A 28-year-old woman presented to our tertiary care hospital reporting concerns of left arm weakness and paresthesia for three hours. The weakness started suddenly when she was sitting in her office. Two weeks before presentation, she developed right leg weakness at breakfast that resolved completely within 1.5 hours. One week before presentation, she developed the blurred vision in both eyes that also resolved completely within one hour. Her mother was diagnosed with MS at age 40 and is on treatment with frequent relapses. The rest of the patient’s medical and surgical history was unremarkable.
Her Glasgow Coma Scale score was 13/15 (eye [E] 4, verbal [V] 5, motor [M] 4). Her blood pressure was 110/70 mmHg, heart rate was 80 beats/minute, respiratory rate was 20 breaths/minute, and she was afebrile. Her neurological examination showed normal mentation with intact cranial nerves with unremarkable results from her funduscopic examination. Her motor examination showed normal bulk in all muscles with no fasciculation and tremors. Her motor strength, as tested on the Motor Research Council scale, was as follows. Her neck muscles flexion was 5/5, and extension was 5/5. Her right deltoid was 5/5, left was 4/5. Her biceps and triceps were 5/5 (right) and 3/5 (left). Her right iliopsoas was 4/5; her left was 5/5. Her knee flexion/extension was 4/5 (right), 5/5 (left), and foot dorsi/plantar flexion was 5/5. Her right biceps/triceps reflexes were 2+, her left biceps/triceps reflexes were 3+. Her patellar reflex was 2+, and her ankle reflex was 2+. Her Babinski reflex was absent. She was able to walk without support. The findings of her cerebellar and sensory exams were unremarkable.
Her care team suspected transient ischemic attack, and she was sent for urgent computed tomography (CT), which showed no remarkable findings. Blood and metabolic profile test findings were unremarkable, and her low-density lipoprotein was 150 mg/dl. Her cerebrospinal fluid detailed report findings were within reference ranges with no oligoclonal bands and a healthy IgG index, but her MRI showed periventricular hyperintensities in the periventricular area (Figure ). Magnetic resonance angiography findings were unremarkable.
We started the patient on 1000 mg of IV methylprednisolone daily to treat the suspected acute flare of MS. After three days of treatment, the patient’s symptoms were improved, and she was discharged on aspirin and glatiramer acetate (GA) with instructions to return after one month for follow-up if she remains stable. She visited the outpatient clinic after six months and was doing fine, but she reported that she was experiencing difficulty concentrating and was unable to work with enthusiasm. She also reported concerns about frequent mood changes and being mostly tearful when she was formerly a very happy person. We sent the patient for a psychiatric evaluation and checked for NOTCH3 mutation. To our surprise, she had a missense mutation in exon 11 of NOTCH3, a mutation suggestive of CADASIL. Her GA was stopped, and she started aspirin and statin therapy with the advice of further cognitive evaluations and regular psychiatric assessments. She was also advised to seek genetic counseling and testing of NOTCH3 mutation in her mother.


A previously healthy 11-month-old girl was admitted to the pediatric emergency room with fever (38.3°C) and vomiting 6–8 hours after the second dose of the 4CMenB vaccine on the left lateral thigh, although she had received prophylactic paracetamol before vaccination. Her vomiting was not massive and did not repeat in the hospital. Her physical examination revealed irritability and tachycardia with good perfusion. She was not agitated, and the injection site was not painful. Her heart rate was over 200 per minute in rest without any cardiac murmur or additional heart sounds. Laboratory workup results were as follows: hemoglobin 12.9 g/dL, white blood cell 5170/μL, platelet count 380,000/μL, CRP 0.9 mg/L (N < 7.9), and procalcitonin 0.01 ng/mL (N: <0.5), respectively. Influenza A and B, respiratory syncytial virus, adenovirus nasopharyngeal swab antigen assays, and streptococcal pharyngeal swab antigen test were all negative. Her plasma glucose was 90 mg/dl, and other biochemistry values were normal but creatinine kinase-MB was elevated (5.2 ng/ml, N: 0–3.61). After verifying SVT with narrow QRS complex without p waves (), vagal stimulatory maneuvers were applied but her heart rate did not become normal. Then, rapid adenosine infusion protocol with 100 μg/kg was injected via a large antecubital venous catheter. Meanwhile, she was hospitalized and monitored, but SVT did not reverse after the first adenosine injection. Then, second, third, and fourth adenosine injections were given with dosage increment to a maximum dose of adenosine (350 μg/kg, total 3000 μg). Her heart rate was converted after 5 seconds to normal sinus rhythm after infusion of the fourth dose of adenosine, total 2 hours of arrival. Then, oral propranolol (3 mg/kg/day, every 8 hours) maintenance treatment was started. Echocardiography revealed normal cardiac anatomy with slightly decreased left ventricle function (EF: 48%; left ventricle end-diastolic volume was 32.2 mm) during SVT and normalized after two days. She was followed for 3 months, and no recurrence of SVT was detected.


We reported the case of a male patient, 16 years old, with a history of frontal headaches accompanied by photophobia, nausea, and vomiting since the age of 4. He had his first episode of migraine associated with ocular pain and ptosis in the right eyelid, lasting 24 hours, in Jun 2010 at the age of 6. Six months later (Jan 2011), he had a heavier and persistent episode of migraine associated with right ocular pain (partial responsiveness to administration of paracetamol), right ptosis, and diplopia, so he was admitted to the Child Neuropsychiatry Unit, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro,” Italy. Family history of migraine in both parents, multiple sclerosis in the father's family, and gastric neoplastic disease in the mother's family was referred. General physical examination was normal; neurologic examination showed paresis of the third and sixth cranial nerves. Laboratory investigation, including virological and organ-specific serum antibodies, and instrumental examination including awake/sleep electroencephalograph produced normal results. Brain and cervical-spine magnetic resonance imaging (MRI) enhanced after contrast administration and magnetic resonance angiography (MRA) produced normal findings. Diagnosis of “ophthalmoplegic migraine” was made according to ICHD 2, as discussed in a previous publication []. During the following years, about one time a month, the subject suffered from a moderate to severe intensity headache in the frontal and supraorbital region on the right side with a transient remission with paracetamol. Since his first hospitalization, he had 2 more episodes, in Jul 2013 and Jun 2016, of OM, with ocular pain ptosis in the right eyelid and diplopia. In both episodes brain MRI confirmed normal images. The diagnosis was revised as RPON according to the new diagnostic criteria of ICHD-3 beta (2013) []. At the age of 15 years (Sep 2018), the patient was again admitted to our Child Neuropsychiatry Unit manifesting moderate and persistent migraine, nausea, vomiting, phonophobia, and photophobia associated with right ocular pain, diplopia, and ptosis. Neurologic examination showed right eyelid ptosis, and ophthalmologic evaluation showed paresis of the III cranial nerve. Brain MRI with MRA revealed a 5-6 mm nodular enhancement mass, located within the fork of the right basilar artery near to perimesencephalic and interpeduncular cisterns, suggesting an oculomotor nerve schwannoma without any vascular malformation (Figures and ). The subject was treated with corticosteroid therapy because of the partial and transient responsiveness with paracetamol during acute episodes of right eye pain. He showed gradual and progressive improvement of headache symptoms in about one week.


A 44-year-old Han Chinese woman who had pain in the left hypochondrium for 10 days was admitted to the hepatobiliary surgery department at Dazhou Central Hospital, Sichuan Province, China. The patient came from a small county of Dazhou in eastern Sichuan. She moved to Tibet at the age of 32 years where she lived for 10 years. She had a history of contact with dogs and livestock at her hometown and in Tibet. On examination, the left upper abdomen appeared swollen and a mobile tender mass was palpated, but no liver was suspected. In the left upper quadrant, the spleen was enlarged 15 cm below the left costal margin and was slightly tender, without muscular defense areas or signs of peritoneal irritation. The other components of the physical examination were normal.
Abdominal USG revealed a 13.5 × 12.1-cm–sized anechoic solitary, thin-wall cyst in the splenic parenchyma (). Computed tomography scan showed a large well-defined hypodense cystic lesion in the upper pole of the spleen, involving almost the entire spleen and measuring 15.2 × 14 cm (). Laboratory tests revealed mild leukocytosis (11,760 cell/mm3) and eosinophilia (6.8%). Other biochemical tests were in the normal range.
Based on the clinical manifestation and preoperative imaging findings, an SHD was strongly suspected. However, given the high risk of cyst rupture and obvious pressure symptoms, we did not conduct serologic tests, instead we directly performed laparoscopic splenectomy on the 2nd day of admission after communicating with the patient. A standard four-trocar placement was used to establish access ports. Pneumoperitoneum was produced in the supraumbilical area using carbon dioxide (12 mm Hg), after which a 10-mm port was placed. A 5-mm port was positioned to the left of the falciform ligament below the xiphoid and a 10-mm port was placed on the left midclavicular line as the main manipulation port. An additional 5-mm port was positioned at the inferior pole of the spleen to the left midaxillary line for injection and aspiration. An old rupture was found on the surface of the cyst in the upper pole of the spleen, which adhered to the diaphragm. Any adhesion between the cysts and neighboring organs was lysed. After locating the spleen cyst, gauzes moistened with hypertonic saline were placed around the cyst to prevent potential contamination and anaphylactic reactions. Then, a Veress needle was inserted into the cyst via the incision site, after which about 500 mL of the cyst contents were aspirated and 20% hypertonic saline was injected into the cystic cavity as a scolicidal agent. After a 5-minute waiting period, the hypertonic solution was aspirated from the cystic cavity. This cycle of injection and aspiration was repeated five times. Subsequently, the spleen was totally excised and extracted in an endobag. No bleeding points were seen, and the peritoneum was soaked with 20% hypertonic saline for 10 minutes and washed with 0.9% saline three times. Finally, a tubular drain was introduced through the left port and positioned at each of the splenic fossa and pelvic cavity.
The cut section of the cyst capsule appeared curled and soft (). The histopathological examination of the specimen confirmed the diagnosis of SHD (). Postoperative recovery was uneventful and the drain was removed at day 4 after surgery, and the patient was discharged on the 6th postoperative day. Albendazole (400 mg per day) was initiated from the first postoperative day and continued for 3 months. She was followed up every 3 months. At the 12- and 24-month follow-up visits, she was asymptomatic, and her laboratory tests were normal. Both abdominal USG and CT found no disease recurrence ().


