A 75-year-old female presented with right popliteal pain for three weeks. She had first noticed pain in her right popliteal fossa when she had stepped on her bike; it had failed to improve spontaneously, and she had been referred to our hospital. She had a history of myasthenia gravis and hypertension, both well controlled for over 10 years. She had not injured her right knee during any sports activities. Her body mass index (BMI) was 36.8 kg/m2. Initial physical examinations showed effusion of the right knee, tenderness in the posteromedial aspect of the knee, and deep flexion pain. McMurray test conducted when her right knee was externally rotated was positive.
The X-ray showed a femorotibial angle (FTA) of 175 degrees and revealed grade II Kellgren-Lawrence classification (Figure ).
The coronal view of MRI showed a 6.3-mm extrusion of the medial meniscus and a truncation sign, and the sagittal view showed a ghost meniscus sign (Figure ).
Based on the above findings, a diagnosis of MMPRT was reached. Arthroscopic transtibial pull-out repair was performed two months after the onset of the condition.
A routine arthroscopic evaluation found LaPrade classification type 2A MMPRT and International Cartilage Repair Society classification grade 3 cartilage injury on the medial femoral condyle (Figure ).
After the preparation of a bony bed by resecting the cartilage around the insertion site of the posterior horn of the medial meniscus, the anterior cruciate ligament (ACL) reconstruction tibial guide with posterior root aiming device was inserted, aimed at the attachment site of the medial meniscus posterior root. A 20-mm socket-shaped bone tunnel with a diameter of 6 mm was created. Two loop stitches using ULTRATAPE® (Smith & Nephew Endoscopy, Andover, MA) and No. 2 FiberWire 5-mm medial from the torn edge in a horizontal direction were performed. By pulling the ends of the suture materials under adequate tension through the tibial tunnel, the meniscus was reduced and stabilized. Suture ends were then tied over an Endobutton® (Smith & Nephew Endoscopy, Andover, MA) and placed underneath the periosteum overlying the anteromedial tibial cortex.
A long leg splint was applied to the knee for immobilization at a slightly flexed position for four weeks postoperatively. The weight-bearing training was permitted four weeks after the surgery. The patient recovered to pre-injury level after rehabilitation and her Lysholm score improved from 55 points to 82 points and the International Knee Documentation Committee subjective score also improved from 27 points to 60 points two years after the surgery. On the other hand, X-rays showed a progressive formation of osteophytes around the medial joint space. MRI showed that the posterior root of the medial meniscus was continuous from the attachment; however, the width of the MME had increased from 6.3 mm to 9.6 mm (Figure ).
The patient subsequently had several falls, and the right knee pain gradually got worsened with protective limping. Therefore, UKA was performed two years and six months after the initial surgery (Figure ). The posterior root of the medial meniscus was continuous from the attachment and was included in resected proximal tibia at the time of the surgery.


A 38-year-old woman underwent an annual health checkup, and the ultrasonography identified a hepatic mass close to the portal vein. No specific findings were noted in her personal and family history. Her physical and laboratory data were unremarkable. CT showed a well-defined portal hepatic tumor with inhomogeneous moderate contrast enhancement (Fig. a). The tumor measured 4.2 cm × 6.8 cm. The clavate tumor showed low intensity on T1-weighted imaging and was isointense to fat on T2-weighted imaging (Fig. b). The tumor included cystic degeneration and extended along the intrahepatic bile duct (Fig. b). Both MRCP and endoscopic retrograde cholangiopancreatography showed focal bile duct compression without any biliary obstruction and dilatation (Fig. c, d). 18F-FDG accumulation was shown on PET after 5 months of the CT scan; the size of the tumor did not change during the interval (Fig. e), and the maximum standardized uptake value (SUVmax) was 5.0 (Fig. f) and 6.5 in the early and late phases, respectively. Lymphadenopathy was not identified by any imaging methods. Because IgG4-related disease and portal hepatic malignancy, including malignant lymphoma and cholangiocarcinoma, were still of our concern, a needle biopsy via endoscopic ultrasonography was performed. Histological study showed the spindle cells close to the bile duct (Fig. a). The lymphocyte infiltration was not identified, but the small vessels had proliferated moderately. Immunohistological examinations showed that the tumor cells were strongly positive for S-100 (Fig. b) but not for smooth muscle actin and c-Kit. Ki-67 staining was < 1% of the tumor cells. The diagnosis of portal hepatic schwannoma was made. Because of her age and possibly high invasiveness of the surgery for the portal benign tumor, we did not recommend the surgical procedures. She was followed up intensely in another institution.


A 32-year-old female with a past medical history of Hashimoto's thyroiditis and migraine presented with pressure-like left retro-orbital eye pain associated with double vision, nausea, and emesis beginning approximately three days prior. Since then, her pain intensified, prompting her to see her primary care provider who diagnosed an eye vs. sinus infection and prescribed an antibiotic, nasal and oral steroid, which failed to improve her symptoms. Of note, she had experienced a double vision in the same eye one year prior and was evaluated by a neuro-ophthalmologist who told her this was due to ocular muscle weakness and prescribed her prescription lenses.
