intake with dark urine and, thus, was brought to CMHH emergency center (EC). In the CMHH EC, he was febrile (T 39.4°C), hypotensive (blood pressure 78/47 mm Hg), tachypneic (respiratory rate 33 per minute), and tachycardic (heart rate 160 per minute). He was admitted to a pediatric intensive care unit and was started on intravenous cefepime and vancomycin empirically. He lives with his mother and 3 siblings (aged 2, 9, and 10 years), all of whom were healthy with no current or prior symptoms.
Physical examination revealed an acutely ill but responsive boy with crusted lip lesions, cervical lymphadenopathy, nasal congestion, nonpurulent pharyngeal erythema, systolic murmur, and hepatosplenomegaly and no sign of arthritis. Initial lab studies showed a normal white blood cell (WBC) count (11,600/mm3) with an unremarkable differential, thrombocytopenia (36,000/mm3), anemia (hemoglobin 8.9 g/dL), hypoalbuminemia (1.9 g/dL), proteinuria (100 mg/dL), sterile pyuria (WBC 21/high powered field), and markedly elevated inflammatory markers (C-reactive protein 182 mg/L; erythrocyte sedimentation rate >100 mm/hr). Blood cultures drawn on admission along with pharyngeal culture were positive for GAS within 24 hours.
An echocardiogram was obtained due to the severity of presentation, presence of a murmur, and concern for infective endocarditis (IE). The transthoracic echocardiogram revealed echogenic tissues on the septal leaflet of the tricuspid valve (both on septal and anterior leaflets), tricuspid valve leaflet perforation with possible chordal disruption indicative of IE (). Chest radiographs were normal throughout the admission. Magnetic resonance imaging (MRI) of the body was obtained to evaluate for foci of dissemination and revealed bilateral nephromegaly with bilateral wedge-shaped areas of abnormal signal (possible pyelonephritis and/or thromboembolic disease), osteomyelitis involving the right inferior pubic rami and right obturator externus muscle abscess, periportal edema with hepatosplenomegaly, and bilateral pleural effusions.
Meeting the diagnostic criteria for STSS (hypotension with coagulopathy (thrombocytopenia), pleural/peritoneal effusions with hypoalbuminemia, myositis, and isolation of GAS), his antimicrobial therapy was changed to intravenous penicillin G and clindamycin. Subsequent blood cultures were negative. He did not receive intravenous immunoglobulin. Consultations with cardiology and orthopedic surgery were obtained, but no interventions were needed during hospitalization. He progressively improved and was treated with clindamycin for 1 week and penicillin G IV for 6 weeks to treat GAS IE with close cardiology follow-up for possible tricuspid valve repair.
This is particularly unusual presentation in an otherwise healthy child. GAS invasive disease may be associated with specific GAS clones harboring genetic elements or mutations that predispose to severe disease. Given the severity of diseases (STSS) and unusual multifocal presentation with endocarditis, we performed bacterial WGS, as we have previously described [], to define the bacterial strain characteristics associated with the pharyngeal and blood strains. The pharyngeal and blood GAS isolates from the patient were identified as emm89 GAS and were identical at the nucleotide level apart from a pentanucleotide repeat (10 bp deletion) in the gene encoding streptococcal collagen-like protein B (SclB) of the pharyngeal isolate compared to the blood. However, the deletion is not predicted to alter SclB expression as both isolates maintain a frame-shift mutation in SclB and thus likely do not express the protein. We did not identify mutations in virulence gene regulators such as covRS known to lead to hypervirulence. Comparing the case isolates to recent GAS WGS performed by the Centers for Disease Control and Prevention (CDC) [] revealed a similar clonal relationship to nationally circulating emm89 iGAS (). The case of pharyngeal and blood isolates did not have a unique streptococcal pyrogenic exotoxin (spe) gene content compared to non-STSS iGAS in the CDC collection and was similar to emm89 STSS strains in Houston, TX ().