A 46-year-old Chinese woman consulted a physician in our department for an intrahepatic mass incidentally detected by an abdominal ultrasound (US) during her annual physical examination. After a 7-cm hypoechoic mass in the right lobe of the liver was identified and confirmed, the patient was admitted to our hospital for further investigation and treatment of the hepatic lesion. She reported no immunosuppressive medication use and no history of liver disease or surgery.
No mass and discomfort and no signs of other clinical symptoms were detected during the abdominal examination. Hematological and serum biochemical profiles were within normal ranges. Tumor markers including alpha-fetoprotein (AFP), carcinoembryonic (CEA), carbohydrate antigens 199 (CA199), and carbohydrate antigens 125 (CA125) were also normal.
Further investigation of the hepatic lesion with computed tomography (CT) revealed a slightly hypodense 6.5 × 7.2 cm mass in the right lobe of the liver with heterogenous enhancement of arterial phase, and prolonged enhancement through portal venous phase and the lesion (Fig. a, b, c). No other abnormalities were identified in the remaining liver tissue and elsewhere the abdomen.
As the CT imaging was inconclusive, further evaluation with magnetic resonance imaging (MRI) as well as US-guided fine needle aspiration (FNA) biopsy of the tumor for pathological examination was recommended. However, the patient preferred an operation without additional preoperative assessment of the lesion.
In view of the benign features of the hepatic lesion and in accordance with our patient’s choice of treatment, we carried out laparoscopy (Olympus, Tokyo, Japan). A 12-mm optical trocar at the umbilicus as well as three other trocars was used. Two 12-mm trocars were used through the epigastrium and right upper abdomen. A 5-mm trocar was used through the right abdomen near the anterior axillary line. After a laparoscopic exploration and US, a solid 6.5 cm × 7.0 cm × 7.5 cm mass was clearly located in the segment 6 of the liver and outwardly protruding from the liver surface (Fig. d). We decided to perform laparoscopic partial hepatectomy. Hepatic parenchyma was performed using an UltraCision Harmonic Scalpel (Ethicon Endo-Surgery, Cincinnati, OH, USA). The branches of the Glissonian pedicles and hepatic vein within the liver were clipped using a Hem-o-lok® (Teleflex Medical, Morrisville, NC, USA) and a titanium clip (TSCS, Hangzhou, China), and then transected. We put the surgical specimen into a laparoscopic disposable specimen bag (Xueli, Nanchang, China) through the epigastrium incision, and to avoid expanding the incision we cut the specimen into small pieces in the bag before taking them out (Fig. e). Finally, the surgical area was carefully examined and a drainage tube was not placed. Seven days after surgery, the patient was discharged from hospital. After a 2-year follow-up, no recurrence or metastasis occurred.
Postoperative pathological examination revealed a benign smooth muscle tumor derived from the mesenchymal tissue of the liver with clearly visible margins and with no evidence of necrosis or tumor invasion (Fig. a, b). Immunohistochemistry (IH) showed strong reactivity for smooth muscle actin (SMA) (+), desmin (+), and H-caldesmon (+) (Fig. c, d, e), but not for Dog-1 (−), CD117 (−), S-100 (−), and CD34 (−) (Fig. f, g, h, i). According to the diagnostic criteria for PHL, the patient was finally diagnosed with PHL.


The patient was a 50-year-old man with a body mass index of 25.7 kg/m2 and a 1-year history of hypertension who was preoperatively diagnosed with aortic dissection (Stanford B type), a thoracoabdominal aortic aneurysm, and grade 2 hypertension. The treatment plan consisted of staged reconstructive surgeries of the ascending aorta, aortic arch, and full thoracic and abdominal aorta. The patient has provided informed consent for publication of the case.
As the first stage of the surgery, the total aortic arch was replaced, and a stent was placed in the descending aorta. With routine monitoring, the patient was induced of intravenous anesthesia and maintenanced of intravenous-inhalational combined anesthesia. Intermittent blood sampling was conducted for blood gas and electrolyte analysis. Thromboelastography (TEG) was employed to monitor the patient's coagulation function. During surgery, external warming and warming of transfused blood were employed to prevent hypothermia. Autologous blood was collected through the right internal jugular vein and separated into 878 mL of PRP and 497 mL of RBCs using an Autotransfusion Blood Separator device (Xtra Sorin Group Deutschland GmbH). The PRP was stored under continuous shaking at room temperature (22–24 °C). The Autotransfusion Blood Separator device was used to achieve and concentrate the whole blood lost during the time from cutting the skin to closing the chest.
While the right axillary artery and the right femoral artery were catheterized respectively, a median incision was made and both superior and inferior vena cava were incubated to establish a cardiopulmonary bypass. Selective cerebral perfusion was performed to maintain regional cerebral oxygen saturation (rScO2) at least 55%. A 28 × 80-mm stent was placed in the descending aorta. Then a 28-mm-diameter 4 branches aortic graft was used for replacement, the proximal end of which was anastomosed with the end of the autologous vessel and the distal end of which was anastomosed with the proximal end of the descending aortic stent. Circulation arrest lasted for a total of 22 minutes. The ascending aorta was blocked for a total of 92 minutes, with the cardiopulmonary bypass stopped after 22 minutes.
After heparin neutralization with protamine, PRP and autologous RBCs were transfused back to the patient. A total of 251 mL of concentrated RBCs were collected during surgery. Another 2 U of allogeneic RBCs, 2 U of platelets, and 20 U of cryoprecipitate were administered. The total urine volume was 750 mL. The surgery lasted for 4.5 hours and the patient was admitted to the cardiac surgery intensive care unit (CS-ICU) after surgery with endotracheal intubation.
After the first surgery, the patient receives no allogeneic blood products. The platelet count before, immediately after, and 24 hours after the surgery were 218 × 109/L, 173 × 109/L, and 198 × 109/L, respectively. The MA value of TEG before, immediately after, and 24 hours after the surgery were 71.8, 69.8, and 70.1 mm, respectively. The ventilator was withdrawn at 18 hours after surgery and the patient was discharged from the CS-ICU on postoperative day (POD) 4 and discharged on POD 35. At discharge, the general condition of patient was good, with normal limb activity and no nervous system-related complications.
Four months later, as the second stage of the surgery, thoracoabdominal aortic replacement was performed. The patient's body mass index was 24.7 kg/m2 and thoracoabdominal computed tomography angiography suggested that after surgery of the aortic arch and descending aorta, an aneurysm with thrombosis had formed in the thoracoabdominal aorta, as determined by a low-density linear shadow in the distal segment of the aortic arch to the distal part of the abdominal aorta. The lumen was divided into true and false chambers.
On the day before surgery, the L3–4 subarachnoid space was punctured to insert the drainage tube, which was connected with the cerebrospinal fluid drain and pressure monitoring system, and properly fixed after ensuring smooth drainage and normal pressure. Conventional intravenous anesthesia was induced after entering the operating room and an endobronchial blocker tube was placed through the endotracheal tube. The position of the endobronchial blocker tube was confirmed by the fiberoptic bronchoscope. Intermittent drainage of cerebrospinal fluid (10 mL/h) was performed to maintain cerebrospinal fluid pressure <10 mmHg whether intra or post-operation. Blood and electrolytes were analyzed intermittently, and blood coagulation function was monitored by TEG. During surgery, external warming and warming of the transfused blood was employed to prevent hypothermia.
Autologous blood separation and recovery were used for blood preservation. Autologous blood was collected from the right internal jugular vein and separated using an Autotransfusion Blood Separator device. A total of 865 mL of PRP and 521 mL of RBCs were isolated. The device was then used to achieve and concentrate the whole blood lost during the time from cutting the skin to closing the chest.
Surgery was performed with the patient in the right lateral position, with the upper body facing 90° to the right and the lower body at 45°. A left thoracic posterolateral side and left abdominal lateral side combined incision was made, with entry into the chest made at the fourth intercostal space. After systemic heparinization, arterial intubation was performed before the distal iliac artery branch of the abdominal aorta, after that an intravenous catheter was placed to the right atrium entrance through the left femoral vein. The proximal aorta was blocked at the distant end of the aortic arch with the distal thoracic aorta blocked at the T3 level for partial extracorporeal circulation. The main blood vessels and thoracoabdominal aorta were replaced with 26-mm-diameter bifurcated artificial vessels.
After heparin neutralization with protamine, PRP and autologous RBCs were transfused back to the patient. A total of 1353 mL of concentrated RBCs (hematocrit 49%) were collected during surgery. Another 4 U of allogeneic concentrated RBCs, 4 U of platelets, 20 U of cryoprecipitate, and 4000 mL of crystalloid solution were administered. The total urine volume was 900 and 70 mL of cerebrospinal fluid was drained. The surgery lasted for 8 hours and after removal of the endobronchial blocker tube, the patient was admitted to the CS-ICU with tracheal intubation.
The patient received only 400 mL of allogeneic plasma after surgery. Cumulatively, 1019 mL of cerebrospinal fluid was drained during the perioperative period. There were no significant differences in platelet counts on the first morning after and 24 hours after surgery, as compared with before surgery (232 × 109/L and 175 × 109/L vs 191 × 109/L, respectively). The MA value of TEG before, immediately after, and 24 hours after the surgery were 66.7, 64.3, and 68.8 mm, respectively. The ventilator was withdrawn at 68 hours after surgery and the patient was discharged from the CS-ICU on POD 8 and discharged on POD 23. At discharge, the general condition of patient was good with normal limb activity and no nervous system-related complication (Tables –).


A 76-year-old man was admitted to our hospital for abdominal pain and biliary vomiting. He had a past medical history of Alzheimer disease, chronic obstructive pulmonary disease and myelodysplastic syndrome recently treated with blood transfusion. He was diagnosed for intestinal occlusion due to obstructive right inguinal hernia and he was submitted to a surgical resection of an ischemic intestinal loop, ileostomy and hernioplasty. Due to hemodynamic instability, he was transferred to our ICU.
The post-operative period upon admission was characterised by hypotension non-responsive to fluid challenge and vasoplegia that required the administration of dopamine at the dosage of 6 mcg/kg/min to obtain hemodynamic stability. To achieve a better hemodynamic evaluation, an arterial catheter was inserted into femoral artery and a central venous catheter was inserted into internal jugular vein to monitor hemodynamic status using transpulmonary thermodilution (EV1000 system: Edwards Lifesciences, Irvine, CA). Cardiac index (CI) and mean arterial pressure were maintained > 4 l/min/m2 and 65–75 mmHg, respectively.
We recorded values of systemic vascular resistance index (SVRI) between 1000 and 1500 dyn s/cm5 m2. Administration of vasopressors was managed by hemodynamic monitoring with EV1000 (norepinephrine until 0.4 mcg/kg/min). During the first 24 h, a reduction of urine output was noted; hence, a fluid load was performed in association with high doses of diuretics. No response was obtained and we started calcium-citrate continuous venous–venous haemodialysis (calcium-citrate CVVHD Multifiltrate Fresenius System) with blood flow 100 ml/min, ultrafiltration 100 ml/h and dialysate flow 2000 ml/h. In the fourth postoperative day, we observed a recovery of renal function and we could suspend CVVHD.
We monitored haemoglobin (Hb) level and we had to administrate blood transfusion to keep values of Hb > of 7.5 mg/dl. We also measured RRI in the first post-operative day and then every 48 h and we found values lower than 0.7 in each situation. Serum lactate constantly remained lower than 1.5 mEq/l. During the following days, the hemodynamic parameters recorded by EV1000 allowed to reduce vasopressors dosage until interruption of dopamine and decrease of norepinephrine to 0.08 mcg/kg/min. In the eleventh post-operative day, we performed another renal Doppler ultrasound to evaluate organ perfusion because of a condition of slightly tense abdomen and the need to increase norepinephrine dose. Despite stable macrocirculatory parameters recorded by EV1000, acceptable arterial blood gas analyses, normal level of SvcO2 (Table ), we found increased values of RRI (0.86) (Fig. ). Hence, we performed an abdomen Focused assessment with sonography for trauma (FAST) that allowed us to detect free intraabdominal fluid, and then we requested a CT scan that revealed the presence of bleeding from the previous ileostomy. We also measured the intra-abdominal pressure (IAP) that was 19 mmHg. Immediately afterwards, laboratory tests detected anaemia that required blood transfusion. The patient immediately underwent another surgical operation of blood evacuation (above 1000 ml), resection of the ileal loop responsible for the bleeding and new ileostomy was performed. After the operation, we measured IAP lesser of 11 mmHg. The hemodynamic monitoring with EV1000, arterial and venous blood gas analysis (Table ) overlapped with the ones performed before the surgical operation. Despite the evidence of active bleeding from the previous ileostomy, detected with CT scan, the macroemodinamic parameters routinely used were still in normal range and weren't able to reveal hypoperfusion and haemodynamic instability. RRI instead showed an improvement of diastolic (perfusional) phase decreasing to normal values (0.58) (Fig. ) and demonstrating the enhancement of organ perfusion.


