An 88-year-old female underwent a left hemicolectomy for the resection of colonic adenocarcinoma. The histology of the left hemicolectomy showed moderately differentiated colonic adenocarcinoma, with 2 of 6 lymph node involvement i.e. T3N1. She did not receive any adjuvant therapy. Her recovery was uncomplicated, and she was eventually discharged to her general practitioner for ongoing annual surveillance. She had a follow-up colonoscopy, which did not demonstrate any recurrence.
Five years later, at the age of 93, she presented to our service for investigation of a new mass in the left upper quadrant detected on a surveillance abdominal CT. She had only mild non-specific upper abdominal discomfort, and no bowel changes were noted. She also had a history of atrial fibrillation, for which she was on apixaban. No abdominal mass was palpable, and the examination was otherwise unremarkable. The CEA level had been stable and consistently less than 1ug/L (normal non-smoker < 5ug/L). On the abdominal CT, a 4.7 x 3.0cm soft-tissue density mass was evident anterior to the left kidney, adjacent to the tail of the pancreas and the previous colonic anastomosis. (A)
A core biopsy of the lesion was performed and showed an atypical spindle cell lesion, thought initially to represent a desmoid or low-grade sarcomatous lesion. It was unable to be characterized further. Given the lack of clinical symptoms, the small size of the lesion, and her advanced age, a decision was made for observation only with interval imaging. Throughout the observation period, the patient remained functionally very well.
However, over a 12-month period, the lesion showed progressive enlargement, up to 12.7 x 8.6cm (1C).
The patient began to complain of the worsening of the abdominal discomfort and fullness. After an extended discussion with the patient and her family, a decision was made to perform a laparotomy in an attempt to excise the lesion. Intraoperatively, the tumor was found to be adherent and inseparable to the nearby structures suggesting local invasion. These included the previous colonic anastomosis, spleen, tail of pancreas and left kidney. The procedure was abandoned due to the potential morbidity of multi-visceral resection to achieve complete surgical excision. Surgical biopsies were performed, which demonstrated a moderately cellular tumor composed of atypical spindle cells within a collagenous stroma (A), reactivity for MDM2 on immunohistochemistry (B) and MDM2 amplification by fluorescence in situ hybridization (C), consistent with dedifferentiated liposarcoma. The patient was discharged for supportive care and symptom management.


A 68-year-old man with metastatic non-small cell lung cancer presented with several weeks of gastrointestinal hemorrhage requiring transfusion. Computed tomography (CT) of the abdomen revealed a distal jejunal mass centered in the upper pelvis. Upper endoscopy and biopsy confirmed metastatic adenocarcinoma consistent with lung primary. Due to comorbidities, he was ineligible for surgery and was referred to radiation oncology for urgent palliative treatment. A course of 25 Gy in 5 fractions was prescribed. Given the known substantial mobility of the small bowel, a 0.35-T MRgRT system with daily volumetric MR-guided setup and real-time cine imaging and gating during delivery was employed.,
Because this case was urgent, simulation and first fraction of treatment occurred on the same day, 4 hours apart. The suitability of the patient to undergo MRI simulation and treatment was evaluated at time of consult (the day before simulation and treatment), via review of medical history and completion of an MRI questionnaire by the MRgRT team at our clinic.
The MRgRT hybrid linear accelerator system used in this case, including characteristics of the onboard imaging unit and integrated Monte-Carlo-based treatment planned system, has been described., The patient was simulated supine, with arms at sides, without additional immobilization. We specifically elected against custom immobilization in this patient, given the potentially large range of motion of the tumor. Our clinic’s typical custom immobilization includes rigid fixation of the bottom MRI receiver coil to the custom mold. Had we used this typical setup, we would have been unable to move the coils, if needed, to the best imaging position, which is with the center of the coils as close to the target region of interest as possible. The MRgRT system used in our clinic allows for 3° of freedom of couch motion, thus minimizing any issue of adaptation due to gross external patient anatomy/positioning. A 3-minute, free-breathing, volumetric MRI was acquired and used as the primary planning image. The jejunal lesion was identified and contoured as the gross tumor volume (GTV). It was noted that a shorter imaging sequence would be preferred for treatment days, as although the tumor did not move with respiration during simulation imaging, there was a general abdominal wall respiratory motion artifact on the planning MRI that affected visual evaluation of the bowel and ease of target identification ( center). The planning target volume (PTV) was defined as a 1 cm isotropic GTV expansion. A static conformal plan was created, taking advantage of the doubly focused multi-leaf collimators (MLCs) of the MRgRT system to ensure a compact dose distribution. The optimized 3-dimensional conformal treatment plan used 12 gantry angles, with 1 segment per angle. The location of the lesion at the time of simulation and plan isodose distributions are shown in .
For patient setup at fraction 1, a 17-second single end-exhale breath-hold volumetric scan was acquired. The jejunal lesion was noted to have moved substantially from time of simulation, due to peristalsis. An adjustment of the patient’s position via couch translations necessitated a re-evaluation of the dose distribution after adjusting the assigned relative electron density to the patient’s habitus. The dose distribution from the original plan was then recalculated onto the new MRI data set; the PTV was inadequately covered by the original plan. The plan was therefore adjusted using beam weight optimization. This process left intact the beam gantry angles and MLC positions but changed the monitor units to produce a dose distribution similar to the original plan, taking into account the now-different path-lengths of the beams. A secondary dose calculation was performed as part of pretreatment quality assurance for the new plan. Online replanning was rapidly performed while the patient remained on the table in the treatment position. Similar plan adjustments were required at fractions 3 and 5. The criteria for adaptation was occurrence of gross tumor motion beyond the 1 cm PTV expansion and where shift-to-match location was either not possible due to patient collision with the MRI bore (due to large shift magnitude) or because it resulted in large incongruencies between electron density maps such that the predicted dose, when accounting for these changes, was less than 90% of prescription to 95% of the PTV. A single iteration of reoptimization was required for each adaptive plan, which is typical of our clinic’s MRgRT system for both intensity modulated radiation therapy and optimized conformal plans. Before beam-on, a sagittal plane was selected for real-time target monitoring and automatic beam-gating directly upon the target volume using a deformation registration algorithm that has been previously described. The time from image acquisition to completion of treatment delivery was about 20 minutes for each fraction, including the time for evaluation for and need for adaptation. Plan adaptation time was minimized in this case (~5 minutes per fraction), as the palliative dose level used (25 Gy in 5 fractions) was below our institutional 5-fraction abdominal constraint (36 Gy to 0.5 cc), obviating the need to recontour adjacent loops of bowel at each fraction.
This imaging and evaluation process was repeated for all fractions. All daily volumetric images were acquired at end-exhale breath-hold position, in a single 17-second breath-hold, minimizing any contribution of respiratory phase variability to observed interfraction motion. Additionally, all gated delivery (upon the GTV itself) was at the exhale position. After a “radiographic bowel run” to localize the tumor, setup position adjustments were needed at each fraction due to shifting locations of the jejunal tumor. During fraction 4, an additional intrafraction position adjustment was required. For the first 2 minutes of the 5-minute treatment, the lesion was well-visualized in the sagittal plane. However, during real-time cine monitoring, the appearance of the lesion abruptly changed and treatment was immediately paused. Repeat 17-second volumetric scan revealed additional peristaltic motion of the target, and a second position adjustment was performed for successful fraction completion. After completion of treatment, the patient reported resolution of melena, and his hemoglobin improved without subsequent transfusion requirement. He had no evidence of acute toxicity at 3 months follow-up.
A quantitative analysis of the extent of motion of the jejunal lesion as observed on the 0.35-T MR images was performed by determining the lesion’s position relative to a stable anatomic landmark, the L5/S1 interspace. The distance from the center of this landmark to the centroid of the GTV as observed at the time of simulation was designated as the baseline. For each subsequent fraction, the GTV was contoured where observed on that day, and the centroid distance to the landmark was calculated in all cardinal directions. Comparing these distances to the baseline gave the actual distance of each instance of the location of the GTV relative to the original position at time of simulation. The results are summarized in . The minimum distance between the GTV centroid positions was 2.4 cm, greatly exceeding the 1-cm PTV expansion. The maximum distance was over 8 cm.
In addition, without cine gating, the intrafraction motion of the tumor in fraction 4 would have been missed. Even with accurate initial setup, the lesion moved by 1.4 cm during delivery and would have been partially missed by the 2.5 Gy of the latter half of the fraction, resulting in a 10% dosimetric error in the unirradiated region (approximately 2.6 cm of the 4-cm lesion).
Lastly, the availability of weight optimization for a simple conformal plan allowed for restoration of acceptable dose distributions for each fraction (first, third, fifth) at which the lesion changed position enough to warrant it. It should be noted that the position of the mass at the time of the diagnostic CT was within 1 cm of the position observed at the time of simulation. This would have given a false sense of positional stability and resulted in a geographic miss if the patient had received standard, x-ray-based localization and treatment.
The second case is of a 36-year-old man with oligometastatic clear cell renal cancer, originally treated with nephrectomy and stereotactic body radiation therapy to lesions of the lumbar spine (L3), sternum, and the left anterior rib. Two years after his original diagnosis, surveillance CT imaging showed a new solitary omental metastasis. Surgical resection would have required ex-lap with bowel run for intraoperative identification and removal. He was instead consented for stereotactic body radiation therapy for oligometastasis ablation, using the MRgRT system. However, when the patient came in for his simulation, the nodule could no longer be identified on either the simulation CT scan or the MRI scan performed shortly afterward. The treating physician discussed the findings with the patient and at first adopted a watchful waiting approach.
Two months after the initial simulation attempt, the patient had repeat diagnostic CT imaging for follow-up, which reidentified the growing omental lesion. The location of the lesion was markedly different between diagnostic CTs, and it was determined that the lesion had been difficult to identify on the original simulation because its position was unpredictable, from mobility of the omental curtain. The patient underwent repeat simulation that afternoon. The tumor location on the diagnostic CT scan of that morning was quite different from its location on the simulation CT in the afternoon. Therefore, the MRI simulation for MRgRT involved acquiring multiple scans at an exhale breath-hold (to eliminate breathing artifact), while moving the field of view from the upper midabdomen to the pelvis. The nodule was finally identified this way, and it was also observed that the nodule’s movement subsided as a function of time the patient was resting on the treatment couch, over the course of about 15 minutes, as the patient/bowel settled into position.
A treatment plan was created in the MRgRT system’s treatment planning module to deliver 35 Gy in 5 fractions, with dose escalation permitted up to 50 Gy to 95% of the PTV, provided that strict abdominopelvic organ-at-risk constraints could be met. The PTV was defined as the GTV plus 1 cm isotropic expansion. The GTV was spherical, 1.6 cm in diameter, with a volume of 2.2 cc. Potential organs-at-risk primarily included the stomach, duodenum, small, and large bowel. The plan was made to be robust for daily online adaptation.
The first fraction attempt at treatment was unsuccessful—despite waiting 15 minutes for bowel settling, the nodule was not visible. It was suspected that it was too near a loop of bowel to be distinguished from the bowel itself. The patient was therefore not treated, and a second attempt at fraction 1 was made the following day. This time, after multiple scans, the lesion was located but was substantially higher in the abdomen than it had been at the time of simulation. After online replanning to account for this motion and ensure dosimetric constraints were met, treatment was delivered successfully. The nodule was monitored with real-time imaging in the sagittal plane. Fractions 2 to 5 were delivered in the first on-table attempts, with similar requirement for a radiographic bowel run to identify the lesion location each day.
One year after treatment completion, the patient has continued to be seen in follow-up clinic, with no further growth of the omental lesion. Restaging imaging has shown central necrosis of the omental lesion consistent with treatment response. No acute or late abdominopelvic toxicities have been observed, and he has not required any further systemic therapies at this time.
The nodule was observed to move at least 2 cm each day (3 cm average) and had a maximum lateral movement of 5 cm at fraction 4. The L5/S1 interspace was chosen as in case 1 to compare the relative positions of the nodule between simulation and treatment. Results are summarized in , and the simulation image and plan as well as daily treatment images are shown in . As with the previous case, it would be nearly impossible to treat this patient without the use of MRgRT and daily adaptation.