A previously healthy 7-month-old African-American male presented to the ER in late winter after a generalized tonic-clonic seizure. There was no history of trauma or febrile illness. He was exclusively breastfed but had only received a multivitamin supplement for the first three months of life. Physical exam revealed a postictal infant with short stature, length = 64 cm (<5th percentile) and weight of 9.2 kg (75th percentile). Neurologic exam demonstrated brisk patellar reflexes, and the remainder of his physical exam was unremarkable. Initial labs showed severe hypocalcemia with total serum calcium = 5.9 mg/dl (normal range 8.5-10.9 mg/dl) and ionized calcium = .67 mmol/L (normal range 1.18-1.29 mmol/L). He was treated with IV calcium, after which serum calcium levels rose slightly but remained significantly below the normal range. Subsequent evaluation showed an undetectable 25-hydroxy vitamin D level of less than 4 ng/ml, with elevated parathyroid hormone and alkaline phosphatase levels (). Skeletal survey showed rachitic changes ().
The patient was diagnosed with nutritional rickets and was administered vitamin D stosstherapy treatment with ergocalciferol (Virtus Pharmaceuticals, ergocalciferol oral solution, USP, 8,000 international units per mL) 100,000 international units given orally every 2 hours for a total of 600,000 international units over 12 hours. By the last dose, the patient had become lethargic and urine output was decreased from 2.1 cc/kg/hr before treatment to .7 cc/kg/hr after treatment. Labs revealed acute renal failure, metabolic acidosis, and hyperkalemia. Creatinine level rose from .41 mg/dl pretreatment to 3.0 mg/dl following stosstherapy over a 36-hour timespan. He was treated with fluid resuscitation, diuretics, sodium polystyrene sulfonate, bicarbonate, and continued IV calcium. Renal function and calcium levels normalized, and serum creatinine returned to baseline of .41 mg/dl and total calcium = 9.8 mg/dl. The patient was discharged home after 4 days on oral vitamin D and calcium supplementation.


In February 2007, a 30-year-old woman at 16 weeks’ gestation was referred to our department with a one-month history of tongue pain. The patient was an ex-smoker, but had no history of alcohol consumption. A hard, endophytic tumor was present in the midsection of the tongue on the right. The lesion measured 2.6 × 2.2 × 0.8 cm and extended to the floor of the mouth (cT2N0M0).
Neither the patient nor her family wished to continue this pregnancy, preferring to concentrate on treating the SCC. Two weeks after terminating the pregnancy, the patient underwent a supraomohyoid neck dissection and hemi-glossectomy with reconstruction using a free forearm flap. Her post-operative course was uneventful. Pathologic examination of the resected specimen confirmed a well-differentiated SCC with clear margins and no cervical lymph node metastases; it was classified as a pT2 N0 tumor. In the 11.5 years since undergoing surgical treatment for this tumor, the patient has remained healthy, with no recurrence.


In November 2010, a 33-year-old woman who was 8 weeks’ pregnant was referred to our department with a two-month history of tongue pain. The patient was an ex-smoker but had no history of alcohol consumption. Physical examination revealed a painful, ulcerated lesion measuring 2.3 × 1.6 × 4.1 cm on the right side of the tongue (cT2N0M0) (Fig. ). After consulting with an obstetrician, it was decided to avoid performing contrast-enhanced computed tomography (CT) and to use β-lactam antibiotics and acetaminophen in the patient’s perioperative management.
At 13 weeks’ gestation, the patient underwent a trans-oral partial glossectomy under general anesthesia. Fentanyl citrate, thiamylal sodium, and sevoflurane were used for anesthetic induction, and sevoflurane and oxygen in air were used for maintenance of anesthesia. Lidocaine 1% with adrenaline (epinephrine) 1:300,000 was used for local anesthesia. Cefazolin was used to prevent postoperative infection, and acetaminophen was used for analgesia. During surgery, the fetus was monitored by ultrasonic examination. The operation time was 1 h 7 min and the anesthesia time was 2 h 1 min. The patient’s postoperative course was uneventful. The tumor margin was positive, therefore, the patient underwent trans-oral wide excision of the lesion under local anesthesia at 17 weeks’ gestation. The margins of the resected specimen were clear. The child was delivered at term and developed normally. In the 7 years since the operation, the patient has remained free of the disease.