An 82-year-old male presented with a remote history of prior falls and a recent traumatic compression fracture of his L1 vertebral body. He reported no previous fractures, weight loss or antecedent pain. He was initially treated with a brace and underwent physical therapy. At follow-up, he had no neurological deficits but demonstrated severe recurrence of pain with progressive functional impairment refractory to conservative management. An MRI showed a worsening L1 vertebral body collapse, a T12 inferior endplate fracture, and a L2 superior endplate fracture (Fig. ). The imaging was suspicious for a pathologic etiology. With his intractable pain and collapse at the thoracolumbar junction, we proceeded with a kyphoplasty of L1, vertebroplasty of T12, and obtained a bone biopsy for pathology and culture (Fig. ). The initial smear testing for acid-fast bacilli (AFB) was negative with an interim negative report at 2 weeks, and final identification of M. abscessus at 6 weeks. The infectious disease (ID) service was consulted for further management. The smear was presumed to be a contaminant given his history and presentation.
At the 2-month follow-up, he remained neurologically intact, but continued to have functionally limiting pain. A repeat MRI demonstrated a psoas and paravertebral abscess with evidence of continued vertebral collapse. An image-guided bone biopsy confirmed the presence of M. abscessus and Propionibacterium acnes. Per the recommendations of the ID-team, he was started on Rocephin, then transitioned to a multi-agent regimen, including tigecycline, amikacin, meropenem, and oral-linezolid. After a completed course of antibiotics, he still continued to demonstrate clinical signs of infection with persistent pain. Again, advanced imaging confirmed progression of disease. He underwent an anterior T12-L2 corpectomy and debridement with instrumented fusion, as well as a posterior T9-L4 instrumentation and fusion (Fig. ). Repeat AFB culture and smear redemonstrated M. abscessus. Postoperatively, he was placed on a regimen of amikacin, azithromycin, tigecycline, and meropenem.
His postoperative course was complicated by gastroparesis leading to poor oral intake and malnutrition requiring the total parental nutrition. In addition, he developed a right upper extremity deep venous thrombosis by his prior PICC line site. He required inpatient rehabilitation for functional retraining. The side effects of his multi-agent therapy included persistent nausea, antibiotic-induced Clostridium difficile colitis, and new-onset Barrett’s esophagus most likely secondary to tigecycline. Due to ongoing adverse treatment effects and poor quality of life, the patient and family elected to withdraw aggressive care and continue with palliative measures only.


A 53-year-old man was referred to our hospital for evaluation and management of hypertension and hypokalemia. He was diagnosed with hypertension at the age of 40 years, and his blood pressure was poorly controlled with a calcium channel blocker (nifedipine at 40 mg/d). He also had a past medical history of vasospastic angina and was a nonsmoker and social drinker. In addition, he had no family history of cardiovascular diseases. On admission, the patient was 168 cm tall and weighed 59 kg. He was afebrile, with a blood pressure of 161/96 mm Hg and a regular pulse of 61 beats per minute. There was no evidence of lung rales, cardiac murmurs, or an abdominal bruit. His neurological examination was unremarkable. Laboratory tests revealed that his serum creatinine level was 1.1 mg/dL, urea nitrogen level was 19 mg/dL, and serum sodium level was 140 mEq/L. He also exhibited hypokalemia with a serum potassium concentration of 2.9 mEq/L; however, he had no subjective symptoms, including muscle weakness. Plasma renin activity (PRA), plasma aldosterone concentration (PAC), and aldosterone-to-renin ratio (ARR) were <0.1 ng/mL/h, 292 pg/mL, and >2920, respectively. Other adrenal hormone levels were within normal limits. A chest radiograph and transthoracic echocardiogram showed no significant findings. An electrocardiogram suggested nonspecific ST-T wave changes with premature atrial contractions.
Primary hyperaldosteronism was suspected, and therefore, a captopril challenge test and a saline infusion test were performed. All these investigations revealed positive test results (Table ), which confirmed a diagnosis of PA. A low-dose dexamethasone suppression test to exclude the diagnosis of subclinical Cushing's syndrome was negative. An abdominal computed tomography (CT) scan was performed, which showed a left adrenal mass (13 mm) (Figure ). In adrenocorticotropic hormone (ACTH)-stimulated AVS, although aldosterone hypersecretion was observed in the left adrenal gland, the lateralization of the disease was not determined due to incomplete cannulation of the right adrenal vein (Table ). The criteria of successful cannulation were based on the current Expert Consensus Statement.
131I-adosterol scintigraphy under dexamethasone suppression showed an equivalently increased uptake in both adrenal glands (Figure ). Because we could not exclude the bilateral PA, including aldosterone-producing adenoma (APA) with microadenoma in the right adrenal gland, we performed the medical therapy with mineralocorticoid receptor antagonists (MRA). Although we administrated multiple antihypertensive agents including an MRA (eplerenone at 100 mg/d), an angiotensin II receptor blocker (azilsartan at 40 mg/d), a dual action beta blocker/alpha-1 blocker (carvedilol at 20 mg/d), a calcium channel blocker with an increased dose (nifedipine at 80 mg/d), an alpha-1 blocker (doxazosin at 2 mg/d), and an alpha-2 agonist (guanabenz at 4 mg/d), a home reading of the patient's blood pressure was above 140/90 mm Hg. Moreover, he needed a large quantity of potassium chloride to compensate for his hypokalemia.
Despite intensive medical therapy, he underwent percutaneous coronary intervention due to stable angina. Following this, we performed AVS again, but the right adrenal vein was not successfully cannulated (Table ). We discussed further the indication for surgery and decided to remove the left adrenal gland. After laparoscopic left adrenalectomy, his blood pressure and serum potassium remained normal after the withdrawal of eplerenone, doxazosin, guanabenz, and potassium chloride and a dose reduction of azilsartan (at 20 mg/d), carvedilol (at 10 mg/d), and nifedipine (at 10 mg/d). The PRA and PAC were 0.8 ng/mL/h and 57.1 pg/mL, 3 months after the adrenalectomy, respectively. Macroscopic findings of the resected specimen showed a yellowish colored nodule (13 mm in diameter) in the adrenal gland. We confirmed a diagnosis of an adrenocortical adenoma based on a histopathologic examination (Figure ); we also confirmed that the tumor cells were rich in the cytoplasm and were eosinophilic without malignant cells.


A 54-year-old Caucasian female presented to the emergency department with nausea, vomiting, and fatigue for 5 days. She had visited her primary care physician for these symptoms and was given ondansetron and normal saline infusion without obvious improvement. With further questioning, the patient stated that she had felt poorly for at least 1 month, including poor appetite, fatigue, and unintentional weight loss. She had occasional vague abdominal pain which usually resolved spontaneously. She stated that her skin recently became very tan which she attributed to be in Arizona a month prior. The patient has a 17-year history of hypothyroidism. She was initially treated with levothyroxine, but she had decided to switch to animal thyroid extract several months prior. The patient started taking TMP-SMX 160 mg b.i.d. for sinus infection 1 week prior.
On admission, her orthostatic was positive: supine BP 131/80 mm Hg and HR 81/min; standing BP 107/67 mm Hg and HR 96/min. Otherwise her vital signs were within normal range. The patient was ill appearing, generally dehydrated with dry skin and mucosa. Capillary refill time was 3 seconds. The abdomen was not distended, normal bowel sounds, mild tenderness to palpation in the epigastric area, and no rebound tenderness or guarding. The remainder of the clinical examinations including heart and lungs were normal. Patient was alert and oriented, and no focal neurologic deficits observed. Further neurologic assessment by several specialists did not reveal any pathological signs.
Initial laboratory tests showed the following: WBC 10.2 k/µL, RBC 4.95 k/µL, hemoglobin 15.1 g/dL, hematocrit 47%, sodium 101 mmol/L, chloride 73 mmol/L, potassium 5.2 mmol/L, CO2 16 mmol/L, AG 11, BUN 20 mg/dL, Cr 0.8 mg/dL, and eGFR > 60 mL/min/1.73 m2. The rest of the biochemical analysis including liver function, calcium, phosphorus, glucose, total protein albumin, lipid panel, and globulin were within normal range.
With patient's extremely low serum sodium, our attention focused on the investigation of the cause. Further tests showed plasma osmolality 225 mOsm/kg (275-295 mOsm/kg), sodium in urine sample was 128 mmol/L, and urine osmolality 128 mOsm/kg. Since hyperglycemia and other causes of nonhypotonic hyponatremia were excluded, our patient had hypotonic hypovolemic hyponatremia. Given increased urine osmolality, elevated urine sodium, and no history of diuretic use, according to the diagnostic algorithm for hyponatremia based on the European guideline (Figure ), the most likely explanation was adrenal insufficiency (AI). Therefore, lab tests to evaluate adrenal function were ordered. The results showed basal morning cortisol was 6.2 µg/dL (7-28 µg/dL) and ACTH 125 pg/mL (9-52 pg/mL), which suggests primary adrenal insufficiency. The patient failed her cortisol stimulation test afterward which confirmed the diagnosis. Thyroid function test showed TSH 12.1 mU/L (0.5-5.0 mU/L)and free T4 0.7 ng/dL (0.9-2.4 ng/dL) which revealed inadequately controlled hypothyroidism.
Review of the history: The patient had fatigue, poor appetite, unintentional weight loss, and tanned skin for at least 1 month. Five days before admission, which was 3 days after taking TMP-SMX, the patient started to have nausea and worsening fatigue. Based on the whole history and test results, our impression was that she had baseline mild-to-moderate chronic hyponatremia due to uncontrolled primary adrenal insufficiency, and this situation was acutely exacerbated by TMP-SMX use several days prior. Obviously, the cause of the patient's hyponatremia was multifactorial. We also believe that inadequately controlled hypothyroidism due to self-switching from levothyroxine to animal thyroid extract a few months prior may have played a minor role in the development of the hyponatremia.
After the initial diagnosis of severe hyponatremia, the TMP-SMX was discontinued immediately. The patient was given normal saline 60 mL/h, combined with fluid restriction limiting water intake to 1.5 L per day. The patient was given neither hypertonic saline nor tolvaptan because she had chronic hyponatremia and was neurologically asymptomatic. According to the guidelines, the patient has risk factor for osmotic demyelination syndrome (ODS) (Serum Na < 105 mmol/L), optimal correction rate should be <8 mmol/L per day. The patient's serum sodium level increased from 101 to 112 mmol/L in the first 22 hours, so we drove the correction rates down by holding the normal saline infusion. The patient's sodium level increased 5-8 mmol/L per day in the following days which was at our goal. The patient was monitored closely in the process of hyponatremia correction. No neurologic symptoms or signs of ODS were observed. Her serum sodium had increased gradually to 129 mmol/L with significant clinical improvement in the following days (Figure ).
Based on the final diagnosis of primary AI, the patient was treated with prednisone 5 mg daily and fludrocortisone 0.1 mg daily. At the same time, she was started on levothyroxine instead of thyroid extract to better control her hypothyroidism. The patient was discharged home with outpatient follow-up. Sodium level was 129 mmol/L at discharge.