A 42-years old male patient was referred to a local hospital with a sudden onset of dizziness, nausea, as well as vomiting, and MRI revealed a partially thrombosed aneurysm adjacent to the left portion of the medulla (). The patient was admitted to our hospital without any major symptoms. An initial DSA image demonstrated dilatation at the fourth segment of the left VA, thus indicating a VADA without the involvement of the posterior inferior cerebellar artery (PICA) (). The right vertebral and basilar artery showed no major abnormalities. He had a medical history of hypertension and hyperlipidemia, but no previously reported head trauma and family history of aneurysm. The patient had a history of smoking 20 cigarettes a day for 20 years, which was ceased just at the time of this admission.
We treated the left VADA using endovascular pipeline embolization for preserving the normal blood flow. In addition, a dual antiplatelet therapy, comprising 300 mg aspirin and 300 mg clopidogrel were administered 5 days before the surgery. Under general anesthesia, a pipeline embolization device (PED) was successfully implanted with satisfactory adherence between the PED and vessel wall. No intraoperative complications were encountered, and the right VA was preserved. He was discharged home 1 week after the operation and prescribed dual antiplatelet therapy (aspirin 100 mg/day and clopidogrel l00 mg/ day) for 6 months. Angiography conducted at 5 months after initial treatment revealed the patency of the VA and partial aneurysm residues (). This residual of the left VADA persisted on 14 months () and 2 years (), and completely occluded at 3 years angiography follow-up (). The volume of the aneurysm did not significantly alter from 14 months () and as noted in 2 years of follow-up MR images (), and the patient did not display any adverse symptoms after the surgery.
In addition, no major abnormalities were found in the right VA at 5 months after initial treatment (). Surprisingly, follow-up imaging 14 months postoperatively showed a segmental dilatation and narrowing of the right VA (), which suggested the formation of a de novo VADA. Stent-assisted coiling was performed for this de novo VADA. Under general anesthesia, Guglielmi detachable coils were positioned in the dissecting aneurysms after placing an LVIS stent in the true lumen of the VA (). Dual antiplatelet therapy was prescribed to him as done before. The patient had an uneventful postoperative progression with no observation of any occurrence of neurological deficits. Moreover, a 20 months angiography follow-up revealed complete occlusion of the aneurysm ().


A 51-year-old male patient with a past medical history of type 2 diabetes mellitus on oral hypoglycaemic agents presented to the emergency room with complaints of cough with haemoptysis for the last five days following a recent trip to the state of Bihar, India. Haemoptysis was initially scanty in amount (about 25 mL/day) and increased to 200 mL/day for two days. There was no history of fever, shortness of breath, chest pain, skin rashes, jaundice, the passage of blood in stool or urine, loss of appetite, or loss of weight.
The patient had a history of exposure to tuberculosis at his workplace (the worker was sputum positive) one year ago. The patient also had a history of vertigo one year ago for which he received treatment. The patient had no history of hypertension, bronchial asthma, or ischaemic heart disease. He has no history of smoking or alcohol use. The patient had no significant family history.
On examination, the patient was afebrile and haemodynamically stable. Chest examination revealed left-sided fine inspiratory crepitations. The rest of the local and systemic examinations were found to be within normal limits. The patient was admitted for further evaluation.
Laboratory investigations (coagulation profile, complete blood count, and renal and liver function tests) were found to be within normal limits. Computed tomography (CT) thorax with contrast showed ground-glass densities in the right upper lung and left lower lung, features highly suggestive of alveolar haemorrhage (Fig. ). It also showed normal calibre bronchial artery at D5–6 level. This necessitated an interventional radiologist consultation to assess the feasibility of bronchial arterial embolization (BAE) to arrest the bleeding. In this case, the interventional radiologist ruled out any hypertrophied bronchial arteries or collaterals. This precluded the possibility of BAE. Echocardiography was normal with no evidence of pulmonary embolism, clots, or vegetations. The patient was initiated on intravenous tranexamic acid, cough suppressants, and empirical broad-spectrum antibiotics, and was observed closely.
The in-hospital course was complicated by worsening haemoptysis threatening to compromise the airway. The patient was intubated with an 8.5-mm internal diameter endotracheal tube, mechanically ventilated at 40% fraction of inspired oxygen (FiO2), and was paralysed with atracurium. The patient was transferred to the medical intensive care unit. Check bronchoscopy performed under conscious sedation showed an active ooze of bleeding along with clots in the left lower lobe posterior segment (Fig. ). An emergent therapeutic bronchoscopy was done using the Olympus BF1T 150 (Japan) with an outer diameter of 6 mm and a working channel diameter of 2.8 mm. As there was no access to the conventional EWS and the patient was bleeding incessantly, the team devised an innovative method of using the classic peanut surgical gauze as a suitable alternative. The gauze ball was made up of gauze pads rolled into the shape of a peanut and secured with a regular silk thread tied around its neck (Fig. ). The gauze tamponade was sprayed with tranexamic acid. A forceps was introduced through the working channel of the bronchoscope with the peanut gauze held at the tip. It was then carefully lowered into the ET tube and manoeuvred into the anterior segment of the left lower lobe so that it would fit snugly in the segment. It resulted in a successful tamponade of the bleeding site (Fig. ).
Bronchoalveolar lavage (BAL) samples were collected (which showed no bacteria or fungal elements, was negative for organisms/granulomas, and had no growth on culture after 48 h of incubation). The patient was continued on mechanical ventilation under deep sedation and paralytics. Check bronchoscopy performed after two days revealed the in situ peanut gauze. Using forceps, the peanut and clot were cautiously dislodged and removed through the ET tube. No active bleeding was noted and the mucosa at the site of tamponade was healthy. The patient was weaned off the ventilator and extubated to face mask oxygen support. He was observed for the next few days before discharge. The patient had review visits after one week and three and six months, and reported no further episodes of haemoptysis.


Our patient is a 3-year-old male with a significant history of 27-week prematurity, mild cerebral palsy, epilepsy, and chronic constipation. He presented with severe electrolyte derangements in the setting of prolonged seizure activity. The patient had seizure activity that lasted 20-40 minutes on the day of presentation to our hospital. This was the longest seizure he had ever experienced. He had used a homemade saline enema on the day before this event. He was found to have abnormal electrolytes with a serum potassium of 6.8 mmol/L (Ref: 3.5-5.1 mmol/L), serum bicarbonate of 9 mmol/L (Ref: 23-28 mmol/L), serum calcium of 4 mg/dL (Ref: 8.6-11.2 mg/dL), serum phosphorus of >13 mg/dL (Ref: 2.5-4.5 mg/dL), and serum magnesium of 1.2 mg/dL (Ref: 1.6-2.3 mg/dL) at presentation. A head CT was performed, and it was normal. Blood and urine cultures were also obtained. The initial workup was also notable for troponin of 0.1 ng/mL (Ref: 0.000-0.034 ng/mL), ionized calcium of 0.4 mmol/L (Ref: 1.14-1.29 mmol/L), c-reactive protein of 1.4 mg/dL (Ref: <1.0 mg/dL), lactic acid of 3.6 mmol/L (Ref: 0.7-2.0 mmol/L), and procalcitonin of 57.3 ng/mL (Ref: 0.0-0.5 ng/mL).
Diagnostic assessment
Multiple other labs were obtained, including thyroid-stimulating hormone (TSH), free T4, parathyroid hormone (PTH), vitamin D, uric acid, lactate dehydrogenase (LDH), and creatine kinase (CK). Of these, PTH was elevated to 280.7 pg/mL (Ref: 11.5-82.7 pg/mL), LDH was elevated to 1413 U/L (Ref: 313-618 U/L), and CK was elevated to 703 U/L (Ref: 30-170 U/L). TSH was low at 0.109 iU/mL (Ref: 0.470-4.680 iU/mL) with a normal free T4 of 1.14 ng/dL (Ref: 0.78-2.19 ng/dL). This was thought to be due to sick euthyroid given the patient’s acute illness. The 1,25-vitamin D was normal at 55.6 pg/mL (Ref: 19.9-79.3 pg/mL), as was his 25 vitamin D at 26.7 ng/mL (Ref: 20.0-100.0 ng/mL) and alkaline phosphatase at 138 U/L (Ref: 115-460 U/L). There was no evidence of hypoparathyroidism or vitamin D toxicity based on these studies. We suspected that the initial PTH elevation might be secondary to severe hypocalcemia.
Further workup included an adrenocorticotropic hormone (ACTH) stimulation test and urine calcium and phosphorous. ACTH stimulation test results were normal, with 30-minute cortisol of 48.8 ug/dL and 60-minute cortisol of 59.5 ug/dL (Ref: 4.46-22.7 ug-dL), making adrenal insufficiency less likely. Baseline cortisol was not obtained.
Urine calcium and phosphorous excretion were appropriate in response to electrolyte anomalies with low urine calcium (<1.0 mg/dL) and high urine phosphorous (>286.0 mg/dL). The repeat phosphorus after a few hours was further reported at 15.8 mg/dL. Our patient had significant hypocalcemia, hyperphosphatemia, and expected elevation in PTH in the setting of his significant hypocalcemia, along with evidence of cell lysis with high CK and LDH levels following the seizure episode.
Treatment and clinical course
The patient was admitted to the Pediatric Intensive Care Unit (PICU) for the management of his electrolyte abnormalities with endocrinology and nephrology services actively involved in his care. He received intravenous fluids to help correct his electrolyte abnormalities and acidosis. The calcium was corrected with intravenous calcium gluconate over the course of 24 hours, after which he was transitioned to oral calcium carbonate. He also received intravenous magnesium supplementation for the correction of hypomagnesemia. Sevelamer at the dose of 400 mg PO TID was added to help correct his severe hyperphosphatemia. Ergocalciferol was started for vitamin D supplementation and to help maintain stable calcium levels. The serum calcium and phosphorus improved within 24 hours of admission to the PICU (Figure ).
Procalcitonin was initially elevated, but it improved over the course of a few days. Of note, elevated procalcitonin has been previously reported in the setting of convulsions []. Similarly, the elevated lactate levels returned to the normal range following intravenous hydration. We did not see the presence of persistently high lactic acidosis or evidence of diabetic ketoacidosis that could have contributed to an acute extracellular phosphorus shift.
The family used homemade saline enemas to treat his constipation and there was no recent history of the use of phosphorus-containing enemas. The peak serum creatinine was 0.5 mg/dL and the patient continued to have good urine output during admission. There was no evidence of a significant acute kidney injury episode that could have contributed to phosphorus retention. Also, there was no substantial evidence of the presence of acute phosphate nephropathy. The kidneys had normal size and echogenicity on renal ultrasound. The blood and urine cultures obtained on admission were ultimately negative for infection.
He was able to be weaned off his electrolyte supplementation slowly. The PTH level rechecked on day two of admission had returned to normal at 24.4 pg/mL. The calcium carbonate was weaned off over the course of six days. The patient continued to have normal electrolytes throughout the remainder of his admission and was discharged only on ergocalciferol supplementation.
Follow up
He had no further seizure activity after discharge and calcium levels remained stable on follow up labs. At his endocrinology follow-up appointment one month after discharge, he remained off all calcium supplementation and was only taking vitamin D daily. At that time, his calcium and phosphorus levels remained within normal range, with a normal PTH level. Alkaline phosphatase and vitamin D levels were normal as well.