On admission, she was hemodynamically stable and afebrile. Physical examination was remarkable for tenderness to palpation around the left eye. A neurological examination of the eye was consistent with left third nerve palsy. By inspection, there was left eye partial ptosis with outward deviation and dilated pupil, which responded poorly to light. Additionally, paralysis of left eye adduction and elevation with binocular diplopia maximized by looking to the right was noted. Other cranial nerves were normal (Figure ). Labs were only remarkable for a white blood cwll count of 13.7. Computed tomography (CT) brain without contrast revealed a mixed-density mass measuring 2.7 x 2.6 cm, seen in the medial aspect of the left middle cranial fossa adjacent to the left temporal lobe (Figure ). Magnetic resonance imaging (MRI) brain with/without contrast showed an extra-axial tumor measuring 3.3 x 2.4 x 3.0 cm at the level of the left cavernous sinus with evidence of concavity involving the pituitary gland (Figure ). Differential diagnosis per radiology team was meningioma, melanocytoma, and nerve sheath tumor. The patient was started on intravenous methylprednisone. Neurosurgery was consulted and an angiogram was considered to manage accordingly. The patient underwent a cerebral angiogram, which showed grade III dissection of the left cavernous ICA with a large partially thrombosed pseudoaneurysm (Figure ). The patient was then loaded with clopidogrel and aspirin and then she underwent an angiogram for a left cavernous ICA flow diversion stent embolization procedure. She was discharged on clopidogrel, aspirin, and steroid tapering dose to follow up with neurosurgeon outpatient.


Incidentally, a 33-year-old man was diagnosed as hypertrophied column of Bertin by ultrasound, which demonstrated abnormal echo mass in renal sinus (). The patient was asymptomatic. All laboratory results and physical examinations were normal. No palpable mass and percussion pain were found in bilateral renal areas.
CT urography (CTU) was performed to evaluate the renal lesion more accurately. Plain CT demonstrated an isodensity mass to normal renal parenchyma with unclear boundary in his right renal sinus without hydronephrosis (). The size of lesion was 14 × 5 × 3 mm. Renal contrast-enhanced CT (CECT) showed the intrarenal sinus mass that exhibited the enhancement mode similar to kidney: wheel-spoke shaped enhancement of renal cortex and no enhancement of renal medulla in corticomedullary phase, and homogeneous enhancement in parenchymal phase (). Pyelographic phase images demonstrated that a renal pelvis shaped structure from mass merged into the right major renal calyces (). Coronal maximum intensity projection (MIP) CT image in pyelographic phase directly revealed that the mass in renal sinus sent out a renal pelvis shaped structure and merged into the right upper major calyces (). The curved planar reconstruction (CPR) image could display the aberrant duplex kidney and renal pelvis in renal sinuses and the confluence into the right upper renal calices in one plane ().


We describe a 10-year old boy who was diagnosed with pancolitis VEO IBD-U at the age of 1 and treated with oral mesalazine from the beginning of the disease. The patient received a total of three gut biopsy that confirmed IBD-U.
Over the years, he presented a steroid sensitive disease course, refractory to azathioprine (May 2010- Feb 2012) and methotrexate (Feb 2012- Jun 2012). Afterwards, he obtained clinical and mucosal remission on thalidomide (June 2012- Sep 2017), that was stopped due to progressive peripheral neuropathy, considered as adverse event of thalidomide []. Therefore it was shifted to the chimeric anti-TNF IgG1 monoclonal antibody infliximab (June 2018- Sep 2020), resulting in a progressive resistance to treatment despite the increased dose (10 mg/kg/month). Oral mesalazine was administered from Jan 2010 to Jan 2016 and then stopped after the first episode of hematuria with persisting microhematuria. Topically mesalazine was administered for limited time in 2010 and in 2020. Immunological screening (antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, anti-Saccharomyces cerevisiae antibodies, anti-mitochondrial antibodies, liver-kidney microsomal antibodies, rheumatoid factor) was normal and genetic panel for immunodefinciencies related to VEO-IBD resulted negative.
In February 2016, a first episode of hematuria and dysuria was reported: urine examination tested positive for red blood cells and proteins not in nephrotic range, while urine colture and renal ultrasound were negative. Renal function, erythrocyte sedimentation rate, reactive-c-protein and serum complement components C3 and C4 were normal. In September 2017, the persistence of microhematuria and mild proteinuria (< 1 g/die) led to a kidney biopsy that revealed IgA nephropathy with moderate mesangial hypercellularity (M1,E0,S0,T0 according to the Oxford Classification [, ]) (Fig. ). Steroidal bolus, according to the randomized clinical trial proposed by Pozzi et al. [] were administrated from November 2017 to May 2018 with complete remission of renal disease. Urine sample were monitored every 6 months resulting always negative until January 2020, when macrohaematuria was once again reported during an episode of fever and diarrhea. Renal function was normal with no proteinuria.
After high steroid therapy, IBD was well controlled with Infliximab and rectal mesalazine plus steroid for 2 months. From May 2020 recurrent episodes of isolated fever every 2 to 3 days were reported. The temperature rise was well controlled with paracetamol and never associated with abdominal pain or diarrhea. Macrohaematuria appeared again by August 2020.