A 27-year-old Filipino man presented to Kern Medical with decreased vision in his
left eye, low back pain, weakness in his lower extremities, and masses in his
paraspinal, supraclavicular, and submandibular regions. Thoracic and abdominal
computed tomography scan demonstrated multiple abscesses with involvement of the
left supraclavicular lymph nodes and a left paraspinal abscess extending from T7-T12
with penetration and subsequent osteomyelitis of the T12 vertebra ( and ). Whole-body bone scan also
showed increased uptake of left fibular and tibial regions, left frontal lobe, and
xiphoid process ().
Incision and drainage of the paraspinal abscess and subsequent staining of the
aspirate indicated the presence of double-walled spherules with endosporulation.
Coccidioidal serological immunodiffusion showed immunoglobulin M and immunoglobulin
G reactivity with a complement fixation titer of ≥1/512. The patient was placed on
liposomal amphotericin B for his extraocular disease.
The patient started to complain of floaters in his left eye, which progressed until
he reported of a total loss of vision in this eye. Ophthalmologic examination
discovered “puff balls” in the vitreous overlying the posterior pole in this eye
only. The right eye did not have any abnormal findings (). He was discharged from the
hospital and referred to a retinal specialist as an outpatient. On examination, he
had normal visual acuity in the right eye, with light perception vision only in the
left eye. Anterior segment examination did not reveal an active anterior uveitis in
both eyes. Significant vitreous opacities were found in the left eye (). A large, white
subretinal lesion was present in the temporal macula. There was significant traction
associated with this lesion and a combined tractional/exudative retinal detachment
was present, extending inferiorly (). Given the history of concurrent coccidioidomycosis infection,
the patient was diagnosed with a coccidiomycosis associated chorioretinitis. He was
started on intravitreal amphotericin B deoxycholate 5 µg/0.1 mL every 3 days in
addition to his systemic treatment.


A 52-year-old Japanese woman complained of lower abdominal pain, constipation, and perception of an abdominal tumor for three months. She was gravida 0 and para 0. Her medical history included hypertension and schizophrenia. She had undergone an appendectomy in her childhood and total laparoscopic hysterectomy (TLH) for a leiomyoma four years previously. The uterus had weighed 398 g and two submucosal fibroids had been detected (the larger with 3 cm diameter). She had not undergone computerized tomography (CT) or magnetic resonance (MR) imaging before the initial surgery because the tumors had been small, ultrasonography had not revealed any sign of necrotizing or hemorrhagic tumor, and she had not wanted these investigations. LDH was found to be 196 U/mL at the initial visit and tumor markers were not assessed. The TLH was performed with an uncovered power morcellator to remove the tissue from the abdominal cavity. There were no immediate postoperative complications and an annual follow-up was recommended, which the patient discontinued on her own. She now presented to the internal medicine clinic, and CT revealed a large tumor in her pelvis measuring 25 cm in diameter. She was referred to our hospital for a suspected ovarian tumor.
The tumor extended till the inferior border of the ensiform cartilage, and ultrasonography showed a homogeneous solid tumor like a leiomyoma. The tumor received its blood supply mainly from the left internal iliac artery, but it did not show enhancement following contrast-enhanced CT ().
No tumor metastasis was detected. Contrast-enhanced MR imaging showed high-intensity signals on T2-weighted MR images, which indicated a degenerating myoma ().
Laboratory evaluation revealed that CA125 was elevated to 361 U/mL, and LDH was within the normal range at 225 U/L. The vaginal stump cytology was negative. Edoxaban was administered for deep vein thrombosis of the left soleal vein caused by the pressure of the large tumor.
Considering her past medical history of TLH for fibroids, a parasitic leiomyoma was diagnosed, and tumor excision and bilateral salpingo-oophorectomy were performed. There were no adhesions in the abdominal cavity except on the vaginal stump and on part of the left side of the retroperitoneum ().
Bilateral uterine adnexa were normal, and the tumor weight including the bilateral uterine adnexa was 7286 g. The specimen was a solid tumor that contained hemorrhagic necrosis ().
Pathological evaluation revealed that the tumor comprised fascicles of spindle-shaped cells that possessed hyperchromatic fusiform nuclei. The mitotic index exceeded 10 figures per 10 high-powered fields ().
Coagulative tumor cell necrosis and hyaline necrosis were seen. In addition, immunostaining showed diffuse and focal α-smooth muscle and desmin, respectively. The positive rate of Ki-67 was 33%. However, immunostaining was negative for CD34, S-100, c-kit, and DOG-1. Thus, the tumor was diagnosed as a leiomyosarcoma and not a leiomyoma. Both uterine adnexa were benign, and the ascites cytology was negative. The patient developed ileus after the surgery, but was discharged on the 15th postoperative day. CA125 testing was subsequently negative. Although it was a malignant tumor, lymph node dissection was not performed as per the patient's wish. Moreover, as a benign tumor had been suspected prior to surgery, the tumor had been removed completely. She has been followed-up carefully now without any additional treatment and has been recurrence-free for 20 months postsurgery so far. Although the initial pathological evaluation was reviewed at the time of the second evaluation, malignancy was not detected.


29-year-old African American woman presented to the emergency department for three weeks of nausea, vomiting, and diarrhea; and five days of anuria. She was found to be uremic with renal failure (Creatinine: 5.5 mg/dl, blood urea nitrogen: 34 mg/dl, creatinine clearance: 6 ml/min). Renal biopsy showed necrotizing glomerulonephritis (Immunoglobulin G, perinuclear anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane positive). She was treated with intravenous methylprednisolone started on day 5 of hospitalization (1 g intravenous daily for three days followed by 24 mg twice a day), plasmapheresis on day 8 of hospitalization, and cyclophosphamide (induced at a dose of 510 mg because of renal failure and plasmapheresis) on day 9 of hospitalization. Two days after cyclophosphamide induction, the patient became encephalopathic and developed clinical seizures consisting of left gaze deviation, left neck tonic deviation, left eye blinking, left arm flexion with rhythmic jerking in conjunction with the head. Fosphenytoin (loaded with 20 mg/kg followed by phenytoin maintenance at 100 mg three times a day) was initiated for seizures, and the patient was intubated and sedated on propofol drip. Blood pressure remained normotensive throughout hospitalization (Mean: 122.5/77, Median: 122/78 over a range of ten days of the event). The initial working diagnosis was cerebral vasculitis versus cerebral venous thrombosis. Magnetic resonance angiography (MRA) showed clear patent vessels, with no signs of venous thrombosis. Magnetic resonance imaging (MRI) revealed areas of cortical and subcortical white matter T2 Fluid-attenuated inversion recovery (FLAIR) hyperintensities in bilateral occipital-parietal and the right frontal region, as shown in . Continuous electroencephalogram monitoring showed diffuse interictal slowing. Seizures and encephalopathy in the setting of chemotherapy treatment with the radiographic findings were most consistent with PRES. Patient self-extubated three days later and was oriented to person, place, and time with no clear neurologic deficits on examination. Repeat MRI done six days after the initial scan showed resolution of previously seen areas of T2 FLAIR, white matter hyperintensities as shown in . She was discharged home on carbamazepine 400 mg BID and taper of phenytoin (100 mg every third day followed by stopping), and a steroid taper (methylprednisolone 16 mg BID for two weeks with a plan to taper by 4 mg BID every two weeks if tolerated).