In March 2012, a 32-year-old woman developed SCC recurrence of the right side of her tongue. At that time, the lesion measured 0.7 × 0.4 cm (rT1N0M0). She was then 22 weeks’ pregnant. She was a non-smoker and had no history of alcohol consumption. In consultation with the doctor in charge of obstetrics and gynecology, it was decided that the following drugs be used in the patient’s perioperative management: cefazolin or cefcapene pivoxil hydrochloride (antibiotics) and flurbiprofen axetil and diclofenac sodium (analgesics).
At 25 weeks of pregnancy, a trans-oral partial glossectomy was performed under general anesthesia. Pathologic examination confirmed a well-differentiated SCC with clear margins. Remifentanil hydrochloride, thiamylal sodium, and sevoflurane were used for anesthetic induction, and remifentanil hydrochloride and oxygen in air were used for maintenance of general anesthesia. Lidocaine 1% with adrenaline (epinephrine) 1:300,000 was used for local anesthesia. Cefazolin and cefcapene pivoxil hydrochloride were used to prevent postoperative infection, and acetaminophen was used for analgesia. Ultrasonic examination was used to monitor the fetus intraoperatively. The operation time was 1 h 13 min and the anesthesia time was 2 h 22 min. The patient’s postoperative course was uneventful. Four months after the operation, she delivered a healthy baby. Six years after the final operation, the patient remains free of the disease.


In December 2011, a 38-year old woman was diagnosed with T2 N0 SCC of the left side of the tongue; the diagnosis was confirmed by pathologic examination of a biopsy specimen. Brachytherapy was delivered via a Cs needle, up to a dose of 70 Gy. In May 2012, the patient developed cervical lymph node metastasis and underwent a left modified radical neck dissection. Cervical lymph node metastases were found in two (out of 48) level II lymph nodes, with extracapsular spread. In December 2012, CT revealed multiple pulmonary metastases, as shown in Fig. . However, the patient was at this point five-weeks’ pregnant. She and her family wished to continue the pregnancy, and therefore rejected the option of chemotherapy. Radiotherapy was thus administered for the pulmonary metastases. The patient underwent a caesarean section at 29 weeks’ gestation. Thereafter, she received 6 cycles of chemotherapy with cisplatin and 5-fluorouracil. The SCC relapsed in the patient’s neck and lungs, and she died 10 months after undergoing chemoradiotherapy.


A 23-year-old male presented to the emergency department (ED) with pain in his lower back radiating down his left leg. He had awoken from sleep five days prior with lower back pain radiating into both legs. He went to a hospital in another city where he was prescribed morphine, cyclobenzaprine, and naproxen. His pain was initially controlled enough that he could return to work while taking naproxen. The pain continued to progressively worsen and had begun to cause difficulty walking. He went to a family physician who suspected sciatic nerve pain and sent him to the ED for imaging of his spine.
On presentation to the ED, his pain was 7 to 8.5 out of 10. There was no history of trauma, and he had no bowel incontinence, urinary retention, or saddle anesthesia. He had no recent fevers, chills, or weight loss. His appetite was decreased due to his pain, and he had not had a bowel movement in three days. He had no significant past medical history and usually took no medications. He had consumed seven to nine alcoholic drinks and used cocaine the night before the pain began.
On examination, his temperature was 37.3°C, his heart rate was 96 beats per minute, his respiratory rate was 16 breaths per minute, his blood pressure was 124/60 millimeters of mercury, and his oxygen saturation was 100%. His abdomen was soft and non-tender. Testicular and rectal exams were normal. Palpation of the left sacroiliac joint revealed exquisite tenderness, identifying the more precise location of the lower back pain. Neurologic exam revealed normal tone, strength, and coordination in all extremities. Radiographs of the pelvis and sacroiliac joints were normal.
On laboratory workup, white cell count was 6.89×109/liter (L) (normal range, 4.5–11), serum hemoglobin was 100 grams (g)/L (normal range, 140–180), platelet count was 143×109/L (normal range, 150–350), and C-reactive protein (CRP) was 227 milligrams/L (normal range, <8). Peripheral blood smear showed increased polychromasia, some poikilocytosis with occasional teardrop cells, mature neutrophils, roughly 20% circulating blasts, and rare giant platelets, all consistent with acute leukemia. In the ED he was administered two milligrams (mg) of hydromorphone and 600 mg of ibuprofen orally. He was later admitted to the hematology service. He was diagnosed with precursor B-cell ALL and initiated on the Dana-Farber chemotherapy protocol. Two years post-diagnosis, his leukemia was in remission and he had recently completed his final cycle of chemotherapy.