In September 2020, the boy was admitted to Gastroenterology department of our Paediatric Hospital with a relapse of IBD-U. Blood exams revealed acute kidney injury with increased levels of creatinine (1,5 mg/dL), urea (44 mg/dL) and limited proteinuria 0,3 g/24 h. Reactive-C-protein was 2.9 mg/dl, serum eosinophils and IgE in norma range. At urine microscopy we detected 20 red blood cells per field and less than 20% were dysmorphic; leucocytes (20–25/filed) were also present. Renal Ultrasound revealed an hyper-echogenity of renal parenchima, suggesting interstitial chronic lesions. The patient underwent a second renal biopsy, described in Fig. , that revealed a non-necrotizing granulomatous interstitial nephritis, characterized by a prevalence of T lymphocytes. Tuberculosis and infective causes were excluded. Moreover, patients resulted positive for for IgG against Bartonella henselae. Therefore we performed a rtPCR for Bartonella henselae in renal tissue that resulted negative.
As therapy, we administered oral steroid at the dose of 60 mg/m2 for 1 month, than tapered to 40 mg/m2 for further 4 weeks. As long-acting treatment, considering the relapse of IBD and the granulomatous interstitial nephritis occurred during therapy with infliximab, we started adalimumab (160 mg at baseline, 80 mg at week 2 following with 40 mg/week). At 6 months of follow up, serum creatinine was 0.7 mg/dl (eGFR 81 ml/min) and no clinical manifestations of IBD are reported.


A 62-year-old woman with a history of tobacco abuse (30 pack-years) and chronic cannabis use, presented with severe retrosternal chest pain with peripheral vascular collapse (weak peripheral pulses, pale skin), sweating, and vomiting after 30 min of excessive cannabis consumption, i.e. more than 15 cigarettes.
The physical examination found a pale, agitated patient, with a blood pressure limit of 100/60 mmHg; the cardiovascular examination was normal; electrocardiogram (ECG) revealed ST-segment elevation in inferior and basal leads (Figure ). An echocardiogram was performed, revealing dilated cardiomyopathy with global hypokinesia, a severely reduced ejection fraction (EF) of 20%, and associated right ventricular dysfunction (Figure ). After a drop in blood pressure, the patient was started on inotropic agents (dobutamine 10 gamma/kg/min). We noted the disappearance of chest pain and regression of ST-segment elevation after hemodynamic state stabilization (Figure ). A coronary angiogram which was performed at hour eight of chest pain showed normal coronary arteries without stenosis (Figure ). The ECG monitoring showed atrial fibrillation at 100 bpm. Laboratory measurements showed elevation of cardiac biomarkers troponin (41600 ng/mL, the upper limit of normal < 26 ng/mL).
The patient was admitted to the ICU, and started on an IV vasodilator and inotrope agent. The hemodynamic status was stabilized after 48 h, with the persistence of severe ventricular dysfunction and atrial fibrillation. The patient was discharged after a week with diltiazem, ACE inhibitor, diuretic; anticoagulation by rivaroxaban 20 mg was initiated.
Clinical follow-up after three and six months later was favorable with nonrecuperation of a normal ventricular function.


A graphical summary of this case report is provided in .
A 41 year-old female with an unremarkable medical history underwent a medical examination fora vague abdominal discomfort and asthenia for three months. She had no cancer-related familial history, except for the paternal grandmother who died of esophageal carcinoma. No other cancer-related events were recorded in the family history. A computed-tomography (CT) scan revealed the presence of a well-circumscribed mass of about 3 cm in the pancreatic body, without evidence of distant metastasization. Based on this finding and the histopathological diagnosis based on material from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), which supported a diagnosis of SPN vs. neuroendocrine tumor, the patient underwent robot-assisted distal pancreatectomy with surgical resection of the pancreatic mass. At the first intraoperative frozen section analysis, the pancreatic margin was involved with few neoplastic cells, thus the resection was extended (1 cm). The successive pancreatic margin, also examined on the frozen section, was considered negative. Globally considered, the pancreatic mass was surgically resected with free margins. The subsequent gross sampling revealed a brownish tumor with pushing borders, mainly located in the central-posterior portion of the pancreatic body. Histologically, the tumor showed a mixture of solid, pseudopapillary, and cystic-hemorrhagic areas. Solid areas included poorly cohesive, monomorphic, and polygonal cells, intermingled with a rich net of blood vessels. At the same time, in the pseudopapillary areas, neoplastic elements showed focal detachment and the remaining cells were left to surround the blood vessels, resembling papillary structures. Neoplastic cells presented an eosinophilic cytoplasm and monomorphic roundish nuclei with granular chromatin, without an evident nucleolus. Mitotic figures were absent. Although at grossing the tumor mass seemed very well-demarcated, at microscopy, the periphery tumor cells showed a focal invasion of adjacent pancreatic parenchyma and adipose tissue. Immunohistochemistry (IHC) showed that neoplastic elements were positive for β-catenin (nuclear positivity), CD10, progesterone receptor, vimentin, and LEF1, and were negative for Bcl-10, trypsin, and chromogranin-A. The histological examination, coupled with immunohistochemical analysis, was conclusive for a diagnosis of solid pseudopapillary neoplasm (SPN) of the pancreas.