A 56-year-old man was diagnosed with metastatic pancreatic cancer to the liver, lung, and duodenum in April of 2017. He had a gastrostomy tube placed for venting due to malignant bowel obstruction and a biliary drain due to invasion into the biliary tree. He also had a peripherally inserted central catheter (PICC) placed to provide continuous total parental nutrition (TPN), as he was malnourished from intractable abdominal pain, nausea, and vomiting every time he ate. He had attempted chemotherapy but stopped due to intolerance of its side effects. His pain regimen when on home palliative care was fentanyl 250 mcg/hr patch every 72 hrs and one to two tablets of Dilaudid 4 mg by mouth every four hours as needed, which he eventually required around the clock.
Pain management
His pain continued to worsen and after he started hospice care in September of 2017. He was placed on an IV continuous Dilaudid infusion by continuous ambulatory delivery device (CADD) pump with prn IV Dilaudid administered by patient controlled administration (PCA) because he became too cachectic to have reliable delivery of fentanyl with multiple patches. He was started on Dilaudid 1 mg/hr with 2 mg q15min prn breakthrough pain, which was increased weekly by 50%-100% due to inadequate pain control. He was also on adjunctive medications at various points throughout his care including a serotonin-norepinephrine reuptake inhibitor (SNRI), gabapentin, steroids, lorazepam, and octreotide. He was offered but declined a celiac plexus block. Concurrently, he was receiving non-pharmacological management of counseling and psychological support for anticipatory grief through our clinical licensed social worker and nurse case manager.
In the last two weeks of his life, he required exponential amounts of Dilaudid up to 30 mg/hr with 15 mg prn q15min for breakthrough, which seemed to be making his pain worse. At one point he or his family clicked the PCA button 107 times in a 24-hour period with worsening symptoms such as progression to back pain, agitation, delirium, and myoclonus.
Differential diagnosis
In a patient with metastatic cancer with chronic pain and elevated levels of distress, there is a wide range of diagnoses to consider. This includes but is not limited to opioid tolerance, opioid dependence, worsening of disease such as metastasis to the brain, malfunction or deep venous thrombosis (DVT) occluding the PICC line affecting delivery of Dilaudid, metabolic derangements, hypoxia, and infection. Often, pain tolerance will present as an increase in pain in the previously localized area and gradually responds appropriately to an increase in dose of pain medication []. This is a key differential marker from OIH where pain distribution spreads, or worsens with increase in pain medication. Opioid tolerance is defined as the need for an increased dose of pain medications to have the same effect on pain control. This is a physiologic phenomenon occurring in all patients with chronic pain treated with opioid pain medications. Tolerance leads to higher opioid dosing to achieve adequate analgesia, putting patients at risk for OIH. Given the acuity of the patient’s distress and an extremely short prognosis of days, the family agreed to have the patient transferred to the hospital to quickly identify the diagnosis and safely rotate the Dilaudid to an alternative opioid as OIH was suspected.
Treatment
In the emergency room (ER) at Kaiser Permanente Los Angeles Medical Center, the patient had a computerized tomography (CT) scan of the brain, which was negative for brain metastasis. His blood work did not show significant metabolic derangement, nor did his vitals show evidence of hypoxia or hypotension. A PICC line nurse assessed his PICC line to be flushing and functioning well to be delivering his IV medications. Rapidly escalating opioid doses without a desired effect of pain relief should alert clinicians to consider other diagnoses including OIH. If OIH is suspected, it is suggested to stop the offending drug. Alternatively, other treatment options are to rotate opioids or wean the current opioid and add medications that antagonize the NMDA receptor such as methadone or ketamine, which create an opioid sparing effect. The inpatient palliative care team was consulted and upon review of the chart and his clinical picture, the team confirmed the suspected diagnosis of OIH.
The treatment plan was to rotate IV Dilaudid to IV methadone. This was discussed extensively with his wife, his durable power of attorney for healthcare, as the patient did not have capacity by this time. His dose was calculated based on his total oral morphine equivalent (OME), which was 46,500 mg in a 24-hour period. The conversion to methadone after intense dose escalation can pose significant problems, as there is no exact reference ratio.
Existing conversion regimens do not address the specific setting of dose escalation and OIH, so a conservative morphine-methadone ratio is recommended. Alternatively, calculating the initial dose of methadone can be based on the opioid usage prior to the pain crisis where rapid escalation was required []. Methadone is characterized by extra opioid effects, non-linear pharmacokinetics, and high potential for drug interactions, which makes it difficult to predict appropriate conversion ratios. Based on the patient’s extremely high OME requirements, a conservative 20:1 ratio was taken calculating to methadone 15 mg q3h prn pain. One dose was given in the ER as the IV Dilaudid dose was decreased by 60% from 15 mg/hr to 6 mg/hr. He required three more doses in 12 hours before stabilizing, which equated to 90 mg of IV methadone in a 24 hr period, and he was discharged home two days later on Friday 11/3/17 on IV methadone of 3.5 mg/hr continuous and IV morphine of 30 mg q30min prn breakthrough pain by PCA.
Outcome and follow-up
In less than six hours of being home the patient started developing signs of OIH again with each demand morphine dose and worsening agitation. Since the patient was in his final hours to days of life and had previously stated preferences to die at home, his family declined taking the patient back to the hospital. It was decided to try using IV methadone as a prn breakthrough medication instead of morphine since it logistically was too difficult to get alternative medications such as IV fentanyl or ketamine from the pharmacy on a weekend and delivered to the patient’s home in a timely manner. With minimal data available for reference, prn methadone was conservatively dosed at 5% of his total basal rate requirements, and given the time to peak effect of parenteral methadone is one to two hours, methadone 4 mg IV q1h prn breakthrough pain was prescribed via his CADD pump PCA. This adjustment was made by his visiting home hospice nurse the same day of hospital discharge and explained to his wife who was in agreement with the plan.
On a follow-up phone call later that night, his wife reported that he only required three doses of prn methadone within six hours of the adjustment. She admitted that the first time they pushed the PCA button it was out of fear of pain and agitation rather than actual symptoms. She reported that night was the first night he had slept comfortably in the last several weeks. The next day on 11/4/17, 18 hours after the prn opioid was rotated to methadone, he died peacefully surrounded by loved ones. His family appreciated the hard work and efforts of the entire hospice and palliative medicine teams to honor his wishes of dying at home in peace. The timeline of events is listed in Table .


Patient 1, a 17-year-old female, was hospitalized because of a headache and giddy feelings lasting for 2 months and hypertension for 1 month. Her average daytime systolic blood pressure was 134 mmHg, her diastolic blood pressure was 96 mmHg, and her heart rate was 86 beats per minute. She had a normal BMI but had immature breasts and vulva and no menstruation, hirci or pubic hair. Hormone testing showed decreased plasma estradiol (E2), testosterone (TESTO) and renin activity but increased progesterone (PROG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), aldosterone and aldosterone-renin ratio (ARR) (Table ). She had reduced blood cortisol and increased ACTH. Further examination indicated that she had hypertension fundus changes, and her urine microalbuminuria test was more than 150 mg/l. Pelvic magnetic resonance imaging (MRI) did not detect the uterus or ovaries. Her chromosome karyotype was 46XY.


Patient 2 was a 14-year-old girl who was hospitalized because of hypertension lasting for 2 months. Her hypertension was also found in a school physical examination. Her average daytime blood pressure was 169/136 mmHg, and her heart rate was 83 bpm. She had normal BMI but immature breasts and vulva and had not experienced menstruation. Blood potassium was 3.52 mmol/l, which was on the low threshold. The hormone test indicated a disorder with decreased plasma E2, TESTO and renin activity but increased PROG, FSH, LH, aldosterone and ARR. She had reduced blood cortisol and increased ACTH (Table ). Pelvic MRI showed an immature uterus and ovaries. Her chromosome karyotype was 46XX.


Patient 3 was a 13-year-old female who was hospitalized because of hypertension accompanied by headache lasting for 2 months. She was found to have high blood pressure at a school physical examination. Her average daytime blood pressure was 158/105 mmHg, and her heart rate was 85 bpm. Blood potassium was slightly lower than the normal value of 3.32 mmol/l. She had normal BMI but immature breasts and vulva and had not experienced menstruation. Her plasma E2, TESTO and renin activity were all decreased, whereas her PROG, FSH, LH, aldosterone and ARR were increased. Her blood cortisol was reduced, and ACTH was increased. She had hypertension fundus changes, and the result of the urine microalbuminuria test was 439.9 mg/l, which suggested that she had hypertension complications. Pelvic MRI displayed her immature uterus and ovaries. Her chromosome karyotype was 46XX.


Patient 4, who had the appearance of a 12-year-old girl, was hospitalized because she had felt dizzy for 1 week. Her average daytime blood pressure was 165/120 mmHg, and her heart rate was 90 bpm. Blood potassium was extremely low, with a value of 2.96 mmol/l. She had a normal BMI but immature breasts and vulva and had not experienced menstruation. Hormone analysis showed that she had hormone disorder with reduced plasma E2, TESTO and renin activity but enhanced PROG, FSH, LH, aldosterone and ARR (Table ). She had reduced blood cortisol, and ACTH was extremely high. Pelvic MRI could not find her uterus and ovaries but showed suspected testis. Her chromosome karyotype was 46XY.


Patient 5 was a 13-year-old girl who was hospitalized because of high blood pressure lasting for 2 months. Her average daytime blood pressure was 187/127 mmHg, and her heart rate was 76 bpm. Blood potassium was extremely low, with a value of 2.7 mmol/l. She had a normal BMI but immature breasts and vulva and had not experienced menstruation. Her plasma E2, TESTO and renin activity were all decreased, whereas PROG, FSH, LH, aldosterone and ARR were increased (Table ). She had reduced blood cortisol and increased ACTH. Pelvic MRI showed an immature uterus and ovaries, and her chromosome karyotype was 46XX.


A 82 years-old multiparous Caucasian woman was referred by family physician as she presented abdominal distension and pain and a palpable mass in the right iliac fossa. The past medical history included essential hypertension under pharmacological treatment and gastro-esophageal reflux. She denied any alcohol abuse or smoking. Blood tests showed CA 125 277 U/mL (reference range 0–36 U/mL) and CA 19.9 64.5 U/mL (reference range 0–37 U/ml). An abdominal ultrasonography and computed tomographic (CT) scan were obtained. Abdominal ultrasonography identified a heterogeneous, multi-septated mass with solid components occupying whole pelvis and a sclerotrophic gallbladder with wall thickening and biliary sludge. Abdominal CT-scan confirmed the thick-walled gallbladder close to the duodenum and the ovarian mass presenting hypodense areas with necrosis and calcifications with 17 × 11.5 cm in size, as shown in A–B. The patient, after careful anesthesiology evaluation, was considered fit for surgery. Explorative laparoscopy, performed by a senior surgeon with large expertise in laparoscopic surgery, identified an advanced gallbladder cancer with diffuse peritoneal carcinosis and a voluminous unilateral ovarian mass with initial signs of vascular distress. The other ovary was normal. Resection of the ovarian mass was performed and two peritoneal samples were sent for histologic examination. Peritoneal citology was positive for adenocarcinoma. Post-operative course was uneventful. Final histological examination of the ovarian tumor showed dilated glands of different sizes with well-differentiated architecture, delimited from loose ovarian stroma and the glandular epithelium presented strong cytoplasmic positivity for CK19, compatible with a pancreatic-biliary origin (A–D). The diagnosis of Krukenberg tumor by gallbladder cancer was done. The patient was discharged with a poor prognosis and she died three months after.


We reported the case of a 49 years old Javanese woman with an acute presentation of nausea, vomiting, and abdominal distension at the emergency room of a hospital in the south part of Central Java, Indonesia. She complained about loss of appetite, constipation, and inability to pass gas (flatus). The symptoms intensified during the past 2 days and green vomit appeared at the day of admission. According to anamnesis, there was no history of trauma, previous surgery, liver and biliary problems as well as metabolic diseases. Physical examination revealed tachycardia (112 beats/min), tachypnoeic (22 times/min), non-tender abdomen with hyperactive bowel sounds. Laboratory tests showed leukocytosis (14,970/μL). Abdominal X-ray showed loop dilatation of the small bowel (). Abdominal CT-scan with contrast was available only during daily working hours of the hospital. She was managed with fluid rehydration and antibiotics. The patient was then assigned for an emergency laparotomy. Abdominal exploration revealed massively dilated loops of the entire small bowel to the distal ileum. The obstruction was found 40 cm from the terminal ileum where an antimesenteric enterotomy was performed revealing a large gallstone with the size of 4.5 cm × 3.5 cm × 3.2 cm and 4 small gallstones (1 cm in diameter each) (). After removal of the gallstones, the enterotomy was repaired with seromucous interrupted suturing. The patient was discharged 5 days after the surgery without any postoperative complications and remained symptomatic-free after two year outpatient follow-up.