A 64-year-old female with past medical history of diabetes mellitus presented to the emergency department in November 2017 for left eye pain of two days duration followed by left-sided neck rash. She complained of intermittent, shooting, burning pain along the distribution of this rash. She was examined and found to have nonconfluent grouped vesicles on the posterior neck and diagnosed clinically with herpes zoster reactivation (shingles). Initial electrocardiography (EKG) was unremarkable (no conduction blocks or evidence of pericarditis). She was treated with valacyclovir and oral steroids and advised to seek urgent ophthalmological evaluation at a specialized center. She was readmitted in March of 2018 after presenting with altered mental status. EKG performed at that time showed a new first degree atrioventricular (AV) block as shown in Figure below.
Admission vitals were blood pressure of 96/58, heart rate of 65 beats per minute. Laboratory studies done on admission were unremarkable except for hypoglycemia at 32. Later on that day, she developed bradycardia at 49 beats per minute with blood pressure 117/63 mm Hg. Repeat EKG was performed, this time showing Second Degree AV block (Mobitz I) as seen in Figure .
She denied any fever, chills, arthralgias, myalgias, vomiting or diarrhea. She also denied any chest pain, palpitations, or shortness of breath. Electrolyte abnormalities were corrected and she was continuously monitored on telemetry and followed with serial EKGs (Figures -).
She had a positive chronotropic response with exertion and awakening. Echocardiography done during admission showed preserved left ventricular function (60%) with no wall motion abnormalities and mild grade 1 diastolic dysfunction. Electrophysiology evaluation was obtained, who advised outpatient monitoring within two weeks to evaluate for progression. The patient was not felt to be at high risk of progression due to preservation of the chronotropic response as well as absence of high-grade block.