One year after the surgical resection, the patient developed type II diabetes, which was treated with oral hypoglycemic therapy. The standard follow-up, comprised of blood tests and a physical examination, was performed every 12 months but did not reveal any alteration. During an imaging-based follow-up two years after the pancreatic resection, magnetic resonance imaging (MRI) revealed the presence of a roundish mass of about 4 cm located in the epiploon retrocavity, strictly adjacent to the site of previous surgical resection. A following CT-scan confirmed the presence of the mass, which showed a homogeneous density and a maximum diameter of about 4.5 cm ().
With the suspicion of a relapse of the SPN vs. an inflammatory pseudotumor due to the previous surgery and based on the histopathological diagnosis predicated on material from EUS-FNA, which cannot rule out a relapse of SPN (cells positive for β-catenin), the patient underwent a second operation with the surgical resection of the abdominal mass. The subsequent gross sampling revealed the presence of a roundish nodule; on the cut surface, it was yellowish and showed homogeneous features without necrotic or hemorrhagic areas. Histologically, the mass appeared as a well-circumscribed tumor, arranged in intersecting fascicles. Neoplastic cells were spindle-shaped with elongated nuclei and bipolar cytoplasm with blunt ends. Mitotic activity was virtually absent (less than 1 out of 50 high-power fields). IHC showed tumor cells to be diffusely positive for β-catenin (nuclear positivity), CD10, and vimentin, focally positive for CD99 and LEF1, and negative for S100, STAT6, MDM2, Bcl-2, CD34, CD117, DOG1, smooth-muscle actin, desmin, and progesterone receptor. The histopathological and immunohistochemical features were consistent with the diagnosis of desmoid tumor.
Given the peculiar association of SPN and DT in the same patient, these neoplasms, as well as a normal tissue sample (spleen), were further examined by targeted next-generation sequencing of 174 cancer-associated genes.
Both the SPN and DT were microsatellite stable and showed a low tumor-mutation burden (SPN 5.6 mutations/Mb; DT 6.1 mutations/Mb). Somatic mutations were only found in the CTNNB1 gene, while a double germline mutation was detected in the BRCA2 gene.
Both SPN and DT harbored a somatic mutation of the CTNNB1 gene, but each neoplasm carried a different mutation. SPN featured a heterozygous c.97T>C transition, which causes a missense p.S33P mutation resulting in enhanced activity of the CTNNB1 gene product []. This variant falls within a known mutational hotspot of the CTNNB1 gene that has been reported in multiple solid tumors []. It is registered in dbSNP (rs105719886) and is pathogenic according to ACMG/AMP criteria []. DT showed a somatic heterozygous c.121A>G transition, which leads to a missense p.T41A resulting in enhanced activity of the CTNNB1 gene product [,,,]. This variant is also located in a mutational hotspot of the gene and has been reported in multiple solid tumors [,]. It is registered in dbSNP (rs121913412) and is pathogenic according to the ACMG/AMP criteria [].
Sequence analysis of tumors and normal tissue showed the presence of two heterozygous germline variants in the BRCA2 gene. Both variants are classified as pathogenic according to the ACMG/AMP criteria [] and the ClinVar database (, accessed on 18 October 2020). Notably, there was neither loss of heterozygosity (LOH) nor any somatic mutation in the second BRCA2 allele of both tumor samples. The first variant of the BRCA2 gene was the c.631G>A transition of the last nucleotide of exon 7. This causes both the p.V211I missense variant and the disruption of a natural splice donor site, which results in abnormal splicing []. This variant is classified as pathogenic in the ClinVar database (accession VCV000052058). The second BRCA2 variant was the c.7008-2A>T transversion of the penultimate nucleotide of intron 13 that alters a natural splice acceptor site, resulting in abnormal splicing and non-functional transcripts []. This variant is classified as pathogenic in the ClinVar database (accession VCV000052246).
After discussion in the multidisciplinary molecular tumor board [], given the presence of BRCA2 germline mutations, the patient was enrolled in screening surveillance and genetic counseling following existing guidelines [,]. A discussion also focused on a possible interconnection between BRCA2 and CTNNB1 mutations. However, on the one hand, BRCA genes (tumor suppressors)/the encoded proteins belong to the homologous recombination (HR) DNA repair machinery [], and on the other hand, the CTNNB1 gene (oncogene)/the encoded protein β-catenin, belong to the Wnt pathway [,,]. Currently, there is no evidence of any interconnection of these two pathways/mechanisms, and our report (CTNNB1 activating mutation, mono-allelic BRCA2 mutation) is in line with this knowledge.


A 62-year-old Japanese man was referred to our department by the urology department because of hyponatremia. In 2003, he was diagnosed with right renal cancer, and he underwent right nephrectomy. Seven years later, a cancerous lesion was found in the right clavicle. Subsequent bone biopsy revealed that it was caused by metastasis of the renal cancer. He then underwent multiple rounds of chemotherapy (Fig. ), and developed thyrotoxicosis after starting sunitinib treatment. Sunitinib treatment was discontinued, and the patient has been treated with the ICPI nivolumab (3 mg/kg) every 2 weeks since 2018.