A 45-year-old woman from Achefer, near Bahir Dar, northwestern Ethiopia, presented to the emergency department of our hospital on February 18, 2020, with a complaint of generalized fatigue for 18 years and worsening abdominal pain, vomiting, and diarrhea of 1 month duration. The history dated back 18 years to the birth of her seventh child in home delivery, following which she experienced excessive vaginal bleeding due to delayed expulsion of the placenta. She had lost consciousness following the vaginal bleeding and had been treated locally by traditional healers and survived. After the delivery, she had failed to lactate and remained amenorrheic and could not conceive, but had no any gynecological evaluation. She also complained of progressive generalized fatigue and decreased work capacity, preventing her from doing her routine activities. She had experienced repeated abdominal pain, nausea, vomiting, and diarrhea as well for the past 6 years and had repeatedly visited a nearby clinic and was managed for dyspepsia and gastroenteritis but with no lasting improvement. In addition, she had associated weight loss, anorexia, dizziness, cold intolerance, myalgia, arthralgia, and progressive loss of axillary and pubic hair. These symptoms had worsened over the past month, and she had developed generalized weakness and extreme fatigue even at rest and experienced excessive sleepiness. She also had mild to moderate intermittent headache, but otherwise no blurring of vision or diplopia She had no history of head trauma, surgery, or irradiation, and no history of polyuria or polydipsia on physical examination, and she was conscious but sleepy. Her blood pressure was 90/60 mmHg, pulse rate 86 beats per minute, respiratory rate 24 breaths per minute, and temperature of 36.9 °C. She had mild epigastric and periumbilical tenderness. She had dry, coarse skin and sparse axillary and pubic hair. Examination of other systems was unremarkable. Laboratory findings showed the following: white blood cell count 2590 cells/μL, hematocrit 26.9%, mean corpuscular volume (MCV) 81.3 fl, creatinine 1.2 mg/dL, normal liver function tests, sodium 126 mEq/L, potassium 2.52 mEq/L (repeat 4.2 mEq/L), random blood sugar 113 mg/dL, total cholesterol 152 mg/dL, triglyceride 86 mg/dL, and low-density lipoprotein (LDL) 161 mg/dL. Brain magnetic resonance imaging (MRI) revealed an empty sella turcica, as shown in Fig. . As the clinical manifestations related to the patient’s previous obstetric history suggested Sheehan’s syndrome, relevant available hormone studies were performed (Table ). After all these tests were performed, she was diagnosed with Sheehan’s syndrome presenting with imminent adrenal crisis.
The patient was rehydrated with one bag of normal saline (NS), and started on prednisolone 2.5 mg in the evening/5 mg in the morning and subsequently levothyroxine 75 μg/day to be titrated based on clinical response. She was strictly instructed on the nature of her illness and was told to take these medications for the rest of her life. She was referred to an endocrine clinic and discharged. On subsequent clinical assessment, abdominal pain, nausea, vomiting, and diarrhea had subsided; her appetite had returned and she had started to gain weight.


The patient was a 31-year-old lactating woman who had delivered her first child 4 months before. Her medical history included infantile asthma, and her family history revealed hyperuricemia and hypertension in her father, and Hashimoto’s disease in her mother.
Upon developing pruritis on bilateral lower limbs, she visited a dermatology clinic and was prescribed a steroid cream. One week after the onset of pruritis, she developed lower limb edema. She visited our hospital two weeks after the onset of edema. She reported no history of parasitic or non-parasitic infections.
Physical examination revealed striking, non-pitting edema of both lower legs and feet (). She did not have fever or urticaria. Her weight had not changed significantly. Otherwise, she showed no symptoms, and her vital signs were normal. Initial laboratory findings were as follows: white blood cell count was 1.82×104/μL, and it increased to 1.91×104/μL with 68.6% eosinophils later (eosinophil count was as high as 1.31×104/μL) (). Serum lactate dehydrogenase was slightly elevated (). Serum immunoglobulin G (IgG), IgM, rheumatoid factor, antinuclear antibody, complement component 4, and erythrocyte sedimentation rate were within normal range. The maximum C-reactive protein level was only 0.51 mg/dL throughout the course of illness (). There was no evidence of anemia, hypoalbuminemia, or thyroid dysfunction ().
Chest radiography showed no signs of heart failure or renal failure, and ultrasound cardiography was negative for postpartum cardiomyopathy.
Since she had edema with eosinophilia but no involvement of internal organs, we diagnosed her with angioedema with eosinophilia. She had no fever, urticaria, or weight gain. Serum IgM concentration was normal. Based on these findings, the final diagnosis was NEAE. She gradually recovered in approximately three months without any medication throughout the course. The follow-up period of 1 year was completely uneventful. Written informed consent was obtained from the patient.
To measure the degree of edema objectively, we used bioimpedance analysis using InBody® (InBody, Seoul, Korea). The high ratio of extracellular water to total body water (ECW/TBW) in the trunk and lower limbs, especially on the left side, concurred with the finding of edema (
). Although the total amount of body water and intra- and extra-cellular water remained unchanged (), bioimpedance analysis revealed edema of the trunk and lower legs.
Next, we investigated the role of various cytokines and chemokines. We found that interleukin-5 (IL-5), thymus- and activation-regulated chemokine/C-C motif chemokine ligand-17 (TARC/CCL-17), eotaxin-3/CCL-26, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF) showed correlation with the extent of disease (). Furthermore, we found the relationship between monocyte chemotactic protein-4/CCL-13 (MCP-4/CCL-13), eotaxin-1/CCL-11, and regulated on activation, normal T expressed and secreted/CCL-5 (RANTES/CCL-5), and the extent of disease ().
We explored the correlation between the index of edema (ECW/TBW) and these cytokines/chemokines. We found that each parameter we measured had a positive correlation with ECW/TBW. In particular, eotaxin-3/CCL-26, eotaxin-1/CCL-11, TARC/CCL-17, and MCP-4/CCL-13 were highly correlated (ρ value>0.9) with the index of edema (). In contrast, VEGF and RANTES/CCL-5 demonstrated a weak positive correlation (ρ value <0.5) with ECW/TBW.


An 80-year-old man with hypertension presented to the emergency center after he noticed painless swelling over his right groin of two days duration. He also visited the emergency department two weeks earlier after an accidental fall caused a small facial laceration that was repaired with stitches. Patient had mild dizziness associated with the fall, which resolved spontaneously. Patient stated he was missing his antihypertensive medication occasionally. Otherwise he denied any chest, back, or abdominal pain. Patient has been smoking 5-6 cigarettes a day for more than 20 years. He denies any recreational drug use. Examination during previous emergency center visit showed blood pressure of 160/95 mmHg, heart rate of 76 beats/minute and respiratory rate of 12 breaths/minute. No other abnormal physical findings except laceration on forehead. Electrocardiogram (EKG) and CT head were normal. Forehead wound was sutured; patient was advised to take his antihypertensive medications. He was discharged home, and he was recommended to have follow-up with his primary care physician. During the second hospital visit, blood pressure was 184/94 mmHg, pulse rate 77 beats/minute; respiration rate 16 breaths/minute, body temperature 98.20F, and oxygen saturation was 96% in room air. Patient was well-looking and not in pain. There was a healthy sutured wound on the forehead. Chest was clear bilaterally. Heart sounds were normal with no murmurs or gallop. Abdominal examination revealed a right reducible inguinal hernia, the abdomen was otherwise soft and nontender. There was no significant pulse deficit. Patient was alert and oriented with no neurological abnormalities. His laboratory results revealed: White blood cell count of 5,600/ul, hemoglobin 12.5 gm/dl, BUN 17 mg/dl, creatinine 1.3 mg/dl (baseline creatinine was 1.2 mg/dl). Urine studies were within normal limits and negative for drug screen. Transthoracic echocardiogram revealed left ventricular ejection fraction of 55%, thickening of aortic valve, and mild left ventricular hypertophy. Scrotal ultrasound showed minimal bilateral hydroceles and right inguinal hernia. Chest X-ray revealed mediastinal widening with positive calcium sign (see Figure ). Abdominopelvic CT with contrast showed an incidental finding of aortic dissection and indirect right inguinal hernia. In order to further delineate the extent of the dissection, CT angiogram was done and it confirmed Type B aortic dissection that extending from the origin of right subclavian artery to the bifurcation of the common iliac arteries (see Figures -). The patient was admitted to the medical intensive care unit for blood pressure control and close monitoring. Vascular surgery was consulted and recommended conservative medical treatment. He was managed conservatively with labetalol and IV nicardipine in the unit and subsequently transferred to the general medicine floor. Patient remained hemodynamically stable; his blood pressure was well controlled, and he was discharged in stable condition with an outpatient follow-up appointment.