A 63-years-old Chinese female presented with asymptomatic palpable abdominal mass, increased carbohydrate antigen 19-9 (CA-199) level and pelvic mass on CT scan. An opening surgery observed an appendiceal mass involving the entire layer of the appendix, rupture, invasion of bilateral ovaries, wide-spreading nodular implantations with pseudomyxoma in peritoneal cavity, greater omentum, small intestine mesentery and hepatic and splenic regions. Debulking surgery with peritoneal nodule ablation and mucus reduction was performed in Beijing 301 Hospital. Postoperative pathology confirmed mucinous adenocarcinoma of the appendix T4NxM1, stage IV with peritoneal carcinomatosis (). After surgery, the patient received one time standard perioperative hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C. Because of the excessive peritoneal carcinomatosis, the patient was given three cycles of postoperative intraperitoneal chemotherapy (EPIC) with 5-FU plus mitomycin C. The patient remained symptom free for 1 year until she developed progressive abdominal distension, loss of appetite and worsening nourishment. The patient failed to response to further systemic chemotherapy, and a large number of PPM (). Then a second surgery was performed, intestinal obstruction by mucous cavities was observed, and a colostomy was given. Shortly after operation, cetuximab, a monoclonal antibody binding to and inhibiting EGFR, was given to the patient for 20 days (yet without gene testing) at a local hospital, but failed to show any improvement. By then the patient had tried all available approved options and became refractory to the treatments.
At the time when the patient visited us, she was severely wasted, with progressive abdominal distension and elevated CA-199 level at 5436.7 U/ml. Considering her weak constitution and failure of previous interventions, alternative treatment strategies, especially a rationally designed targeted therapy, emerged to be the last-ditch option to the patient. Targeted therapy is usually based on a patient's genomic profile by genetic testing. In order to find the accurate target, we decided to use the paraffin-embedded surgical tumor tissue from the patient, and detect gene mutations using the TruSeq Rapid Capture Exome Kit for whole exome sequencing (WES) on the Illumina NextSeq500 sequencing platform. The WES data was then analyzed using OncoDecoder™ (Genomic Future, Inc. USA). Several key gene mutations were identified including a missense mutation p.Gln472His (exon 11) in KDR/VEGFR-2, a missense mutation p.Arg281Gln (exon 8) in FGFR1, a missense mutation p.Lys296Arg (exon 7) in FGFR2, a missense mutation p.Thr654Ser (exon 14) in FGFR3 and a missense mutation p.Gly12Asp (exon 2) in KRAS. Additional 38 gene mutations including TP53, ERBB2, KIT, GNA11, and JAK3 were also detected ().
Although no NCCN-guided targeted therapy regime for appendiceal mucinous adenocarcinoma is documented as of to-date, there are two approved drugs for colorectal cancer may be considered as potential candidates: bevacizumab and cetuximab. Bevacizumab is a monoclonal antibody blocking the VEGF ligand, and bevacizumab in combination with standard chemotherapy has been approved by FDA as first line treatment for metastatic colorectal cancer (, ). We predicted that bevacizumab may be a suitable targeted drug candidate for our case based on the following three reasons: Firstly, the gene testing results showed several mutations involving KDR/VEGFR-2, FGFR1, FGFR2, and FGFR3. Although these mutations are currently classified as variation of uncertain significance (VUS), hyperactive VEGF pathway is a common event in colorectal cancer and contributes to tumor metastatic activity (). A recent study from the MD Anderson cancer center showed improved average overall survival and progression-free survival by providing anti-VEGF treatment to patients diagnosed with unresectable appendiceal epithelial neoplasm (yet no gene testing was performed) (). This finding suggests that VEGF hyperactivity could be a common event in appendiceal cancer, and bevacizumab could be a promising targeted drug. Next, it has been known that the efficacy of certain EGFR monoclonal antibody drugs, including cetuximab and panitumumab, could be affected by KRAS mutation (). Indeed, in the present case, we identified KRAS p.Gly12Asp missense mutation, which could cause inefficient response to cetuximab (). However, the efficacy of bevacizumab for colorectal cancer treatment has been testified to be independent from KRAS mutation (). Thirdly, there was no contraindication of bevacizumab usage to the patient. The common risk factors include low WBC count, high blood pressure, impaired heart function and poor renal function.
Under our advice, the patient received treatment of bevacizumab (7.5 mg/Kg, in total 450 mg, IV-GTT) plus oxaliplatin (130 mg/m2, in total 200 mg IV-GTT) on day 1 every 3 weeks for 6 cycles since August, 2016. Follow-up examination after treatment showed significant improvement of the patient's condition, and CT scan imaging results showed dramatic reduction of her peritoneal mucus (as shown in ). In addition, the patient's CA-199 level decreased from 5,436.7 U/ml (before treatment) to 1121.4 U/ml (after treatment). Afterwards, the patient received continuous maintenance treatment using bevacizumab (7.5 mg/Kg, in total 450 mg, IV-GTT on day 1 each 3 weeks) plus capecitabine (1,500 mg, oral, twice a day) for days 1 to 14 until now. The patient has been followed up routinely to evaluate the treatment efficacy and to monitor the adverse effects. The main adverse effects were numbness in the hands and feet, dry nose and epistaxis, dry throat, fatigue, loss of appetite. The patient has been progression-free as of recent follow-up on September 26th, 2018 with the most recent CA-199 being 401.26 U/ml on August 15th, 2018.