After administration of the seventh cycle of nivolumab treatment, the patient complained of fatigue and dizziness, and was admitted to the urology department. On physical examination, the patient’s blood pressure was 93/59 mmHg, his pulse was 73 beats per minute, and his body temperature was 36.5 °C. His weight and height were 56.3 kg and 165 cm, respectively. Results of the laboratory tests are shown in Table . The patient had hyponatremia (120 mmol/l), with low levels of cortisol (0.4 μg/dl) and adrenocorticotropic hormone (ACTH) (6.64 pg/ml), suggesting adrenal insufficiency. The serum levels of luteinizing hormone (LH) (11.4 mIU/ml) and prolactin (PRL) (38.5 ng/ml) were high, and those of insulin-like growth factor (66 ng/ml) were low. His symptoms and laboratory data suggested that the clinically suspected adrenal insufficiency was possibly due to pituitary adrenocortical hypofunction induced by nivolumab immunotherapy, despite the absence of changes in the size and density of the pituitary gland revealed on brain magnetic resonance imaging (MRI). The patient was started on steroid replacement therapy with 40 mg/day prednisolone. After starting steroid therapy, his physical condition improved rapidly. The dose of steroid was tapered and was finally maintained at 20 mg/day of hydrocortisone. The patient became hyperglycemic because of the steroid treatment, which was managed with insulin. Because the ability to secrete insulin was unimpaired (C-peptide immunoreactivity [CPR] 2.37 ng/ml), he was started on liraglutide therapy, and nivolumab treatment was continued. After his symptoms subsided, the corticotropin-releasing hormone (CRH) load test was performed, which revealed that the serum ACTH level and cortisol response to CRH were very low (Table ).
Following the 10th cycle of nivolumab treatment, the patient was referred to our department again because of high blood sugar levels. He was admitted to the hospital for suspected FT1DM associated with nivolumab treatment and was started on drip infusion therapy. On physical examination, the patient’s blood pressure was 148/72 mmHg, his pulse was 75 beats per minute, and his body temperature was 36.3 °C. His mouth was dry and his skin turgor was poor, but he did not complain of any other symptoms. Although his plasma blood glucose levels were high (601 mg/dl), his hemoglobin A1c (HbA1c) levels were low (8.1%), suggesting rapid progression of hyperglycemia. Abdominal computed tomography showed no pancreatic abnormality. Both his serum C-peptide levels and his urinary C-peptide excretion levels were low. A glucagon stimulation test revealed insulin depletion, but he showed serum anti-glutamic acid decarboxylase (GAD) antibody negativity (details are outlined in Table ). Laboratory investigations revealed hyperglycemia, but no acidosis or ketonuria. On the basis of these findings, we excluded FT1DM, and diagnosed the patient with insulin-dependent diabetes. The patient was treated with intravenous fluid infusion and continuous insulin infusion. His potassium and other electrolyte levels were within the normal range, and serum potassium fluctuations were within the normal range even after the introduction of insulin therapy. On the second day, he was switched to multiple daily injections of insulin therapy (Fig. ). Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for RCC for over a year.


A 13-year-old girl, known with kidney failure with replacement therapy (KFRT), was referred to the Nephrology and Dialysis Department of the Emergency Hospital for Children “Maria Sklodowska Curie” of Bucharest, Romania, for high fever (38.5–39 °C), chills, frequent dry cough, and dyspnea with tachypnea on 9 July 2020.
The patient has a medical history of CKD since 2015, secondary to polycystic kidney disease (PKD), which is the most common genetic disorder leading to dialysis dependence. Autosomal dominant polycystic kidney disease (ADPKD), the most common cause of KFRT, was diagnosed in our case on abdominal CT, showing multiple bilateral renal cysts. In this case, we report a pediatric patient with a family history of PKD. The study of the prevalence and causes of kidney imaging correlates with the abdominal imaging from her father, who also has PKD. The images of the brain revealed Bourneville tuberous sclerosis (TSC) with cortical dysplasia (diagnosed at the age of 6 months). The concurrence of TSC and ADPKD is rare, with very few cases reported in the literature. Hypertension is a typical manifestation of ADKPD and the cause of the rapid progression of CKD to KFRT. The complex relationship between TSC, epilepsy, and autism spectrum disorder (ASD) leads to high risk in this category of individuals, and was confirmed in the Neurological Department. In December 2019 she began receiving chronic intermittent hemodialysis, 3 sessions weekly, 4 h per session. She was under chronic treatment with enalapril 20 mg/day and amlodipine 10 mg/day, with partial control of blood pressure values. In June 2020, echocardiography revealed severe left ventricle hypertrophy, normal systolic function of both ventricles, left ventricle diastolic dysfunction (impaired relaxation), and mild pulmonary hypertension.