A 64-year-old man was admitted to a local hospital for limb weakness and facial hyperpigmentation for 2 weeks. He also reported oedema of the lower limbs for 1 week. He had a history of smoking for 40 years(30 cigarettes per day). Lab tests revealed severe hypokalaemia (1.8 mmol/L, normal range 3.5–5.5 mmol/L) and metabolic alkalosis. Potassium supplementation (KCl, 9 g/day) failed to normalize the serum potassium (peaked at 2.3 mmol/L). As the level of serum creatine kinase (CK) was remarkably elevated(1268.4 u/L, normal range 50–200 u/L), the patient was transferred to our hospital. Upon admission, mild moon face and facial hyperpigmentation was noticed when compared with photos taken 2 years before. Oedema of the lower extremities and decreased muscle strength were also found during physical examination. Hyperpigmentation at interphalangeal joints and ecchymosis gradually developed during hospitalization.
The results of the laboratory test on admission and the function of the endocrine glands are summarized in Tables and . Urinary potassium excretion was inappropriately increased (Table ). The serum cortisol level was increased, and diurnal rhythm was lost. The level of serum cortisol at 8 am was > 50 µg/dL after the low-dose dexamethasone suppression test(LDDST), and the patient was diagnosed with CS. ACTH dependency was confirmed based on remarkably elevated ACTH levels (Table ). Pituitary MR was normal (Fig. a and b). The serum cortisol level at 8 am before and after the high-dose dexamethasone suppression test (HDDST) was 212 µg/dL and 208 µg/dL (calculated with the measured value and dilution rate), respectively (Table ). Although the above results strongly suggested EAS, bilateral inferior petrosal sinus sampling (BIPSS) was routinely arranged for verification, mainly for two reasons. First, false positive and false negative results occur in both HDDST and regular imaging(pituitary MR and chest CT). For example, the HDDST results for EAS and CD sometimes overlap. Some patients with EAS have coexisting pituitary adenomas that are not the source of ACTH. Second, in very few patients, CD is caused by hyperplasia instead of adenoma, resulting in a negative finding on pituitary MR. Then, BIPSS was successfully performed (PRLleft/PRLperipheral and PRLright/PRLperipheral were 4.3 ± 0.5 and 2.5 ± 0.3, respectively). The left, right and peripheral ACTH levels were 789.9 ± 5.2 pg/mL, 773.6 ± 18.2 pg/mL and 726.5 ± 26.7 pg/mL (three samples for each), respectively, and the left, right and peripheral ACTH/PRL levels were 12.4 ± 1.4, 21.4 ± 2.4 and 49.1 ± 2.2, respectively. The diagnosis of EAS was made based on the HDDST and BIPSS results. Chest and abdominal CT as well as neck ultrasound were further arranged. Abdominal CT showed diffuse enlargement of the bilateral adrenal glands (Fig. c and d), and there were no abnormalities in the pancreas. Chest CT indicated two nodules in the superior and middle lobes of the right lung (Fig. e f) and prominent mediastinal lymphadenopathy (Fig. g h). Elevated tumour biomarkers, including carcinoembryonic antigen (CEA), cytokeratin 21 − 1 fragment CYFRA21-1 and neuron-specific enolase(NSE), were detected (Table ). Thyroid ultrasound showed no abnormality. 68Ga-PET/CT suggested high-density opacity in the superior lobe of the right lung with a slight abnormally increased uptake of 68Ga-DOTA-NOC, fitting the characteristics of chronic infection (Fig. i). The high-density nodule in the middle lobe of the right lung was found without abnormal uptake of 68Ga-DOTA-NOC (Fig. j). Multiple lymph nodes in the left supraclavicular fossa, right root of the neck, mediastinum and bilateral hili of the lung were found partially fused into a mass with abnormal uptake of 68Ga-DOTA-NOC (Fig. k and l). Considering that the lymph nodes in the supraclavicular fossa and root of the neck might be distant metastases which is differ from the primary lesion, lymph nodes in the mediastinum and bilateral hili were preferable for biopsy. Therefore, mediastinoscopic lymph node biopsy was performed. The lymph nodes were pale and friable (Fig. a). The pathological diagnosis was small-cell and large-cell neuroendocrine carcinoma (LCNEC)according to the 2018 World Health Organization expert consensus proposal on the classification framework for neuroendocrine neoplasms [] (Fig. b and c). Mitosis was approximately 80/10 HPF (Fig. d), and the Ki-67 index was 80 % (Fig. e). ACTH staining was positive (Fig. f).
The fasting plasma glucose (FPG) level was 7.4 mmol/L, and the glycosylated haemoglobin(HbA1c) level was 5.7 % on admission. During hospitalization, the FPG level gradually increased. Diagnosis of diabetes was made, and insulin therapy was initiated. Bone mineral density indicated low bone mass. Blood pressure, lipid profile, and coagulation function were generally normal.No thrombus was found by colour Doppler ultrasound in the arteries or veins of the lower extremities. On admission, remarkably elevated levels of serum CK and myohemoglobin (Mb)were noticed with slightly increased creatine kinase isoenzyme(CKMB) (Table ). ECG was generally normal. Based on the above results and the even higher CK level (higher than 5 times the upper limit) at the local hospital, the diagnosis of RM was made, and fluid infusion was applied. The serum potassium level was 2.49 mmol/L on admission, and potassium supplementation (KCl, 15 g/d) was initiated. After the assessment of renin, angiotensin and aldosterone, antisterone was prescribed at a daily dose of 120–160 mg. The CK and Mb levels decreased gradually as the serum potassium level increased. On day 10, a saline and glucose solution was applied after the enhanced pituitary MR and chest CT to prevent acute kidney injury, and transient decline in the serum potassium level and re-elevation of the CK and Mb levels occurred (Fig. a, b and c). On admission, an increased troponin T level, a decreased serum calcium level and an increased parathyroid hormone(PTH)level were also observed and were gradually relieved with the improvement in RM.
After discussions among specialists from multiple disciplines (pathology, respiratory medicine, oncology, anaesthesiology, urology, thoracic surgery and endocrinology department), the urologists and anaesthetists considered it very risky for the patient to undergo bilateral adrenalectomybased on hypokalaemia, infection and general status. Additionally, aggravation of the condition was more related to malignancy than hypercortisolaemia, especially after the application of mifepristone. As the priority was determined to be to treat neuroendocrine carcinoma, which was unresectable, the patient was transferred to the oncology department to receive chemotherapy. In addition, mifepristone was applied at an initiating dosage of 75 mg per day and a maintaining dosage of 150 mg per day. The patient received one cycle of chemotherapy with the EP regimen (etoposide 100 mg iv drip days 1–3 and cisplatin days 1–3) but could not tolerate subsequent chemotherapy. He died of dyscrasia within 1 month.


A 30-year-old female patient presented with a 6-month history of cough and expectoration, during which time she felt palpitations and sometimes, chest suffocation. She denied fever, dyspnea, asitia, cyanosis, hoarseness, hemoptysis, or night sweats. She had a baby just 1 month prior to the examination and had pain in her right rib 7 days prior. She denied a history of smoking and drinking. Because of ectopic pregnancy, she underwent surgery 7 years ago, during which she lost blood and received transfusion therapy.
Physical examination revealed that the breath sounds in the left lung field were weakened. Laboratory studies showed that her white blood cell count was 12.4 × 109/L; the hemoglobin level was 97 g/L; and the platelet count was 555 × 109/L. D-dimer level was 8.37 mg/L. Tumor marker analysis showed that the squamous cell carcinoma antigen had increased to 3.4 ng/mL, and her CYFRA211 level had increased to 90.2 ng/mL. Pulmonary function test showed maximum voluntary ventilation (MVV) was 67.98 L, accounting for 63.1% of the predicted value; forced expiratory volume in 1 s (FEV1) 2.09 L, accounting for 72.3% of the predicted value. Contrast-enhanced computed tomography (CT) scans revealed a large soft tissue mass in the lower left lobe of the lung; the maximum cross-section was ~11.7 × 15.4 cm. The density of the mass was uneven and showed inner crumb calcifications. The solid parts of the mass were enhanced with moderate heterogeneity. The bronchus of the lower lobe of the left lung was truncated. The bilateral axillary lymph nodes were enlarged, and multiple enlarged lymph nodes were observed in the left hilus of the lung. Pleural effusion was observed on the left side of the chest cavity. CT results are considered as left lower lobe tumor with mediastinal and left hilar lymphadenopathy. Chest radiography showed a patchy shadow in the lower lobe of the left lung. The left hilus of the lung was expanded, and there was a left pleural effusion.
To identify the location and the type of the tumor, a bronchoscopic examination was performed. Bronchoscopy showed that the basal segment of the lower lobe of the left lung was entirely blocked by a tumor, which had a cauliflower-like appearance. The remaining bronchial mucosa of the lower lobe of the left lung was slightly congested, and the ridge was widened. Brush detection revealed a few cells with large bodies, arranged in groups, which is may be considered as lung cancer. A bone scan and abdominal ultrasonography showed no metastases, and the cardiopulmonary function of the patient was adequate; therefore, we performed surgery. The patient provided informed consent and signed the consent form.
During surgery, the left lower lobe of the lung was found to have adhered to the thoracic cavity, and a hard mass involving the entire left lower lobe and inferior pulmonary veins was present, without metastatic nodules in the pleura. To excise the upper and lower pulmonary veins, we opened the pericardium and successfully resected the total left lung and cleaned the 4, 5, 7, 9, and 10th nodes (). We reinforced the bronchial stump with 4-0 non-traumatic absorbable thread by continuous back and forth sutures. The bleeding volume was 500 mL, with a 400-mL blood transfusion. The operation lasted for ~4 h. Because the patient was young and not at risk of cardiovascular and cerebrovascular diseases before the operation, she was directly transferred to the general ward after operation.
The patient received preventive antibiotic and supportive treatments after the operation. The chest tube was removed on the fourth day after the operation. Postoperative pathology confirmed that the tumor was a small round-cell malignancy with a cross-section of 12 × 11 cm. The tumor was adjacent to the visceral pleura, and a bronchial tangent and nodes were not found in the tumor. One of the lymph nodes showed extensive necrosis. Immunohistochemistry revealed that the tumor cells were positive for creatine kinase (CK), Friend leukemia virus integration 1 (FLI-1), neuron-specific enolase (NSE), CD99, and anaplastic lymphoma kinase (ALK). The cell proliferative index (KI-67) was ~50%. The tumor cells were negative for cytokeratin 7, P40, thyroid transcription factor-1, CD56, chromogranin A, vimentin, CD30, CD43, α-inhibin, myeloperoxidase, S-100, and CD138 (). The patient recovered well and was discharged 7 days after surgery