A 19-month-old boy who had born in March 2015 with multiple brown-black skin pigmentation on the face, trunk, and right leg, with multiple satellite lesions (). He was referred to hospital because of repeated vomiting for 4 days. He had a round face, full cheeks, prominent forehead, hypertelorism, periorbital fullness, short nose, and everted lower lip. The largest nevus was on the leg, of about 13 cm in diameter [(13 × 10), (8 × 6), (4 × 2) cm]. Enhanced MRI showed hydrocephalus (). A shunt surgery was done, to relieve the symptoms of intracranial hypertension, followed by MRI and/or computed tomography (CT) assessment every 3 months. The result of 6 months post-shunt MRI revealed the presence of supratentorial ventricular dilatation, brain stem volume reduction, in addition to leptomeningeal enhancement, however, no macroscopic mass was evident. Three months later, MRI showed a mass of 3 cm diameter, in the right frontal lobe. Although the tumor was completely resected, the patient died 4 months after surgery.
Pathological evaluation of CNS lesion, revealed that the mass was grossly dark-red to brown with the size of (4 × 4 × 2) cm. The tumor was firmly attached to the meninges. Microscopically, the tumor cells had atypical nuclei, obvious nucleoli, an increased karyoplasmic ratio, some mitoses, and remarkable necrosis, which infiltrated the brain parenchyma, accompanied with melanin deposition.
Immunohistopathological evaluation as shown in disclosed that the tumor cells were positively expressing the antibodies of HMB45, Melan-A, and S100. Ki-67 was positively expressed in 30% of the cells, while P53 was negative.
Cytogenetic study using fluorescence in situ hybridization (FISH) revealed a lack of allelic deletion of P53. ARMS-PCR disclosed NRAS mutation in the third exon (codon 61), with a wild-type BRAFV600E ().


A 4-year-and-9-months-old girl who had a brown-black skin pigmentation over her neck since birth, presented with headache and vomiting of 10 days duration. The largest diameter of the nevus was 12 cm (12 × 9.5 cm). Clinical examination revealed disturbed walking, balance, and coordination. CT and MRI disclosed a mass occupying most of the left cerebellar hemisphere, reaching the dura (. She underwent complete surgical resection, however, she died 3 months after surgery, due to progressive disease.
Pathological evaluation of CNS lesion, revealed that the mass was grossly grayish-red to brown, of soft consistency, and the size of (4 × 3 × 2) cm. Microscopically, the tumor cells exhibited atypical nuclei, obvious nucleoli, and large number of mitoses, accompanied with outstanding necrosis and melanin deposition.
Immunohistopathological study showed that the tumor cells were positively expressing the antibodies of HMB45, Melan-A, and S100. Moreover, Ki-67 was positively expressed in 50% of cells ().


A 56-year-old woman presented to the ophthalmology clinic with a main complaint of acute onset right eye pain with extra-ocular movement. She also reported right eye periorbital swelling, redness, upper right lid drooping, and bilateral tearing. She received her first zoledronic acid infusion for osteoporosis 24 h prior to presentation. Her significant past medical history included chronic inflammatory demyelinating polyneuropathy, Sjogren’s syndrome, and systemic lupus erythematosus. The patient had been on cyclosporine 75 mg (1 mg/kg) daily and monthly belimumab 120 mg/1.5 ml for her rheumatologic conditions for 3 years prior to presentation.
On ophthalmic exam, her best-corrected visual acuity was 20/25–2 in the right eye, and 20/25–3 in the left eye. Intraocular pressure was 14 mmHg in the right eye and 13 mmHg in the left eye. On external exam of the right eye, there was mild upper lid edema, erythema, ptosis, and − 1 adduction defect. The slit lamp exam was remarkable for conjunctival chemosis without anterior chamber cell or flare. The posterior segment exam was remarkable for posterior vitreous detachment (PVD) (Fig. ). The left eye exam was significant for PVD (Fig. ). 24–2 visual field testing attempted but was not reliable due to frequent fixation loss secondary to eye pain. A contrast enhanced MRI was obtained which showed: 1) ill-defined right orbital soft tissue thickening, 2) enhancement in the retro-orbital intraconal space with extension along the retro-orbital scleral contour and surrounding the anterior optic nerve sheath (Figs. and ). Orbital inflammation secondary to SLE was considered as part of the differential based on the patient’s rheumatologic history. However, based on the clinical presentation, MRI findings, and timing of symptoms with regards to the zoledronic acid infusion, orbital inflammation secondary to bisphosphonate therapy was suspected. The patient was started on oral prednisone 50 mg daily with rapid improvement in symptoms. After 1 week, patient reported full resolution of symptoms and was started on a slow weekly taper of prednisone.