At admission on 9 July 2020, the patient was vitally stable, with fever of 39 °C, a respiratory rate of 35 to 40 breaths/min, oxygen saturation of 80% to 85% in ambient air, and SpO2 was 95% with oxygen 4 L/min, heart rate of 120 beats/min, blood pressure (BP) of 160/110 mmHg, and oliguria (500 mL/24 h). The physical examination revealed a sick patient with dyspnea, tachypnea, decreased vesicular murmur on the right hemithorax, fine bilateral crackles and wheezing, diminished heart sound, systolic murmur, abdominal distension due to enlarged kidney, and peripheral edema.
Based on the COVID-19 outbreak, a nasopharyngeal swab was performed, with a positive result on the following day on real-time reverse transcriptase-polymerase chain reaction assay for SARS-CoV-2. The patient was diagnosed with COVID-19. Her condition worsened over the following few days, and the general condition was modified. During hospitalization, investigators revealed hypoalbuminemia, anemia, and mild inflammatory syndrome, and NT pro-BNP was 32,460 pg/mL (see ).
On 15 July 2020, imaging investigations detected severe pericardial effusion, bilateral pleural effusion, and ascites (20 mm pericardium, 40 mm abdominal, 30 mm left pleura, 20 mm right pleura). Echocardiography revealed moderate/severe systolic dysfunction of the left ventricle, impaired diastolic dysfunction (pseudonormal transmitral pattern), low-normal right ventricle systolic function, moderate pulmonary systolic pressure, and a large amount of pericardial fluid. The clinical picture maintained despite supplemental daily hemodialysis sessions performed with maximal ultrafiltration (13 mL/kg/h) [,]. She was transferred to a COVID-19 designated hospital for isolation and specific treatment. The patient responded gradually to medical therapy (antihypertensive drugs, high diuretic doses, daily hemodialysis sessions), and her oxygenation continued to improve until she was successfully weaned from oxygen. Her systolic and diastolic LV function gradually improved and she could be discharged in good clinical condition.
After 2 months from COVID-19 infection, on 22 September 2020, the patient returned to our clinic for frequent dry cough, dyspnea with tachypnea, and respiratory rate 25 breaths/minute, without fever. RT-PCR test was negative. The patient had bilateral basal crackling rales, more common on the left side, tachycardia AV-120 bpm, hypertension (BP—145/95 mmHg), Sat O2 = 80%, and diuresis 1000 mL/24 h. Radiological images during this hospitalization can be seen in A–C.
The echocardiography indicated severe LV systolic dysfunction (EF = 25%), severe diastolic dysfunction (restrictive transmitral pattern), grade II mitral regurgitation, mild RV systolic dysfunction (EF = 45%), moderate/severe pulmonary hypertension, and a large amount of pericardial fluid. (See , , , and ).
The patient was started on broad-spectrum antibiotics with intravenous ceftriaxone (50–100 mg/kg/day) 2 g/day, and vancomycin (500 mg/day, intravenously, single daily dose—dose adjusted for renal function, treatment maintained for 14 days), intravenous methylprednisolone pulse therapy (2 mg/kg/day, for 3 days). She also followed treatment with high doses of diuretic (furosemide 120 mg/day), inotropic therapy (dobutamine 5 µg/kg/min), angiotensin-converting enzyme (ACE) inhibitor (enalapril 20 mg/day), calcium channel blocker (amlodipine 10 mg/day), and intensive hemodialysis programme (see ).
Her clinical condition progressively improved. After 2 weeks from her September hospitalization, she presented with SpO2 = 95%, partially controlled blood pressure, small pericardial and right pleura effusion, regression of pulmonary hypertension, and improvement of systolic function of the left ventricle (LVEF = 45% at patient discharge).
All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the mother of our patient.


A 29-year-old female, with a history of postpartum SCAD, presented with prolonged labor and eventually underwent a cesarean section delivering a healthy baby boy. Approximately one week following that discharge, she developed severe substernal chest discomfort and severe shortness of breath. Emergency medical services were summoned and she was taken to the emergency department. She was found to have pulmonary edema and was noted to have elevated troponin levels. She was diagnosed with a non-ST elevation myocardial infarction (Figure ). An echocardiogram reported left ventricular end-diastolic pressure 25 mmHg, posterior lateral hypokinesis with a left ventricular ejection fraction (LVEF) of 60%, and mild mitral regurgitation. Left heart catheterization (LHC) revealed a 100% obtuse marginal lesion and mild disease in the right coronary artery. A single drug-eluting stent was placed, and she was started on dual antiplatelet therapy. Following this event, she remained on Plavix for one year.
Later that year, the patient was seen by another cardiologist for complaints of intermittent burning type chest pain on the left side radiating to her back for 1 month. She was evaluated and scheduled for a CTA coronary arteries, MRI neck/abdomen, and cardiac catheterization. The cardiac cath revealed a moderately large distal left main aneurysm extending into the circumflex at the site of the previous spontaneous dissection; another aneurysmal area noted in the mid circumflex above the takeoff of the marginal system. The previously placed stent in the lateral branch of the bifurcating marginal system was noted to be patent. The more medial branch had a focal spontaneous dissection, and a moderate narrowing was noted at the proximal circumflex coming off the left main aneurysm (Figure ).