A 66-year-old man underwent neoadjuvant chemotherapy (XELOX: oxaliplatin and capecitabine) for 4 months followed by surgical resection for poorly differentiated adenocarcinoma in sigmoid colon without lymph node metastases(ypT3N0M0) during October 2016 to February 2017. After surgical treatment, subsequently 3 cycles of concurrent chemotherapy with abdomen radiotherapy were administered. There was no evidence of disease progression after the completion of therapy. In August 2017, he presented to our out-patient department with nonproductive cough for 1 week. He had no fever, chills, hemoptysis, dyspnea, or night sweats. Chest computed tomography (CT) showed bilaterally scattered ground-glass opacities and mediastinal lymphadenopathy. Laboratory test results revealed that the slightly increased serum level of carcinoembryonic antigen, at 4.56 ng/mL (normal range: 0–3.4). Several inflammatory makers, such as C-reactive protein at 97.30 mg/L(normal range: 0–5), interleukin-6 (IL-6) at 48.43 pg/mL (normal range: 0–7), and procalcitonin at 0.17 ng/mL (normal range: 0–0.046), were evidently elevated, considering the possibility of interstitial pneumonia. Given all above clinical symptoms were not alleviated after treatment, he received an 18F-FDG PET/CT scanning for further evaluation, which revealed increased FDG uptake along the thickened bronchovascular bundles (Fig. B–D), in bilaterally scattered ground-glass opacities (Fig. E–G), and in mediastinal lymphadenopathy (Fig. H–J). There was no abnormal FDG uptake in the rest part of the body (Fig. A). The patient underwent transbronchial biopsy of the opening of right inferior lobar bronchus and mediastinal lymph nodes. Histopathological and immunohistochemical studies (Fig. ) revealed that biopsy specimens were composed of marked atypia of epithelial cells (Fig. A, B) and were positive for CK20 (Fig. C) and CDX-2 (not shown), but negative for CK7 (Fig. D). These findings of staining are consistent with metastatic poorly differentiated adenocarcinoma from colon. The patient was transferred to hospital for antineoplastic treatment (cetuximab). In October 2017, he presented to our hospital emergency department with progressive dyspnea. Thickening of the interlobular septa and bronchovascular bundles (Fig. A–C), which are the progress of ground-glass opacities, were shown on chest high-resolution computed tomography (HRCT). HRCT also showed further enlarged mediastinal nodes and more serious pleural effusion (Fig. D) compared with PET/CT in August 2017. All these features on HRCT indicate progressive disease. Unfortunately, he died of respiratory failure within 3 months after the onset of his symptom.


A 58-year-old gentleman with history of BRAF-mutant metastatic melanoma that had initially progressed after 20 months of combination dabrafenib/trametinib (BRAFi/MEKi) and again after palliative radiotherapy and three months of nivolumab (PD1 inhibitor) was started on combination encorafenib/binimetinib in January 2019. Pertinent medical history included hypercholesterolemia (on simvastatin 40 mg/day) and hypertension (on hydrochlorothiazide 25 mg/day and lisinopril 40 mg/day). He had no history of liver or kidney disease.
When encorafenib/binimetinib was initiated, the patient was essentially asymptomatic. Comprehensive metabolic panel (CMP) was unremarkable; baseline AST and ALT were 22 and 25 IU/L, respectively; creatinine was 1.23 mg/dL; and blood urea nitrogen (BUN) was 21 mg/dL. Repeat labs after the first month of treatment were similar. At a routine office visit following his second month of treatment, he reported a three-day history of fatigue, fever, and chills. AST and ALT were found to be markedly elevated, measured at 671 and 1,251 IU/L, respectively. Total bilirubin and alkaline phosphatase were within normal limits. Creatine was 2.32 mg/dL; BUN was 55 mg/dL; and glomerular filtration rate (GFR) was 49 mL/min/1.73 m2. Treatment was withheld, and the patient was later admitted for workup of his abnormal laboratory values due to persistent worsening of his liver function tests (LFTs) over the next two days.
On admission, hepatology was consulted to assist with the diagnostic workup. Evaluation consisted of serial CMPs, complete blood counts (CBCs), hepatitis panel, human herpesvirus panel (HSV-1, HSV-2, and VZV), autoimmune markers (antismooth muscle antibody, antimitochondrial antibody), ceruloplasmin, coagulation studies, and magnetic resonance imaging (MRI) of the abdomen with and without contrast. CMPs revealed persistent elevation of AST and ALT despite discontinuing treatment, reaching peaks of 950 and 1,638 IU/L during the course of the hospital stay. Total bilirubin and alkaline phosphatase remained within normal limits. Creatinine, BUN, and GFR gradually returned to normal with hydration after two days (0.99 mg/dL, 17 mg/dL, and 84 mL/min/1.73 m2, respectively). CBCs revealed normocytic anemia (hemoglobin 11.8 g/dL, MCV 86 fL, and normal iron studies) but was otherwise unremarkable. Viral panels were negative for hepatitis A, B, and C, HSV-1, HSV-2, and VZV. Antismooth muscle antibody and antimitochondrial antibody were negative. Ceruloplasmin was mildly elevated (35 mg/dL). Coagulation studies revealed an elevated prothrombin time (PT) of 14.5 seconds (international normalized ratio (INR) of 1.3), consistent with the known hepatic insult. Abdomen MRI revealed periportal and reactive gallbladder edema, consistent with acute hepatic inflammation, but there was no evidence of chronic liver disease or portal hypertension. Clinical evaluation focused on new symptoms suggestive of progressive liver injury, including jaundice, scleral icterus, nausea, vomiting, and abdominal pain, as well as complications from impaired liver function including edema, bleeding, and encephalopathy. By the time of admission, the patient's fever, fatigue, and chills had resolved. He remained asymptomatic throughout his hospital stay.
Based on the unremarkable workup, it was felt that the liver injury was primarily related to encorafenib/binimetinib, though simvastatin may have played a minor role. The concurrent kidney injury was thought to be multifactorial, with encorafenib/binimetinib, hydrochlorothiazide, and lisinopril all contributing to its development. The patient was discharged after four days with instructions to follow up with oncology and hepatology in the outpatient setting.
The patient was seen in the outpatient oncology clinic three days after discharge, and updated labs were obtained. ALT was markedly elevated at 2,007 IU/L; AST was 825 IU/L. Total bilirubin and alkaline phosphatase were normal. Treatment was not reinitiated at this time, and serial CMPs were obtained every two to three days following. AST and ALT slowly returned to normal over the course of the next several weeks. No complications were noted during this timeframe. summarizes the patient's AST/ALT trends from his baseline prior to the liver injury to his gradual return to normal limits a few weeks later. From a treatment standpoint, a subsequent positron emission tomography (PET)/computed tomography (CT) scan from April 2019 demonstrated tumoral response with decreased fluorodeoxyglucose (FDG) uptake in several previously noted soft tissue and bony metastases.


Patient A was an otherwise healthy 10-year-old girl who participated in competitive figure skating. She experienced insidious onset left knee pain, which was 8/10 in severity and only moderately improved with ibuprofen. Her family initially thought this could be related to skating and waited for it to disappear. However, the pain persisted, and she developed a limping gait. She had no fevers or rash, nor recent illnesses, travel, or tick exposure.
Her pediatrician referred her to orthopedics, who noted pain out of proportion to exam and ordered imaging. MRI of the left knee showed an intramedullary lesion in the proximal tibial and distal femoral metaphyses surrounded by edema and inflammation (). Due to concern for potential malignancy, she was referred to oncology who ordered a technetium 99m-MDP bone scan and CT-guided biopsy. The bone scan was not consistent with acute osteomyelitis, with only mild radio-tracer uptake in the tibial lesion. Curiously, there was also a region of increased avidity in the posterior second rib. Subsequent tibial biopsy showed an inflammatory process in the marrow space extending to the growth plate. All cultures were negative.
The patient was referred to specialists in infectious disease whose differential diagnosis included acute bacterial osteomyelitis vs. CRMO. Due to elevated inflammatory markers, the patient was started on an empiric trial of antibiotics. Over the course of the next few months, her pain decreased, and her inflammatory markers and lesion on MRI imaging improved. The antibiotics were then discontinued after 4 months. Her knee pain remained quiescent for another 7 months but then recurred. Repeat MRI showed exacerbation of the tibial lesion, and repeat biopsy was again negative for growth of organisms. She was subsequently referred to our rheumatology practice for workup of CRMO (1 year after disease onset).
On initial visit, she had tenderness to palpation of the lateral proximal tibia. Her range of motion was fully intact, and inflammatory markers were, at this point, normal. WBMRI revealed lesions in eight regions, including her posterior rib (previously seen on bone scan), T9 vertebral body, bilateral sacroiliac joints, bilateral distal femoral metaphyses, and bilateral proximal tibial metaphyses. She was started on indomethacin, which provided some benefit but did not completely eliminate her pain. Methotrexate was added along with a brief course of oral prednisone, since glucocorticoids can help prevent vertebral collapse in the setting of spinal lesions (, ). She developed new bone lesions while on therapy and was switched to adalimumab (TNF-α inhibitor). She is not currently experiencing any of her pain and has returned to figure skating competition.


Patient B was a 10-year-old girl with a history of scoliosis and hypothyroidism, whose family was living in Europe at the time of symptom onset. She was playing with a sibling and experienced significant pain when poked in the left clavicle. There was no fever or swelling, but the pain persisted, and her primary pediatrician referred her to orthopedics. Radiographs showed no evidence of fracture or dislocation, and she was prescribed ibuprofen. This did not provide relief, as she continued to have intermittent clavicular pain and occasional jaw pain.
She tolerated this discomfort into the next year when her endocrinologist decided to admit her for further workup. Lab evaluation showed elevated inflammatory markers, and she was given antibiotics, which did not lead to symptomatic improvement.
Her family moved back to the United States and visited a hospital, where they were told that she had chronic osteomyelitis and that it would resolve with time. They sought a second opinion at another hospital, where a bone biopsy was performed, which showed no evidence of infection. Her inflammatory markers were still elevated, and she was again trialed on antibiotics. As with before, this did not yield improvement, and they were discontinued due to gastrointestinal intolerance.
She then visited a third hospital, where a rheumatologist clarified her diagnosis as CRMO (3 years after disease onset). She was initially treated with indomethacin but discontinued it due to headaches. Over the next few years, she controlled her flares with ibuprofen. Eventually she established care with a new rheumatologist who started her on sulfasalazine, but this was discontinued.
Over time, her jaw pain worsened, and repeat MRI showed evidence of mandibular lesions. Etanercept (TNF-α inhibitor) was trialed and did not help, and after moving cities, her new pediatrician prescribed high dose steroids and referred her to our practice (7 years after disease onset).
At the time of initial visit, she continued to complain of jaw pain and swelling. Physical exam was positive for jaw edema, and tenderness over the left clavicle (). There was no loss in range of motion. WBMRI revealed an additional lesion in her right clavicle, and she was started on adalimumab, on which she has had improvement in inflammatory markers and pain level.