A 45-year-old Saudi male presented to the emergency department of a local hospital in March of 2018 with a typical picture of acute appendicitis; he was admitted for an open appendectomy. Intraoperatively, they discovered a perforated appendix; histopathology revealed a severely inflamed perforated appendix. After 4 days, his first operation was complicated by a feculent discharge from the peritoneal drain due to a complicated cecal fistula with a septic clinical picture. He was admitted for an exploratory laparotomy, and segmental resection of the involved bowel with primary anastomosis was done. Two days after the second operation, he had an anastomotic leak with peritonitis, and he had feculent discharge from the wound site and the peritoneal drain; he was shifted to the operating room for an exploratory laparotomy where a right hemicolectomy was done with primary anastomosis. On the seventh day, and despite the two operative attempts, the patient had intraperitoneal dissemination of fecal material and generalized peritonitis for the third time; he was sent for an exploratory laparotomy where a diverting ileostomy and a colostomy as a mucus fistula was done.
The patient did not have any remarkable family history, he is medically free, not a smoker or alcoholic and doesn't have any significant medical history.
After 9 months, the patient was admitted to the General Surgery department in Al-Hada Armed Forces Hospital for an open ileostomy and colostomy reversal surgery. His abdominal examination revealed a normal soft and lax abdomen with a right ileostomy and left colostomy openings. On admission to Al-Hada Hospital, his white blood cell count was 6.12 × 10−9/l, mostly lymphocytes (3.27 × 10−9/l). His hemoglobin was 146 g/l, platelet count was 370 × 10−9/l. C- reactive protein () was 1.5 mg/l, erythrocyte sedimentation rate () was 15 mm/h. Carcinoembryonic antigen () was 0.9 ng/ml.
White blood cell count normal range is 4 to 11 × 10−9/l, lymphocytes normal range is 0.1 to 1.1 × 10−9/l. Hemoglobin normal range is 135 to 180 g/l. Platelets normal range is 150 to 400 × 10−9/l, C- reactive protein normal range is 0.0 to 5.0 mg/l, erythrocyte sedimentation rate (ESR) normal range is 0.0 to 10.0 mm/h, and Carcinoembryonic antigen (CEA) normal range is 0.0 to 5.0 ng/ml.
Pre-operative abdominal computerized tomography () with the contrast given intravenously, orally, rectally, and through the ileostomy. The axial CT view is shown in (). The coronal and sagittal CT views are shown in ().
Pre-operative abdominal CT insured a patent passage of the bowel. But the calcified densities and fat stranding opacities were thought to be related to post-operative changes. Intraoperatively, laparotomy under general anesthesia showed adhesions and several irregular bone-like tissues of hard consistency and sharp edges with some spindle-shaped structures resembling needles were found on the mesentery of the small intestine (). All the bone-like tissues were carefully removed.
The bone-like tissues were examined histologically (). It showed trabecular bone fragments, suggestive of heterotopic ossification. Post-operatively, the patient was advanced slowly to a normal diet, and he improved gradually. The patient's last follow-up was in January 2021; he showed complete recovery with no complications.


A 73-year-old male long-term cigarette smoker with no significant past medical history presented for right nephroureterectomy and radical cystoprostatectomy with ileal conduit diversion for bladder and ureteral cancer. Prior to the induction of general anesthesia, a T10-11 epidural catheter was placed to be utilized intraoperatively and for post-operative pain management.
The epidural catheter was placed with components from a B. Braun Perifix® continuous epidural anesthesia tray (B. Braun Medical Inc., Bethlehem, Pennsylvania, USA). A 20-guage closed tip epidural catheter was inserted into the epidural space at T10-11. This was accomplished using a loss-of-resistance technique through a midline approach with a 17-gauge Tuohy needle and a Perifix™ plastic luer slip loss-of-resistance syringe. The epidural catheter was inserted five cm into the epidural space. The epidural catheter was then connected to a clamp style catheter connector which was then attached to a 0.2 μm filter connector.
A test dose of 3mL of 1.5% lidocaine with 1:200,000 epinephrine was administered without significant resistance through the filter connector with a 20mL luer lock plastic syringe. The test dose was negative, general anesthesia was induced, and the procedure began as planned. The anesthetic was maintained in this patient using a combination of inhaled sevoflurane through an endotracheal tube and a continuous infusion of 0.0625% bupivacaine through the epidural catheter. A B. Braun Perfusor® Space Infusion Pump was used to deliver the continuous epidural infusion. Infusion rates varied between 2 and 8mL per hour for the duration of the operation, and high-pressure alarms on the pump never activated during the case.
At the conclusion of an uneventful and successful surgical procedure, the patient was extubated smoothly. The patient endorsed incisional pain, and the patient’s blood pressure, heart rate, and respiratory rate were all mildly elevated from baseline. The continuous epidural infusion was stopped. A bolus of 5mL of 0.25% bupivacaine with 1:200,000 epinephrine was delivered by hand using a BD 10mL Luer-Lok™ syringe (Becton, Dickinson and Company, Franklin Lakes, New Jersey, USA) via the epidural filter connector. Midway through the hand delivered bolus, the epidural filter connector top popped off from the rest of the mechanism spraying the contents of the syringe several feet in multiple directions (Fig. ). The bottom half of the epidural filter connector that remained connected to the clamp style catheter connector and epidural catheter itself recoiled and struck the patient near his shoulder which did not cause any immediate noticeable harm.
It was estimated that the patient received 2mL of the epidural bolus before the filter connector broke. An additional 3mL was then administered to the patient via the clamp style catheter connector without significant resistance. The patient was then taken to the post-anesthesia care unit (PACU) where a new filter connector was attached to the clamp style catheter connector. A BD Alaris™ patient-controlled analgesia (PCA) pump was then used to deliver 0.0625% bupivacaine with 10mcg/mL hydromorphone at 6mL/hour with a 2mL every 20 minutes demand option. The epidural catheter was removed on post-operative day (POD) 3 as the patient transitioned to oral pain medications. The patient was discharged from the hospital on POD 5 in stable condition.


A 62-year-old woman was found to have an elevated serum CA125 level of 50 U/ml (normal < 35 U/ml) at a local hospital in November 2018. Her serum CEA and CA19-9 levels were within normal limits, and no obvious abnormalities were found on transvaginal ultrasound (TUS). In November 2019, at the same hospital, her CA125 level had increased to 75 U/ml. TUS performed at the local hospital revealed a large pelvic mass.
She was then referred to our hospital for further diagnosis and treatment. Laboratory test results, including assessment of tumour markers, routine reproductive hormone examination and routine blood tests, were within the standard levels. The patient was asymptomatic, and a physical examination revealed no abdominal mass. The patient’s family history indicated that the patient’s mother died from ovarian cancer.
Abdominal computed tomography (CT) revealed a right adnexal well-circumscribed hypodense mass (Fig. ). On a contrast-enhanced CT scan, slight enhancement of the mass was noted and a fluid–fluid level sign was observed. Routine and contrast-enhanced MRI demonstrated well-defined lobulated cystic mass in the right pelvic cavity that was approximately 4.9 × 4.8 cm in size (Fig. ). The mass was of mixed signal on T2-weighted imaging (T2WI) and T1-weighted imaging (T1WI). Nodular hypointensity on both T1WI and T2WI was observed within the lesion. Diffusion weighted imaging (DWI) showed severe hyperintensity. A fluid–fluid level sign was also observed in the cystic mass. The patient was suspected of having a chocolate cyst according to the clinical CT and MRI results. Routine preoperational TUS showed a right adnexal mass with a size of approximately 5.6 × 4.4 × 5.5 cm. Conventional ultrasound showed a well-defined cystic mass with mural and septal nodules. The largest size of internal papillary excrescences was 3.0 × 1.4 × 1.7 cm. Doppler flow could be detected in the internal septation, cystic wall and papillary excrescences. The resistive index of the cyst wall was 0.9. The right ovary was visible. There was no ascites. Considering the appearance and features on TUS, a primary diagnosis of malignant neoplasm was made. To further clarify the nature of the lesion, the patient underwent a CEUS examination, during which 2.4 ml of ultrasound contrast agent (SonoVue; Bracco SpA, Milan, Italy) was injected from the peripheral vein by bolus injection. Hyperenhancement of cystic wall, septations, and papillary excrescences were observed in the arterial phase on CEUS. The mass becomes hypo-enhancement in the late phase. The mural-nodule-like solid component measured approximately 1.7 × 1.7 cm and the smaller one 0.5 × 0.5 cm (Fig. ). Based on the contrast ultrasound results, the diagnosis of cystadenocarcinoma was first considered.
Surgical resection of the retroperitoneal mass was performed. During the operation, a mass approximately 5 cm in diameter was found in the Douglas cul-de-sac. It was soft and had no obvious adhesion to surrounding tissues. The tumour was cystic and solid, the cyst wall was thick, and the cyst contained solid tissue. Both ovaries and fallopian tubes are normal. Frozen biopsy showed (pelvic) adenocarcinoma, mainly with papillary growth. Da Vinci robot-assisted laparoscopic pelvic tumour resection was conducted. Expert pathologists with more than 10 years of experience determined the pathologic results. Grossly, the tumour was multi-cystic, well-encapsulated and filled with serous fluid. The inner surface contained several papillary nodules protruding into the cavity. Under microscopic examination, the tumour tissues were arranged in a papillary shape; a glandular tube, invasive growth, haemorrhage and necrosis were observed. The tumour cells were abnormally shaped, nuclear division was visible, and nucleoli were obvious. The immunohistochemistry results were as follows: CK20(−), CK7(−), p53(+), CA125(+), CDX2(−), PAX-8(+), ER (+), PR(−), WT(+), calretinin CR(−) and vimentin(+) (Fig. ). The final pathological finding was high-grade serous adenocarcinoma. The patient’s serum CA125 levels decreased after the operation, but the level was slightly higher than the normal range (< 35 U/ml). The patient was treated with a combination of adjuvant carboplatin and paclitaxel (544 mg carboplatin and 268 mg paclitaxel intravenously every 3 weeks) at 3-week intervals for eight cycles. After two cycles of chemotherapy, her serum CA125 level decreased to a normal level. The patient has completed all chemotherapy cycles and is now in good condition. Her serum CA125 level has remained within the normal range as of publication of this report. Written consent was obtained from the patient for publication of the case.


A 79-year-old woman had chronic heart failure (New York Heart Association functional class III), with ischemic heart disease that had been treated by coronary artery bypass grafting 20 years earlier, and multiple percutaneous coronary interventions had been performed. Eight years earlier, heart failure with a low ejection fraction (<35%) had developed, and she then underwent cardiac resynchronization therapy for compromised electrical activity. While she had been repeatedly hospitalized for heart failure, mitral regurgitation (MR) developed. Transthoracic echocardiography (TTE) showed severe MR with a very low ejection fraction of 33% and diffuse severe hypokinesis. Since the surgical risk for mitral valve replacement was quite high, with a Society of Thoracic Surgery (STS) score of 19.9% and a European System for Cardiac Operative Risk Evaluation (EuroSCORE II) of 21.9%, MitraClip (Abbott Vascular, Chicago, IL, USA) implantation was scheduled [].
Anesthesia was induced with remimazolam, remifentanil (0.20 μg/kg/min), and rocuronium (0.7 mg/kg). Remimazolam was administered at 6 mg/kg/h until loss of consciousness, followed by 1 mg/kg/h of remimazolam for maintenance. Time to loss of consciousness was about 2 minutes after the start of remimazolam administration. The patient was intubated 3 min after rocuronium administration of 0.7 mg/kg. Monitoring followed a routine protocol for mitral clip implantation that included the use of transesophageal echocardiography and the FloTrac monitoring system (Edwards Lifesciences, Irvine, CA, USA), which can measure continuous cardiac output, cardiac index, and stroke volume. shows the anesthetic chart from anesthetic induction to the start of surgery. During the period from anesthetic induction to the start of surgery, no vasopressor agent was used to maintain hemodynamics. The dose of remimazolam was adjusted to a bispectral index range from 40 to 60, and it could be decreased by 0.15 mg/kg/h during surgical procedures. MitraClip implantation via a femoral vein approach was successfully performed without any complications. After firm pressure was applied for 15 minutes to treat bleeding at a catheter insertion site, remimazolam was discontinued, and 0.2 mg of flumazenil was administered. About three minutes after the administration of flumazenil, the patient's eyes opened and she breathed spontaneously. The tracheal tube was removed. After extubation, there were no adverse events, including resedation or desaturation.