The following day, the patient presented again to the emergency department for complaints of midsternal chest discomfort. She was placed on the telemetry floor for further monitoring and management. Her Society of Thoracic Surgeons (STS) score was 0.39%, and CABG was scheduled later that week. The patient underwent three-vessel CABG (left internal mammary artery (LIMA)->left anterior descending artery (LAD), right internal mammary artery (RIMA)->first obtuse marginal (OM1), saphenous vein graft (SVG)->second obtuse marginal (OM2) with sternal plating. The patient is doing well three months post-CABG with complete resolution of the pain.


A 65-year old male patient was sent to our outpatient department with rapidly growing black macules on the penis (). He reported no clinical symptoms at that time but was concerned about the increasing extent of these spots. The patient had a history of larynx carcinoma with neck dissection and adjuvant radiotherapy and squamous cell carcinoma of the left conjunctiva also excised with clear margins. Both tumors occurred more than 10 years ago. The patient had smoked for several years but had quit 12 years prior. The family history was unremarkable concerning malignant diseases.


A 66-year-old woman with a medical history of hypertension, hyperlipidemia, and pulmonary embolism on warfarin therapy presented with acute right upper quadrant abdominal pain ongoing for 4 weeks. On physical examination, tenderness was elicited in the right upper quadrant without rebound or guarding. Laboratory testing revealed an international normalized ratio of 3.2 and normal liver chemistries. An abdominal computed tomography (CT) showed a 15-cm expansile cystic lesion replacing the left lobe of the liver with mild heterogeneous attenuation and thin internal septations (Figure ). Because of ongoing concerns for malignant transformation, a laparoscopic left hepatic segmentectomy with cyst resection was performed. The cyst contained about 1.5 L of bile and blood (Figure ). Histopathologic evaluation revealed a benign hepatic cyst with chronic inflammation, organized hemorrhage, hemosiderin encrustation, and calcification with surrounding normal liver parenchyma.
Simple hepatic cysts are believed to arise from congenital bile duct malformations that fail to communicate with the biliary tree. The prevalence of simple hepatic cysts ranges between 5% and 15% depending on the imaging modality and increases with age. Hemorrhagic hepatic cyst (HHC) is a rare complication of simple cysts, with less than 40 cases reported thus far. The clinical presentation is not a reliable indicator of active bleeding in simple hepatic cyst. However, it is essential to consider hemorrhagic rupture when patients present with severe abdominal pain. Abdominal ultrasound findings such as hyperechogenic septa, a thick wall, and mural nodules suggest hemorrhage. Accurate diagnosis of the primary etiology of the HHC by imaging studies is challenging because cystic neoplasms such as biliary cystadenomas or cystadenocarcinomas share the same findings as HHC. Magnetic resonance imaging shows hemorrhage as high-intensity areas on T1- and T2-weighted sequences without enhancement of mural nodules after contrast. CT scan showed heterogeneous attenuation raising concerns for malignancy; hence, the patient was offered surgical resection. The surgical treatment of choice for HHC is tailored toward patient preference and eligibility. Percutaneous aspiration of the cyst is less invasive but has a higher risk of recurrence and infection. Sclerotherapy is being used more and has gained traction because of reduced recurrence. Cyst resection is preferred over wide unroofing/fenestration for suspected hemorrhagic contents. In conclusion, hemorrhagic features on imaging are considered a “red flag” for malignancy, which can only be definitively ruled out with a surgical biopsy.


A 66 year-old gentleman presented to his chiropractor with lower back pain having been asymptomatic for the previous 6 months. An ultrasound scan of his kidneys and a subsequent CT KUB + Abdo/Pelvis showed two solid lesions at the mid pole and lower pole of the right kidney and one heterogeneous solid lesion at the lower pole of the left kidney. It also showed a lesion in the pancreatic head measuring 3 cm with a dilated pancreatic duct and two small lymph nodes in the periportal region.
A CT scan of the chest was done to complete staging and this showed a 3 mm nodule in the inferior segment of the lingula. This was indeterminate and too small to be characterized. Apart from that, his CT of the abdomen and pelvis was reviewed and this confirmed two solid lesions in the right kidney and also one in the left kidney. The pancreatic head lesion was also identified with the two small lymph nodes in the peri-portal region. In terms of blood tests, his tumour markers were all within the normal limits. This included a CA19.9 of 32, CEA 1.8, PSA < 0.1 and alpha feta protein of 4.
An open distal pancreatectomy was carried out. After two years there was no clinical, radiological or biochemical evidence of recurrence of the neuroendocrine tumour.