Patient C was also a 10-year-old girl, who was otherwise healthy other than exhibiting poor growth. At baseline, she was involved in gymnastics; however, this changed when she started to experience right hip pain. This pain persisted at all times of day and was partially relieved by ibuprofen. It was never in the left hip or knees, but she reported some discomfort in her ankles. She had no fevers but developed a transient pustular rash on her palms and soles.
As the pain became increasingly disabling, she developed a limp. She was referred to orthopedics, who prescribed crutches and obtained a hip MRI. This showed a lesion in the right medial proximal femur (). A bone scan was then performed to look for additional lesions, but none were found. Biopsy of the lesion was consistent with osteomyelitis but was undifferentiated between an infectious vs. inflammatory cause. The patient was thus referred to both infectious disease and rheumatology.
Infectious disease specialists suggested that the patient's presentation was more consistent with CRMO than bacterial osteomyelitis, given the chronicity and negative culture on biopsy. Our rheumatology team came to the same conclusion (1-year after symptom onset). When we saw the patient, she was tired and pale appearing, with thinning hair. Her BMI percentile was 1%. Musculoskeletal examination was notable for tenderness in the sacroiliac region and right femur, as well as reduced range of motion of her ankles. There were no skin lesions at the time of our exam. WBMRI showed lesions in her proximal right humerus, proximal right femur, bilateral proximal tibias, and bilateral distal femurs. She was treated with indomethacin and has since clinically improved.
Given her history of poor growth, a fecal calprotectin was performed to screen for IBD and was positive. This led to a colonoscopy, which showed granulomas throughout her intestinal tract (Chronic Granulomatous Disease was evaluated and excluded). She was given the diagnosis of Crohn's disease despite her lack of gastrointestinal symptoms. Her CRMO treatment was advanced to adalimumab, which treats both disease processes, and she has symptomatically improved.


Our patient is a 74-year-old male, with a 40 pack-year smoking history, with recently diagnosed stage II squamous cell carcinoma of the base to the tongue. According to the National Comprehensive Cancer Network (NCCN) guidelines, he was started on cisplatin. He presented to the emergency department five days after the initiation of cisplatin with worsening confusion and anxiety. He was also having some word-finding difficulty and was more forgetful. The patient denied seizures, syncope, chest pain, shortness of breath, weakness/numbness, diarrhea, polyuria, vomiting or thirst. There was no history of alcohol consumption and diuretic intake. On examination, the patient had normal vitals and euvolemic without any focal neurologic deficits. He was found to have a serum sodium of 115 mmol/L. Prior to starting chemotherapy, his serum sodium was 138 mmol/L and chloride was 102 mmol/L. He had normal kidney function. Other electrolytes were within the normal range. Serum osmolality was 244 mOsm/kg with urine osmolality of 422 mOsm/Kg and urine sodium of 68 mmol/L consistent with SIADH. Thyroid-stimulating hormone (TSH) level was 1.44 uIU/ml (normal range 0.34-3.0 uIU/ml) and serum cortisol was 17.9 ug/dl (normal range 3.0-27.0 ug/dl) which ruled out hypothyroidism and adrenal insufficiency. Chest imaging was within normal limit without any pulmonary metastasis. Based on the temporal relationship of his condition with chemotherapy, diagnosis of cisplatin-induced hyponatremia due to SIADH was made after ruling out other causes of hyponatremia.
His fluid intake was restricted to less than one liter per day and he was also started on salt tablets with goal of sodium correction of no more than 6 mmol/L in 24 hours. On this regimen, his sodium markedly improved upto 129 mmol/L and he was discharged home with fluid restriction and salt tablets. His chemotherapy was switched to carboplatin and paclitaxel and he was continued on radiation treatment as an out patient. His sodium steadily improved and went up to 140 mmol/L in three months duration. His salt tablets were steadily tapered down over one month and later discontinued.


This is a 73-year-old Caucasian female with history of hypertension and irritable bowel syndrome who presented to the hospital due to sudden onset retrosternal, squeezing, nonradiating chest heaviness during an episode of diarrhea. The pain was associated with minimal shortness of breath. She received aspirin 325 mg by EMS along with sublingual nitroglycerin. On examination in the emergency room, she had a blood pressure of 115/64 mm Hg, a regular heart rate of 67 beats per minute, a respiratory rate of 18 breaths per minute, and saturating 97% on room air. She had normal breath sounds and heart sounds on examination. She was started on nitroglycerin infusion, after which her chest heaviness partially improved but persisted. Initial EKG showed no acute changes but prolonged PR interval of 324 milliseconds ().
The patient was known to have a history of prolonged PR interval noted on prior EKGs. Initial labs showed serum sodium 136 mmol/L, potassium 4.1 mmol/L, bicarbonate 22 mmol/L, chloride 102 mmol/L, BUN 42 mg/dL, creatinine 1 mg/dL, glucose 118 mg/dL, calcium 8.7 mg/dL, white cell count 7.3/nL, hemoglobin 12.1 g/dL, and platelet count 219/nL. Coagulation profile and hepatic function panel were also within normal limits. Initial troponin was 0.46 ng/dL which increased to 3.06 ng/dL after five hours. An initial diagnosis of NSTEMI was made, and the patient was started on a heparin infusion. Urgent coronary catheterization was organized.
Coronary angiogram demonstrated a nonobstructive coronary artery disease (Figures and ) with a ventriculogram showing apical ballooning and ejection fraction of 40% suggestive of takotsubo cardiomyopathy (Figures and ). The patient was admitted to the CCU, and a transthoracic echo was done and consistent with the findings of coronary catheterization: it showed an ejection fraction of 45% with hyperdynamic inferobasal and anterior basal walls with apical ballooning indicative of takotsubo cardiomyopathy (). She was diagnosed as having takotsubo syndrome, and her heparin infusion was discontinued. Her hospitalization was complicated by Mobitz 1 AV block (), wide complex escape rhythms, and subsequent complete heart block (). Because of her baseline prolonged PR interval and very high projected pacing burden, biventricular pacer was inserted. The patient remained hemodynamically stable and was discharged home after a couple of days.
A repeat echocardiogram was done outpatient, two months after hospitalization, and showed improvement: she had an ejection fraction of 55-60% with resolution of the apical ballooning and hyperdynamic wall motion changes, which were initially noted during hospitalization (). Pacemaker interrogation revealed 100% ventricular pacing and continues to show 100% ventricular pacing even twenty months after hospital discharge. This signifies the persistence and chronicity of the AV block even after her hospitalization and after the resolution of her cardiomyopathy.


A 10-year-old Chinese boy was admitted to our hospital with the chief complaint of the pain in the dorsal base of the penis. He presented with occasional discharge from an accessory meatus located in the midline of the dorsal proximal penis, combined with dorsal penile curvature (Fig. a, b). The curvature made the urine easily spray to his face when he urinated without pushing the penis down (Fig. c). Seven months ago, he suffered from the pain in the dorsal base of the penis and the skin around the abnormal opening was red and swollen when the meatus soaked in sweat after vigorous activities.
Physical examination revealed normally developing bilateral testicles and penis, and urethral meatus at the normal position of the glans. There was an accessory meatus located in the midline of the dorsal proximal penis. Moderate dorsal penile curvature was identified with deficient dorsal foreskin. No remarkable abnormality was found in hematological, biochemical, urinary, or endocrinologic tests. Patent foramen ovale, which required no intervention, was identified by echocardiography. Retrograde urethrogram, retrograde sinogram and computed tomography (CT) showed that the epispadiac tract did not communicate with either normal urethra or urinary bladder, and ended blindly at the level of the symphysis pubis (Fig. d). Thus, CPS was diagnosed.
Methylthionine chloride was injected into the sinus through the dorsal opening at the initiation of the procedure, and the intact 4-cm-long sinus was completely separated and excised (Fig. e, f). Then a circumcoronal incision was made and the skin coverings of the shaft of the penis were taken down. Penile curvature was corrected after dorsal proximal fibrous cord beneath the skin was detached (Fig. g, h). The patient was discharged from hospital uneventfully.
Histological examination showed that the lining epithelium inside sinus was transitional epithelium, and a few smooth muscle bundles were identified around the sinus (Fig. i). These findings confirmed the diagnosis of urethral duplication.


Twin A and B were idenitical monoamniotic twins born to a 24-year-old G3 P2 mother and a 31-year-old father. The pregnancy was complicated by twin gestation diagnosed at 7 weeks, and gestational diabetes in the last month of pregnancy, which was controlled by diet. Delivery by repeat Caesarean section at 35 ½ weeks of secondary to prior uterine surgery for an ectopic pregnancy.
The neonatal period was unremarkable. At two and a half months he had an incarcerated left inguinal hernia that was repaired surgically. He has had a history of clinical seizures since the age of 15 months controlled by medication including topiramate, clonazepam, and sodium valproate.
On examination at 8.4 years his height was 127.3 cm (50%), weight 25.9 kg (50%), and head circumference 52.5 cm (50%). Physical findings included brachycephaly, mid-facial retrusion, prognathism, macrostomia, wide-spaced teeth, tongue thrusting and strabismus. General examination of heart, lungs, and abdomen was unremarkable. On neurological exam, cranial nerves were grossly intact. His motor examination was notable for truncal hypotonia and increased tone in all extremities. He had jerky movements and a wide-based gait with his arms held in flexion when walking. His EEG at age 8 years was abnormal with widespread delta slowing maximal posteriorly at the fully alert state but dominant frontally in addition to delta, notched delta blunted spike waves or frank spike waves were seen of which one was associated with a clinical event (grunting).
Twin B had mild respiratory distress at birth and was admitted to the Neonatal Intensive Care Unit for 10 days for antibiotic therapy for pneumonia. He began to have seizures at 15 months of age, during which he would tighten his jaw, make growling noises, and have rhythmic tremors. His seizures were controlled by medication EEG obtained at 8 years was suggestive of an active seizure disorder, very characteristic of Angelman syndrome with widespread posterior discharges consisting of delta, notched delta and spike waves. On examination at 8 y. and 5 mo., his height was 128.2 cm (50%), weight 26 kg (50%) and head circumference 53 cm (50-75%). Craniofacial features were identical to his twin. Unlike his twin, he aexhibited mild scoliosis. Both twins were diagnosed with Angelman syndrome at 16 months of age through FISH testing with probes from D15S11 and GABRB3 that showed a typical Angelman syndrome Class I deletion at chromosome 15. DNA methylation studies were conducted and concluded to be diagnostic of AS.
Twins C and D were born to a 29 year old G2 P0 mother and 34 year old father. The pregnancy was naturally conceived and a routine ultrasound at 16 weeks gestation revealed monoamniotic monochorionic twins. There were no exposures during the pregnancy. An ultrasound disclosed no problems. The pregnancy was complicated by preterm contractions beginning at 29 weeks, treated with bedrest and terbutaline, and HELLP syndrome, treated with MgSO4. At 34 weeks gestation, rupture of membranes occurred, and induction of labor was undertaken. Twin D was born vaginally, but twin C was delivered by emergency caesarean section due to cord prolapse.
Both twins had severe muscle hypotonia that persisted beyond a year of age and were diagnosed with Prader-Willi syndrome based on FISH at 13 months. Breast feeding was not successful due to a weak suck and they were fed breast milk in a bottle with a preemie nipple for 1 month and then transitioned to formula. Their coloring was lighter than expected for the family. At 2 years of age, the diagnosis was changed to Angelman syndrome based on DNA methylation results. Twin C was examined at 5 years and 8 months and twin D was examined at 7 years of age. Their chromosome 15q11-q13 deletion associated with Angelman syndrome was characterized as a Class I deletion.
Twin C weighed 2.15 kg, measured 47 cm, and had Apgar scores of 4 and 7. He stayed for 9 days in the Neonatal Intensive Care Unit for temperature regulation and feeding issues. He had febrile seizures in association with a respiratory infection at age 4 months, and non-febrile convulsions began at age 28 months. He had several episodes of status epilepticus and failed management with 6 anti-epileptic medications. Severe failure to thrive necessitated percutaneous gastrostomy tube placement at 3 years of age. When evaluated at age 5 years 8 months, he weighed 16 kg (12%), measured 112 cm (70%), and had a head circumference of 49 cm (75%). He had microbrachycephaly with an occipital ridge, exotropia, midface retrusion, prognathism, and macrostomia with widely spaced teeth. He had a moderate rightward thoracic and leftward lumbar scoliosis and pronated ankles. He had generalized muscle hypotonia.
Twin D weighed 2.13 kg, measured 47 cm, and had Apgar scores of 4 and 7. He was gavage fed for 3 days and discharged home at 9 days. Exotropia and sleep disturbance were noted from infancy. Food refusal and severe failure to thrive necessitated percutaneous gastrostomy tube placement at 3 years of age. There were multiple episodes of otitis media and pneumonia, the latter presumed due to aspiration. Gagging and gastroesophageal reflux disease resulted in many episodes of emesis per day.
Seizures with fever began at 4 months, and afebrile seizures started at 28 months of age. Nearly all developmental skills were lost until seizure control was achieved approximately several months later, following which skills were regained slowly. On examination at 7 years of age, he weighed 19.5 kg (10%), measured 119.3 cm (30%) and had a head circumference of 49.4 cm (50%). He had alternating exotropia, midface retrusion, prognathism, widely spaced teeth, and mild rightward thoracic and leftward lumbar scoliosis. His truncal tone was low, and there was high extensor tone in all extremities.