A 64-year-old African American male with a history of hypertension, hyperlipidemia, type 2 diabetes mellitus, and hyperplasia of the prostate presented to the emergency department with subacute low back pain for two weeks, which did not improve with conservative medical management, and symptoms of weight loss, anorexia, ageusia, nausea without emesis, chills, fatigue, malaise, and weakness. The patient endorsed taking ibuprofen 400 mg every six hours over the past two weeks without relief of symptoms and noted decreased urine output without dysuria or hematuria. The patient was admitted to the intensive care unit (ICU) due to renal failure with hyperkalemia with a potassium level of 9.2 mmol/L, uremia with a creatinine level of 28.5 mg/dL, blood urea nitrogen (BUN) level of 201 mg/dL, and glomerular filtration rate (GFR) of 2 mL/min/1.73m2, and anion gap metabolic acidosis with a carbon dioxide level of 8mmol/L, blood pH of 7.14, and anion gap of 22 mEq/L. Upon admission, he also tested positive for COVID-19, and later radiographic chest imaging revealed right middle lobe infiltrate.
The patient was initially diagnosed with a stage 3 non-oliguric AKI, with hyperkalemia and uremia thought to be due to normotensive ischemic renal failure due to his multiple co-morbidities, concurrent COVID-19 infection, and medication usage including NSAIDs (nonsteroidal anti-inflammatory drugs) and angiotensin-converting enzyme (ACE) inhibitors. The patient received medical management for hyperkalemia; however, later he became anuric and was started on hemodialysis via trialysis line. However, he experienced intermittent hypotensive episodes and two seizure episodes on hemodialysis despite receiving mannitol thought to be due to dialysis disequilibrium syndrome. He was then started on continuous renal replacement therapy (CRRT) and developed a mixed metabolic and respiratory alkalosis with pH of 7.49, an arterial partial pressure of carbon dioxide of 36 mmHg, and an arterial partial pressure of oxygen of 82 mmHg.
Notable labs for this patient upon admission included leukocytosis with a white blood cell count of 15.1 K/mL and anemia with a hemoglobin level of 8.9 g/dL. The patient continued to have back pain throughout his ICU stay, one episode of melena, and intermittent episodes of altered mental status. His hemoglobin level dropped to a trough of 5.9 g/dL on the second day of admission, and his iron panel was consistent with anemia of chronic disease with a hypoproliferative absolute reticulocyte count of 0.01 cells x 106/mL. His urinalysis showed more than 500 mg/dL of protein and a urine protein-to-creatinine ratio of 9:1, which is in the nephrotic range. The patient also had an active urine sediment with 273 WBCs/hpf and 4,532 RBCs/hpf, which raised concern for rapidly progressive glomerulonephritis since his creatinine prior to this admission was previously normal. A full hepatitis and autoimmune antibody panel did not reveal any abnormalities, ruling out other possible causes for his nephrotic syndrome and AKI.
A workup for MM was also conducted given his symptoms and clinical findings of subacute back pain, anemia of chronic disease, discrepant urine protein-to-creatinine ratio, and microalbumin-to-creatinine ratio, and acute renal failure. A urine protein electrophoresis test was positive, and serum protein electrophoresis revealed hypoalbuminemia, with free lambda light chains with a level of 17,700 mg/L and free kappa light chains with a level of 88.30 mg/L, with a kappa:lambda free light chain ratio of 0.005. Additionally, serum Bence Jones protein level was elevated at 240.0 mg/dL, and serum beta-2 microglobulin level was elevated at 31.41mg/L. An Ig panel also showed low levels of IgG, IgA, and IgM. Bone marrow biopsy revealed sheets of plasma cells (approximately 80% of total cells). Many of the plasma cells were positive for CD56. Kappa and lambda in situ hybridization showed lambda light chain restriction in the plasma cells.
Kidney biopsy of this patient showed light chain cast nephropathy with mild interstitial inflammation and fairly extensive interstitial fibrosis (Figures , ). Mild sclerosis and interstitial fibrosis most likely attributable to the patient's chronic co-morbidities. The patient was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD). The patient’s AKI secondary to cast nephropathy was treated with plasmapheresis for six cycles to help decrease light chains and improve kidney recovery. A bone marrow biopsy using hematoxylin and eosin stain showing bone marrow plasma cells ≥ 60%. The patient received plasmapheresis and is currently receiving hemodialysis on Tuesdays, Thursdays, and Saturdays. He is currently being evaluated for autologous hematopoietic stem cell transplantation.


An 87-year-old male with a past medical history notable for small bowel resection and anastomosis following obstruction, paroxysmal atrial fibrillation, basal cell carcinoma of the skin, and open cholecystectomy about 30 years ago, presented with complaints of generalized weakness and abdominal discomfort for two weeks prior to presentation. The abdominal discomfort was mostly after meals and progressively worsened. This was accompanied by high-grade fevers, nausea, and generalized weakness prompting the ED visit. Previously, this patient had three admissions over the last couple of years with abdominal pain, nausea, and vomiting, diagnosed as small bowel obstruction secondary to adhesions, managed conservatively to spontaneous full resolution, except for the last admission five months ago during which he required a repeat laparotomy and lysis of adhesions. During each of his previous admissions, pneumobilia was noted on CT scans of the abdomen, despite the lack of any symptoms related to cholangitis or sepsis.
On physical examination, this elderly male was found to be in moderate distress, with a temperature of 100.2°F, respiratory rate of 17/min, blood pressure (BP) of 106/64 mmHg, heart rate of 79/min, and SpO2 of 97% on room air. On auscultation, he had dual heart sounds with a holosystolic murmur noted at the apex. Breath sounds were diminished bilaterally but equal with no crackles or rhonchi heard. The abdomen was soft, non-distended but slightly tender. On laboratory testing, the patient had a white blood cell count (WBC) of 7.13 K/uL, hemoglobin of 14.6 g/dL, and a platelet count of 147,000 which were all within normal limits. The basic metabolic panel revealed creatinine of 1.0 mg/dL, electrolytes were within normal limits except potassium of 3.3 mmol/L. Liver chemistries revealed an elevated alanine aminotransferase (ALT) of 425 U/L, aspartate aminotransferase (AST) of 898 U/L, total bilirubin 2.5 mg/dL, and alkaline phosphatase (ALP) 612 U/L. Lactic acid was found to be at 2.5. CT scan of the abdomen without contrast showed branching air throughout the central aspect of the left hepatic lobe along with mild wall thickening of the common hepatic duct as shown in Figures , . This finding of pneumobilia was consistently unchanged from previous CT scans over the last two years as shown in Figure below.
A provisional diagnosis of sepsis secondary to cholangitis was made and the patient was started on IV fluids and antibiotics. He was found to be bacteremic with blood cultures growing Klebsiella. Gastroenterology was consulted and an endoscopic retrograde cholangiopancreatography (ERCP) was performed, which showed dilation of the common bile duct as shown in Figure . A 4 mm sphincterotomy was performed and numerous small biliary stones and sludge were removed along with occasional pus. A plastic stent was also placed in the common bile duct.
Initially, the patient's pneumobilia was attributed to his current cholangitis, however, the patient had pneumobilia since at least 2018. No choledochoduodenal fistula, choledochoduodenostomy, or evidence of the previous sphincterotomy was observed during the ERCP. Antibiotics were deescalated to an oral regimen, and the patient was discharged home following stabilization.


A 36-year-old male known to have glucose-6 phosphate dehydrogenase deficiency was presented with a one-week history of fever followed by cognitive impairment and decreased responsiveness. Before admission, he was screened for COVID-19 due to low-grade fever and contact with a suspected COVID-19 patient, but the result was negative. He was brought by ambulance to the emergency department, where he found to be stuporous but with stable vital signs. Neurological examination showed decreased consciousness level where he was opening his eyes to the pain, verbalizing noncoherent words, and localizing to pain. As a result, the patient was admitted to the intensive care unit.
Laboratory investigations, including the CSF study and COVID-19 polymerase chain reaction (PCR) swab, were sent (Table ). The swab of COVID-19 was positive, inflammatory markers, including C-reactive protein (CRP), white blood cells (WBC), D-dimer, and procalcitonin, were high. Blood and urine culture and sensitivity showed no growth, and platelets were adequate. Initial radiological studies, including chest X-ray and non-contrast CT scan of the brain, were unremarkable (Figures , ).
Empirical triple antimicrobial therapy (ceftriaxone/vancomycin/acyclovir) meningitis dosing was administered in addition to dexamethasone. First prolonged video-EEG monitoring (24-hour recording) showed generalized encephalopathy-2-3 Hz delta waves (Figure ). CSF study results came back unremarkable for which antibacterial (ceftriaxone/vancomycin) were discontinued (Table ). An enhanced cranial MRI and CT scan of the chest was unremarkable (Figures -). Over a period of 10 days, the patient started to show a gradual improvement in the conscious level and was transferred to the medical ward. Aciclovir was discontinued later based on a negative herpes simplex virus-polymerase chain reaction (HSV-PCR) result from the CSF sample. A follow-up prolonged video-EEG monitoring (for 24 hours) showed moderate diffuse encephalopathy with evidence of cerebral dysfunction over the left frontocentral region (Figure ).
Although the patient showed continuous improvement clinically, a second COVID-19 PCR swab turned out to be positive. However, the third COVID-19 swab came back negative, for which he was discharged with regular follow-up in the neurology clinic. Upon follow-up in the neurology clinic, he showed significant neurological improvement with unremarkable laboratory investigations. A routine EEG follow-up showed a normal posterior background of 9-10 Hz, but intermittent polymorphic 2-5 Hz slowing generalized, indicating a mild diffuse encephalopathy (Figure ). Although a specific test for CSF SARS-CoV-2 was unavailable, the final diagnosis was made on the basis of clinical presentation and supportive laboratory and EEG findings in the absence of other common encephalitis-related etiologies. Up to our knowledge, this is the first case report with multiple prolonged EEG recordings.