The patient was a forty-five-year-old man who worked at a soybean paste making factory. He had no specific past or family history. While working with a soybean milling machine, his clothing became entrapped by the mixing rotator (). His clothing was wound around the rotator and tightened around his neck and chest, causing strangulation and a loss of consciousness. He was rescued by coworkers and transported to our hospital by a physician staffed helicopter. Upon arrival, his vital signs were as follows: Glasgow Coma Scale, E4V4M6; blood pressure, 128/80 mmHg; pulse rate, 78 beats per minute; respiratory rated, 16 breaths per minute, peripheral oxygen saturation on 10 liters of oxygen per minute with a reservoir mask, 100%; and temperature, 35.8°C. A physiological examination revealed multiple petechiae on his face and strangulation marks with subcutaneous hemorrhage on his neck and upper trunk (). In addition, he had motor weakness of the right upper extremity and bilateral paresthesia from C5 to Th1. Chest roentgenography, electrocardiography, whole body computed tomography, and cervical magnetic resonance imaging revealed no specific findings. The results of blood biochemical analyses on arrival revealed leukocytosis (16,800/μL) and rhabdomyolysis (creatine phosphokinase, 723 IU/L). He was admitted for observation. After the patient's creatine phosphokinase level peaked and his focal neurological signs improved, he was discharged on foot on the 6th hospital day.


A 45-year-old woman originally visited a different hospital because of a focal asymmetric density of the left breast identified by screening mammography. She had a medical history of Sjogren’s syndrome. Ultrasonography showed no abnormality in the left breast, whereas an indistinct hypoechoic mass of 25 mm in diameter was detected in the outer side of the right breast. Although cytology of the right breast mass indicated no malignant feature, she came to our hospital for further examinations.
A lump of 3 cm in diameter was palpable on the outer side of the right breast. Mammography at our hospital showed no abnormality (Fig. ). Ultrasonography showed a well-defined and rough hypoechoic mass of 32 mm in diameter at the site of the lump (Fig. ). With suspicion of breast cancer, an ultrasound-guided vacuum-assisted breast biopsy was performed.
For pathological diagnosis, hematoxylin and eosin staining showed deposits of nonstructural substances in the interstitium (Fig. a). The specimen was positively stained by Congo red (Fig. b) and showed green birefringence under a polarizing microscope (Fig. c). Thus, the mass was diagnosed as an amyloid tumor. She had no systemic symptoms suggestive of systemic amyloidosis. We considered further therapy to be unnecessary, and annual follow-up was recommended.


A 51-year-old man was admitted to the Emergency Room in a state of altered sensorium, with motor deficit of the lower limbs. The patient had been suffering from chronic alcohol abuse for 30 years, with an average daily intake of 700 mL/die. Physical examination revealed a Glasgow Coma Scale score of 9 (E2V3M4). No meningeal signs were present. Pupils showed normal size and were reactive to light. The patient did not suffer from diabetes, hypertension, seizure nor other significant diseases. Routine blood test and cerebrospinal fluid studies were negative. Electroencephalographic examination was normal. Brain MRI showed an area of high signal on fast-spin-echo (FSE) T2-weighted images and high signal on diffusion weighted imaging (DWI) with a decreased apparent diffusion coefficient (ADC) value of 670 x10-3 mm2/sec, observed with a region of interest size of 19 mm2, in the splenium of the corpus callosum (Figures –). On the basis of history, findings on physical examination, and MR imaging features, the diagnosis of MBD was hypothesized. He was transferred to the intensive care unit where he required noninvasive ventilation and was treated with thiamine 400 mg/day [] hydration and parenteral nutrition with vitamin supplement, so the electrolyte balance was quickly restored. We did not use steroid therapy. He showed improvement of symptoms with a good recovery in twenty days. Thirty-day follow-up brain MRI showed resolution of the abnormal callosal finding on both T2-weighted images and DWI-ADC maps (Figures –).