A 48-year-old woman with a long history of TNBC (Fig. ) was enrolled in the Phase 1a study of single agent atezolizumab (PCD4989g; NCT01375842) on March 5, 2013. In 1986, she presented with an early right breast cancer negative for the estrogen and progesterone receptors. Initial management included lumpectomy and radiotherapy, and then two chest wall recurrences were treated with surgery and adjuvant chemotherapy (1993). In 2009, the patient presented with another early right TNBC treated with surgery followed by chemotherapy with docetaxel + cyclophosphamide (T + C). She then developed skin nodules and left axillary lymphadenopathy and received palliative capecitabine. In 2010, she developed progressive mTNBC involving the sternum and mediastinal lymph nodes and received 9 cycles of gemcitabine, carboplatin, and iniparib (GCI) until summer 2011. In late 2011, lymph node recurrence was treated with axillary lymph node dissection (2/5 lymph nodes involved with tumor) and radiotherapy. In 2012, she developed progressive disease (PD) and received 3 cycles of a whole cell breast tumor vaccine, trastuzumab, and low dose cyclophosphamide (NCT00971737). Upon progression, she was enrolled in the Phase 1a PCD4989g atezolizumab monotherapy trial, first dosed on March 11, 2013. She had a partial response (PR) by Response evaluation criteria in solid tumors (RECIST) and Immune-related Response Criteria (irRC) after 4 cycles. On May 31, 2013, the patient had an irPR per irRC and unconfirmed PR per RECISTv1.1. In July 2013 she experienced a pseudoprogression: appearance of a new nodal lesion (PD by RECISTv1.1) while still responding according to irRC. She was clinically well and continued treatment. On November 2013, the patient progressed by both RECISTv1.1 and irRC with the appearance of two new nodal lesions. On January, 2014, her target lesions were still in response (Fig. a), while the new nodal lesions were enlarged but stable. On February 2014, after 16 cycles, she discontinued atezolizumab exposure per protocol, with close surveillance.
On March 26, 2014, she was diagnosed with a catheter-related deep vein thrombosis, with left arm edema and enlarged lymph nodes; lymph node biopsy showed scattered tumor cells, while she had an ongoing PR in the target lesions. On July 2014, she developed palpable left axillary lymph nodes with poorly differentiated carcinoma with extensive necrosis (Fig. b). On January 2015 a CT scan showed nodal PD and she re-initiated single agent atezolizumab on February 2015. While on re-treatment with atezolizumab she first had a PR in April 2015, and then a complete response (CR) in June 2016. As of the clinical data cutoff (December 31, 2016), she remained on treatment and in CR (Fig. ). This patient provides a unique opportunity to profile the immunogenomic evolution of the TiME before and during atezolizumab therapy.


A 69-year-old male patient was admitted to our rehabilitation facility at the Pirawarth Clinic following a second, probably embolic stroke of undetermined source (ESUS) in the area of the right middle cerebral artery in March 2017 (proximal ACMD, M1 segment). He suffered a first ischemic stroke in the same vascular area on October 2016. When he was admitted to our clinic in May 2017, he already had completed four weeks of rehabilitation as an inpatient in another rehabilitation facility with only minor improvements in his upper limb motor functions.
The patient presented with left-sided hemiparesis, left hemianopia, and left hemineglect. He was able to walk with a cane and the hemiparesis was affecting especially his left upper limb with distal weakness (distal MCR Grade 1-2, proximal MCR Grade 3-4). He was not able to manipulate small parts or perform isolated finger movements (e.g., to pick up coins, use the cutlery and so forth).
The patient was treated with 75 mg of Clopidogrel in combination with Aspirin (100 mg) for secondary stroke prevention. His diabetes, hypertension, and hyperlipidemia were well-controlled medically. As he already was an ambulatory patient, the primary goal of our rehabilitation efforts was to improve the motor activity-level of his left upper extremity and to promote manual dexterity.
In early June 2017, we decided to offer the patient a two weeks course of an innovative multimodal therapy, including:
intensive occupational therapy with a minimum of one hour of task-oriented training per day during tDCS stimulation; additional conventional rehabilitation therapy for 2-3 hours per day for 28 days
daily anodal transcranial direct current stimulation (anodal tDCS 2x20 minutes, over the left motor cortex M1), five days a week from Monday to Friday.
A 2-week treatment course with daily intravenous infusions of 30 mL Cerebrolysin for 14 days.


The patient was a 42-year-old female with a known case of asthma. She had recurrent episodes of upper abdominal pain referred to back and right shoulder which was associated with fatty meals. Ultrasound showed multiple gall stones. She was admitted for elective laparoscopic cholecystectomy on January 8th 2019.
Intraoperatively, there was a maroon-colored nodule attached to the anterior gall bladder wall as shown in . En-bloc resection along with the gall bladder was done. Postoperatively, the patient stayed at the hospital for one day and was then discharged home. The resected specimen was sent to the histopathology department, and the report showed normal lobular architecture as shown in .


A 63-year-old woman presented with a two-day history of right-sided abdominal pain and swelling associated with dyspepsia. She had no history of jaundice. Abdominal examination revealed abdominal fullness on her right side with a palpable right iliac fossa mass. She was admitted for further examination. Blood tests showed high concentrations of inflammatory markers. She experienced an episode of pyrexia, requiring the commencement of intravenous (IV) antibiotics. A computed tomography (CT) scan of the abdomen demonstrated a markedly enlarged gallbladder (Figure ). She was subsequently readmitted for an elective mini-laparoscopic cholecystectomy which was successful. Her postoperative recovery was unevenly and she was discharged at 24 hours postoperatively. A review at six weeks after discharge in the outpatient general surgery clinic was satisfactory.
The removed gallbladder weighed 73.8 g. Histologic examination showed an accumulation of hemosiderophages within the wall mixed with foreign body type multinucleated giant cells, but no evidence of malignancy. The largest stone was cuboid and 27 mm in diameter.


The patient was a 64-year-old male with a past medical history significant for hypertension, hyperlipidemia, and diabetes mellitus type 2. He presented to the emergency room with severe abdominal pain with an episode of almost passing out at home. He was in his usual state of health and noticed intermittent abdominal pain associated with nausea and vomiting for two to three weeks. He was brought to the emergency room where a computerized tomography (CT) scan of the abdomen showed a perforation involving the distal jejunum/proximal Ileum and free air. Subsequently, he underwent exploratory laparotomy and small bowel resection.
The pathology of the resected specimen showed EATL type 2. The neoplastic cells had medium-sized round, darkly staining nuclei with a rim of pale cytoplasm (Figure ). Intraepithelial lymphocytosis appeared to involve the adjacent intestinal mucosa. Immunohistochemistry showed the tumor cells were CD3+, CD 2+, CD8+ (Figures -), CD56+, and CD 4-negative, which are markers for EATL. The Ki-67 stain, which is a marker of proliferation, showed an 80% proliferative rate. In-situ hybridization for Epstein-Barr virus-encoded ribonucleic acid (EBER) was also performed which was negative for the Epstein-Barr virus (EBV) antigen. EBER is key to differentiate EATL type 2 from natural killer (NK)/T-cell lymphoma, which would demonstrate positivity in NK/T-cell lymphoma and be negative in EATL [].
His postoperative course was complicated by a wound infection and delayed healing, leading to multiple antibiotic courses which resulted in the delay of subsequent care. A positron emission tomography/computed tomography (PET/CT) scan and bone marrow biopsy were done as an outpatient which showed multiple metabolically active pulmonary nodules. The largest nodule measured 2.6 cm in the posterior right lower lobe (Figure ). The bone marrow biopsy revealed cellular marrow with maturing trilineage hematopoiesis and no morphologic evidence of lymphoma.
The patient subsequently presented to the hospital with shortness of breath. A CT scan of the chest showed a nodular mass-like component measuring 3.1 cm with moderate pleural effusions and multiple pulmonary nodules (Figure ). Biopsy of the lung nodules was consistent with peripheral T-cell lymphoma consisting of small to intermediate-sized neoplastic lymphoid cells (Figure ). The tumor cells were positive for CD3 and negative for CD20 and CAM 5.2. Ki-67 revealed a proliferative rate of 75%.
Of note, he had recurrent admissions for abdominal pain where he had small bowel perforations and had surgical resections. Subsequently, he was started on chemotherapy with the CHOP regimen (cyclophosphamide, hydroxydaunomycin, Oncovin®, prednisone) once he recovered from his surgery. After he underwent the first cycle of chemotherapy, he, unfortunately, again had a perforation of the small bowel. In view of the poor prognosis, the family chose patient comfort measures only, and he succumbed to his disease.