A 52-year-old white female with past medical history of hypertension, heart failure with preserved ejection fraction, generalized anxiety disorder, and alcohol dependence/abuse presented to the emergency department with retrosternal chest pain associated with nausea. She has family history significant for hypertension, diabetes mellitus type II, and coronary artery disease. Her home medications include the following: venlafaxine 75 mg, metoprolol tartrate 12.5 mg, and zolpidem 10 mg. Patient reports long history of 10 years or more of alcohol abuse reported as half a bottle of vodka or whiskey on daily basis. Vitals upon admission were blood pressure 155/100 mm Hg and a heart rate of 110 beats per minute. Her electrocardiogram showed sinus tachycardia with no acute ST-T wave changes. Initial troponin level was negative <0.012 (ng/mL). She was admitted for observation in the progressive care unit. Further laboratory data showed triglyceride 122 mg/dL (0-149), total cholesterol 265 mg/dL (107-200), LDL 41 mg/dL (0-99), HDL 218 mg/dL (39-61) with repeated level of 200 mg/dL. Her hemoglobin A1C was 5.3% (0-5.99), TSH 1.67 uIU/mL (0.465-4.68), folic acid >20.0 ng/mL (2.76-19), and vitamin B12 of 197.0 pg/mL (239-931). Other laboratory data including complete blood count and comprehensive metabolic panel were within normal limits. The trend of cardiac markers was negative. She had myocardial perfusion scan done showing no reversible ischemia. However, due to persistent chest pain, the decision was made to send the patient for left heart catheterization which showed nonobstructive coronary artery disease with 50% stenosis in the right coronary artery. She was discharged home on omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) 1000 mg folic acid 1 mg, atorvastatin 40 mg, aspirin 81 mg, and thiamine 100 mg with recommendations for further lipidology and genetic testing.


In May 2001, a 65-year-old Caucasian woman with chronic hepatitis B (CHB) and Child-Pugh Score (CPS) A cirrhosis, was referred to our unit with a 15 mm nodule in liver segment VII detected at the ultrasound surveillance. The abdomen computed tomography (CT) confirmed the lesion as a well-differentiated HCC (BCLC stage 0); Eastern Cooperative Oncology Group performance status (ECOG PS) was 0. AFP values, that were high (243 ng/mL) because of liver regeneration following a recent ALT flare (461 U/L) of her untreated HBeAg negative CHB, dropped to normal shortly thereafter, when nucleoside analogue (lamivudine) treatment was started. For HCC treatment, the patient underwent four sessions of percutaneous ethanol injection (PEI) between January and February 2002 with CR at the control CT, but in February 2010, after eight years of radiologic remission, magnetic resonance imaging (MRI) detected a novel 13 mm HCC in segment IV, and she underwent six sessions of PEI with CR. In June 2013, local recurrence was detected in segment IV with normal AFP, and two additional sessions of PEI were performed. However, 6 months later, CT demonstrated the increase in the size of the segment IV lesion to a diameter of 25 × 15 mm with invasion to the proximal section of the left portal vein, AFP was 12.4 ng/mL. HCC was classified as advanced stage (BCLC C, CPS A, ECOG PS 0) due to the portal vein invasion. The patient underwent trans-arterial radioembolization (TARE) in April 2014, achieving a radiologic remission with disappearance of the neoplastic portal vein thrombosis for approximately two years. In a follow-up control in January 2016, despite the negative MRI performed four months earlier, a sharp increase in both AFP and PIVKA-II serum levels occurred (AFP: 2377 ng/mL; PIVKA-II: 30362 mAU/mL). CT scan showed the appearance of 75 × 45 mm sized HCC in the left lobe with invasion to the main trunk of portal vein and hepatic veins. For the first time, the patient was symptomatic, complaining of fatigue and weight loss. She was considered to have an advanced stage HCC (BCLC C, CPS A, ECOG PS 2) and she was started on sorafenib 400 mg/day. A striking radiologic response was observed at 3 months (), accompanied by partial regression of vascular invasion.
AFP and PIVKA-II levels declined to normal range within 8 and 12 months, respectively. The clinical condition of the patient improved and she gained 8 kg in 6 months, even with drug-related side effects (grade 3 diarrhea with abdominal distension, fatigue, hitching and alopecia). Her maximum tolerated dose of sorafenib (600 mg/day) was maintained only for 1 month, till July 2016, when it was diminished to the initial dose (400 mg/day). Then, side effects of fluctuating intensity (grade 2–3) allowed her to assume variable doses (on average 300 mg/day) until July 2017, when the dose was decreased at 200 mg/day. Since October 2017 the dose of 200 mg was taken every other day with minimal side effects. Follow-up CTs demonstrated the progressive reduction of the tumor burden with consistent shrinkage of the left lobe and complete regression of the vascular invasion. Based on modified RECIST2 criteria [] a CR was achieved after 15.5 months of therapy, when no arterial phase contrast enhancement was documented in a residual lesion of 32 mm in diameter. At the last CT performed on February 2021, the residual area of the lesion was about 15 mm in diameter, yet without arterial contrast enhancement.
Best fitting of experimental data before therapy was reached by setting the cancer cells C(t) daily rate production equal to 0.360 × C(t)0.931, with the exponent <1 indicating that new cancer cells produced by a single cancer cell decreased as the tumor mass increased; C(t) decay at a daily rate equal to 0.11 × C(t), corresponding to cancer cells mean life-time of 9.1 days. AFP was produced at a daily rate of 0.0022 × C(t) and decayed at a daily rate equal 0.10 × AFP(t), corresponding to AFP mean lifetime of 10.0 days. PIVKA-II was produced at a daily rate of 0.00025 × C(t)1.22, with the exponent >1 indicating that PIVKA-II produced by a single cancer cell increases as the tumor mass increases, and decayed at a daily rate equal to 0.2 × PIVKA-II(t) corresponding to a mean lifetime of 5.0 days. The number of cancer cells present at the beginning of treatment C(0) = 1.78 × 106 cells/mL was estimated from the TTV measured at the baseline CT (139 cm3), under the assumption that HCC cells have on average the same volume of normal hepatocytes and occupy 50% of TTV. The time required for reaching that volume resulted to be 174 days. Steady-state plasma levels of sorafenib F(t), comparable to those reported in pharmacokinetics studies [] of approximately 0.01 mg/mL at the daily oral dose of 400 mg bid, were reached setting the F(t) daily yield rate equal to 0.000013 × D(t), where D(t) is the daily intake of sorafenib (mg/die). F(t) decayed at a daily rate equal to 0.50 × F(t), corresponding to a mean life-time of 2.0 days. During the first weeks of therapy AFP continued to increase but at a slower rate. For this reason, a time delay between sorafenib bioavailability and actual drug effectiveness [F(t)del] on the hepatocytes was assumed. In the same period, PIVKA-II levels showed a spike (Sp) preceding its rapid decline, and, later on, fluctuations not correlated to C(t). Such complex kinetics could depend from the anti-vascular effects of this drug on cancer cells and/or from their toxicity [Tox(t)] on non-neoplastic hepatocytes [,,,]. Fitting of PIVKA-II levels was reached indeed by computing values of F(t)del, Sp(t) and Tox(t) as described in . The effectiveness of sorafenib in reducing neo-angiogenesis was defined by the model parameter ευ = 1/[1 + ϑ1 × F(t)del], the value of ϑ1 = 220 was obtained by best-fitting of C(t) and PIVKa-II decline, which yielded a 77.4% reduction once reached the steady state of drug activity (about 3 weeks after treatment start). The effectiveness of sorafenib in reducing cancer cells replication was defined by the model parameter εr = 1/[1 + ψ1 × F(t)del], the value of ψ1 = 10 was obtained by AFP fitting and yielded a 13.5% decline once reached the steady state of drug activity. By fitting CT scans measured TVI in the first 9 months of therapy, we calculated the decay constant of tumor vasculature (α2 = 0.0042, which yielded a vasculature mean lifetime of 238 days) However, to acknowledge the fact that HCC did not recur despite lowering the doses of sorafenib in the following years (), the vasculature lifetime had to be reduced setting the parameter α3 = 0.35, thus attributing to the drug the possibility to accelerate vasculature degradation, in addition to that yet described of reducing neo-angiogenesis. According to this hypothesis, the vasculature lifetime was only 23 days with a sorafenib dose of 400 mg qd.


In 2012, a 72-year-old Caucasian man with Child-A cirrhosis, due to prior chronic active hepatitis C and type 2 diabetes, was referred for un unexpected increase of AFP (563 ng/mL) five years after successful treatment of HCV with peg-interferon and ribavirin. In the CT scan performed 6 months earlier no neoplastic lesions were detected, but the MRI performed after AFP elevation () showed the appearance of a widespread HCC in liver segment IV, with aspects of infiltrative growth and almost complete thrombosis of the portal branch for the VII-VI liver segments and partial thrombosis of the right portal branch. He was considered to have an advanced stage HCC (BCLC C, CPS A, ECOG PS 1) and he was started on sorafenib 800 mg/day. He had a partial response to therapy, but eventually the disease progressed, as shown at the last CT scan performed after 20 months of therapy. The patient died 28 months from the beginning of therapy. The progression was, at least in part, attributable to sorafenib dose reductions imposed by side effects, as also suggested by AFP and PIVKA-II kinetics.
Model computed cancer cells daily rate production was 0.250 × C(t)0.959, and C(0) = 3.17 × 106 cells/mL. AFP was produced at the daily rate of 0.0015 × C(t); PIVKA-II at the daily rate of 0.0010 × C(t)1.15, and its mean lifetime was 3.3 days. Best fitting of C(t), AFP and PIVKA-II decline was obtained setting ϑ1 = 50 and ψ1 = 5, which yielded a 50.9% and 9.4% reduction in neo-angiogenesis and cancer cells replication, respectively. Both AFP and PIVKA-II levels showed fluctuations correlated to C(t), and best fitting was reached with Sp(t) and Tox(t) equal to 0 ().


In 2019, upon accidental finding of esophageal varices (stage F1) by upper GI endoscopy performed because of dyspepsia, a 70-year-old Caucasian man was diagnosed with liver cirrhosis due to genetic hemochromatosis. Further investigations, including liver imaging and biochemistry, revealed the presence of Child-A cirrhosis with very high AFP levels (29,953 ng/mL). The CT scan () pointed out a single hypo-vascular nodule of HCC of 65 × 45 mm involving segment V-VII-VIII with satellites and thrombosis of the right portal branch. He was considered to have an advanced stage HCC (BCLC C, CPS A, ECOG PS 1) and he was started on sorafenib 400 mg/day, but one month later he was switched to regorafenib 160 mg/day because CT showed thrombosis progression and AFP levels up to 46,255 ng/mL. A partial response to regorafenib was documented by CT scan after 3 months and continued thereafter. Treatment is still ongoing and it is associated to a slow reduction of the tumor volume and of AFP levels.
By modeling cancer cells daily rate production was 0.32 × C(t)0.932, and C(0) = 5.79 × 105 cells/mL. AFP was produced at the daily rate of 0.0065 × C(t); PIVKA-II at the daily rate of 0.00007 × C(t)1.14, and its mean life-time was 2.5 days. Best-fitting of C(t), AFP and PIVKA-II decline was obtained setting ϑ1 = 30 and ψ1 = 5, which yielded a 27.1% and 5.8% reduction in neo-angiogenesis and cancer cells replication, respectively. Best fitting of PIVKA-II levels was achieved computing the values of Sp(t) and Tox(t) () according to the methods reported in .
Briefly, the reduction of PIVKA-II plasma levels during effective TKI therapy can be preceded by a transient increase, attributed to the ischemia of cancer cells []. The amount of PIVKA-II produced in the spike was computed assuming that it is proportional to PIVKA-II value at the beginning of therapy P(0) and to the density (R) of the cancer cells in the tumor mass. The increase may have a temporal delay and kinetics different from those of cancer cells. In addition, these drugs can also exert anti-vascular toxic effects on non-tumor liver cells [,]; the hypothetical amount of PIVKA-II produced in this way, expressed by the term Tox(t), was computed according to the equation Tox(t) = π4 × F(t) × tπ5, where the coefficient π4 is the parameter that accounts for the dose dependent effect (no toxicity in Case-2 = 0; in Case-3 = 15), and the exponent π5 accounts for the time dependent effect (in Case-3 = 1.52). In this patient, the fluctuations observed after 3 months of therapy are due to the PIVKA-II Tox(t) component, and reflect the dose of active drug F(t) which fluctuates because of the treatment schedule adopted with regorafenib, given every day for 3 weeks followed by one week off ().


A 5-year-old Japanese girl had a 6-month history of pain in her left knee while walking. She then developed increased pain, and knee extension was restricted, with no history of trauma.
She had been diagnosed with Blount’s disease on radiography at our institute at the age of 1 year and 3 months. On radiographs at that time, varus deformity of the proximal tibia with medial beaking and a downward slope of the proximal tibia (Grade 1 in the Langenskiold classification) were confirmed. The metaphyseal-diaphyseal angle (MDA) on radiography was 20° on the right and 23° on the left (Fig. a). She had been using a knee brace up to the age of 3 years, with a significant improvement; the MDA was 10° on the right and 11° on the left (Fig. b). In addition, she had also been diagnosed with Turner’s syndrome at the age of 2 years and 6 months by chromosomal analysis that showed the karyotype of 46, X, r (X) (p22.1 q22.1)/45, X (Fig. ). When she was diagnosed, her height and weight were 80.0 cm (− 2.4 SD) and 9.8 kg (− 2.0 SD), respectively. She was then started on growth hormone injections (0.35 mg/kg/week). Besides short stature, cubitus valgus was found to be associated with Turner’s syndrome. Her family members had never been diagnosed with Turner’s syndrome, discoid meniscus, or Blount’s disease.
At the age of 5 years, when she complained of increased knee pain, the physical findings were as follows. Height and weight were 98.7 cm (− 2.0 SD) and 15 kg (− 1.0 SD), respectively. Both tibias showed slight bowing. She walked with a limp, exhibiting motion pain and tenderness at the medial/lateral joint space of the left knee. Extension of the left knee was restricted, with a range of motion of − 15° to 140°. McMurray’s test was positive with internal/external rotation. There were no symptoms or signs related to the right side. On radiography, the MDA was 8° on the right and 9° on the left. Medial beaking and downward sloping of the proximal tibia were not noticeable (Fig. a). To diagnose discoid lateral meniscus, the height of the lateral tibial spine, lateral joint space distance, height of the fibular head, and obliquity of the lateral tibial plateau were measured, according to Choi’s method [] (Fig. b) (Table ). Her left knee showed tibial eminence hypoplasia, fibular head elevation, and greater obliquity of the lateral tibial plateau, which suggested discoid lateral meniscus. Magnetic resonance imaging (MRI) revealed a thickened lateral meniscus that almost completely surrounded the tibial lateral plateau. Although the ratio of minimal meniscal width to maximal tibial width was difficult to measure, it was clearly greater than 20%. The lateral meniscus was severely damaged and torn, which caused signal variation of the meniscus. It was suspected that the meniscal fragment was locking into the lateral joint. There was a large effusion and synovial proliferation. There were no particular changes in other components, such as the medial meniscus, anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), articular cartilage, and so on. There was no space-occupying lesion on MRI (Fig. a,b).
An arthroscopic procedure was performed. First, at the patello-femoral joint, plica was found, Sakakibara type B. Medial meniscus, ACL, and PCL injuries were not seen. Subsequently, a thickened discoid lateral meniscus almost completely covering the lateral tibial plateau was found. The lateral meniscus was completely torn, and the fragment was locking into the lateral joint space (Fig. a). It clearly restricted knee extension. There was no noticeable damage of the articular cartilage. Using a clamp and a radio-frequency device, the inner region including the injured meniscus was elevated, and a crescent shape was formed, resulting in good stability and shape (Fig. b). The restriction of knee extension was improved by the procedure.
Postoperative rehabilitation consisted of range of motion exercises, muscle-strengthening exercises, and walking exercises. The patient’s pain and restricted knee extension were finally relieved, and she started playing table tennis in junior high school. The symptoms of Blount’s disease have not relapsed; the MDA at the age of 15 years was 8° for both knees. For Turner’s syndrome, she continues to receive growth hormone treatment.


A 56-year-old male with advanced PD developed severe rigidity, dystonic posturing of both feet, and confusion of 4 days duration in November 2020. He is not known to have any chronic medical illness and has been diagnosed with PD 7 years ago, with initial left-sided tremors, bradykinesia, and rigidity. He had a strong positive family history of PD, but genetic testing was not done. His initial MRI of the brain and FDG-PET scan were normal, and he had a stable course on levodopa. He started to develop wearing-off and dyskinesia after few years which were manageable with drug adjustment.
Dopamine agonists (DA) were added, but the patient developed behavioral changes and psychotic features in the form of hallucination and delusions, which improved with the cessation of DA and small doses of quetiapine. Subsequently, with disease progression, levodopa-carbidopa intestinal gel (LCIG) was started with excellent improvement of wearing off symptoms and peak dose dyskinesia. After 2 years, and due to financial issues, the patient stopped LCIG and continued on levodopa with a total equivalent daily dose of 1497 mg and quetiapine 100 mg daily. His last clinical examination was in January 2020 with a stable clinical condition. His Hoehn and Yahr Scale (H&Y) score was 3, MDS-Unified Parkinson’s Disease Rating Scale (UPDRS) part III was 57/132 in off stage, Non-Motor Symptoms Scale (NMSS) was 233/360, and Montreal Cognitive Assessment (MoCA) score was 24/30. During the lockdown period amid the COVID-19 pandemic, he was compliant to treatment, maintaining his daily activities and communicating with the treating physician through telemedicine, and no drug adjustment was needed during this time.
He started to have severe rigidity and bradykinesia on the 1st of November 2020, with poor response to medications. His condition progressed to akinetic-rigid state with bilateral foot dystonia in the following week. On the 9th of November, he was transferred to the emergency room for confusion. His oxygen saturation was subnormal (90%); however, he had no fever or any respiratory complaint. A nasopharyngeal swab reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2 was conducted routinely for hospital admission, as per the Kuwait Ministry of Health (MOH) protocol. He tested positive for COVID-19 and was shifted to a specialized center. He developed fever and respiratory distress with low oxygen saturation, and he was intubated on the 10th day of illness. Computed tomography (CT) of the brain was normal. The patient was maintained on his regular treatment and was successfully extubated on the 19th of November. After discharge, he showed gradual improvement of consciousness and rigidity, and his feet dystonia improved; however, he did not reach his baseline prior to COVID-19 infection after 1 month.


The patient is a 28-year-old female who presents to the outpatient family medicine clinic with multiple raised papular lesions protruding from her umbilicus that bleeds. She states that she noticed a mass at her umbilicus about a year ago right after her cholecystectomy that has continued to grow. Over the past year, the mass has become increasingly painful and bleeds only during her menstrual cycle. She denies having any other abdominal pain, appetite changes, changes in her bowel movement, urinary incontinence or retention, abnormal vaginal bleeding or discharge and fever. She also denied abdominal distension, anal bleeding, melena, hematochezia, nausea or vomiting. She has a past medical history of asthma, chronic back pain, Graves’ disease, and obesity. In addition she also has a past surgical history of an endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy, through-the-scope (TTS) balloon with removal of sludge and a laparoscopic cholecystectomy performed one year prior. She denies tobacco, alcohol, or substance use and has no known drug allergies. On inspection of her abdomen there were scars from the previous cholecystectomy and multiple raised skin colored papular lesions on her umbilicus. The mass was easily visualized and there was no active bleeding from the mass or umbilicus during the exam. A computerized tomography (CT) scan with contrast of the abdomen and pelvis was performed. A 2-cm soft tissue mass involving the umbilicus can be seen in CT scans 1-4. CT scans 1-4 show the mass slowly protruding from the peritoneum to the surface of the abdomen (Figures -).
The patient was then referred to general surgery where the surgeon found the mass to be consistent with endometriosis and that it warranted surgical resection at that time. The patient agreed to the surgery with complete excision of the umbilicus. The patient was prepped and draped in the supine position. A transverse ellipse was made in the periumbilical skin carried down with cautery through the subcutaneous tissue to the umbilical stalk, which contained the mass. The umbilical stalk at the fascial level was transected with cautery and removed from the field. Extra fascia was removed to take any extra margins away, due to some hard tissue still remaining. A 1.5-cm umbilical defect was left which was repaired with an interrupted horizontal mattress and running nonabsorbable sutures that came together under mild tension. The wound was then irrigated, dried and hemostasis confirmed. The patient was given an option to have reconstruction of her umbilicus done, however she declined. The patient recovered well postoperatively and continues to have no complaints.


A 39-year-old African American female with a past medical history of pseudotumor cerebri, migraine, epilepsy, and hypertension was admitted to the hospital from the ED with dysphagia, slurred speech, tongue numbness, and altered voice. She also endorsed progressive right upper and lower extremity weakness and numbness when compared to the left side. She could walk into the ED but later was unable to stand or move her right leg. The patient exhibited left-sided facial asymmetry with an absence of ptosis, dysarthric speech, and right arm weakness on physical examination. Flexible laryngoscopy showed bilateral soft palate paralysis, absent gag reflex, and poor constrictor function with effort. Other cranial nerves (CNs) were intact. Head CT, computed tomography angiogram (CTA), MRI, lumbar puncture, and electromyography (EMG) were all unremarkable.
On day 2 of hospitalization, the patient suffered acute hypoxemic respiratory failure due to secretions and inability to protect her airways secondary to pharyngeal paresis. After several attempts, she was successfully intubated. Due to suspicion of a PCB variant of GBS involving pharyngeal and bulbar muscles, serum ganglioside antibodies were sent. The patient began empiric treatment with five sessions of plasmapheresis. Lab results showed high serum GD1a, GD1b, and GQ1b antibodies, IgG-IgM. After three sessions of plasmapheresis, her gag and cough reflexes recovered, and she was successfully extubated. She finished her last two plasmapheresis sessions and was discharged with a referral to neurology for EMG and follow-up on PCB variant of GBS.