A 70-year-old Asian man visited our hospital complaining of hemoptysis for 6 months. He was a pack-a-day smoker for 50 years and presented with hypertension. He was not taking any antiplatelet or anticoagulant agents. Chest X-ray revealed a mass in the right pulmonary hilum, and chest computed tomography (CT) showed a tumor in the pulmonary hilum with stenosis of the right upper lobe bronchus (Fig. a). Positron emission tomography-CT revealed a tumor in the pulmonary hilum with a standardized uptake value of 8.5 (Fig. b). Semicircular calcification of the ascending aorta was also noted (Fig. c). A bronchoscopic examination revealed redness and irregularity in the bronchial epithelium in an extensive area between the trachea and the lower lobe bronchus, with stenosis of the right upper lobe bronchus. Transbronchial biopsy of the lesion revealed a pathological diagnosis of squamous cell carcinoma. The results of biopsies from the lower trachea, one ring above the tracheobronchial angle and that of the B6/B7–10 spur, were also positive for squamous cell carcinoma. Endobronchial ultrasound-guided transbronchial needle aspiration showed no malignant cells in the subcarinal lymph nodes. The patient was able to tolerate right pneumonectomy, which was concluded from the results of a pulmonary function test; the patient’s forced expiratory volume in 1 second (FEV1) was 2850 ml (116.1% of the predicted value), and the diffusing capacity of the lungs for carbon monoxide (DLCO) was 15.80 ml/minute/mmHg (90.1% of the predicted value). Brain magnetic resonance imaging showed no metastasis or infarction. The clinical stage of the disease was T4N0M0, and right sleeve pneumonectomy was planned.
Right sleeve pneumonectomy was performed using median sternotomy. During surgery, the ascending aorta was repeatedly mobilized to adequately expose the tracheobronchial bifurcation (Fig. a, b). Mediastinal lymph node dissection was performed, and the left main bronchus and the trachea were transected and anastomosed using 4-0 polydioxanone (PDS) under ventilation through the operative field. A running suture in the membranous portion was performed with ventilation of the diseased lung to better expose the operative field. The cartilaginous portion was anastomosed with interrupted sutures after the endotracheal double-lumen tube was forwarded into the left main bronchus. Following the anastomosis, the right main pulmonary artery and right superior and inferior veins were stapled, the right lung was extirpated, and right sleeve pneumonectomy was performed. After surgery, the patient was extubated and admitted to the intensive care unit; however, he was not fully conscious, and mild paralysis of both upper extremities was noted.
Head magnetic resonance imaging was performed on postoperative day (POD) 1, which showed multiple high-intensity areas in the brain, mainly in the cerebellum (Fig. ). Head magnetic resonance angiography (MRA) showed no significant change in the cerebral or vertebrobasilar arteries. No cardiac thrombus, malformation, or valvular disease was detected by echocardiography and contrast-enhanced CT, and the multiple embolic stroke was thought to be caused by repeated mobilization of the ascending aorta to expose the operative field for tracheobronchial anastomosis.
Heparinization therapy and administration of edaravone, a neuroprotective agent, were initiated. From POD 14, warfarin administration was initiated, and the amount of warfarin was adjusted to a prothrombin time-international normalized ratio (PT-INR) of 1.5–2.5. The patient received continuous anticoagulant therapy and rehabilitation and was eventually discharged on POD 30 without any sequelae. The patient is currently doing well without recurrence 5 years after surgery.


A 94-year-old woman, living at home with her family, was admitted to the Emergency Room with deep asthenia. She had the following clinical history: arterial hypertension, dyslipidemia, chronic heart failure (NYHA class II), chronic gastritis, hypothyroidism, chronic renal failure (stage III) with hydronephrosis due to a high-grade urinary bladder cancer. Before admission, the patient was dependent in both Basic Activities of Daily Living (BADL 1/6 —able to feed herself) and Instrumental Activities of Daily Living (IADL 2/8—able to handle medications and use the telephone); moreover, she needed mild assistance to stand and walk. At medical examination and neuropsychological assessment, she was alert and partially oriented in time, space, and person (SPMSQ 6 right answers out of 10). The vital signs were normal: blood pressure 140/80 mmHg, body temperature 36.2 °C, heart rate 67 bpm regular, respiratory rate 12 breaths per minute, peripheral oxygen saturation 98% without any respiratory support. Clinical signs of systemic dehydration (shrivelled skin with decreased turgor, dry oral mucous membranes, and sunken-appearing eyes) were present. The remaining physical examination was normal. At admission, the plasma osmolality was 319 mOsm/kg with moderate hyponatremia and high levels of serum creatinine and urea; the urine specific gravity was increased (1.040 unit of measure). Additional laboratory data at admission and during a hospital stay are shown in Table. Chest and abdominal X-rays and abdominal-US did not reveal any abnormalities, except to the known bladder cancer. Brain CT without contrast showed generalized atrophy, mostly of frontal lobes; no acute lesions were described. The diagnosis was an acute exacerbation of chronic renal failure due to severe dehydration. The most likely cause of dehydration was the contemporary presence of chronic therapy with thiazide diuretics and very low oral water intake, common in older patients with cognitive impairment and physical disability. The estimated total water deficit was 2.8 L, so intravenous fluid therapy was started with crystalloid solutions (0.9% NaCl solution 1000 ml in 24 h/per day); chronic medications (antihypertensive drugs, PPIs, Levothyroxine) were confirmed, except to thiazide diuretics.
During the first night of hospitalization, the patient developed severe agitation interpreted as hyperkinetic delirium, unresponsive to non-pharmacologic interventions, as reorientation, early mobility and family participation. Low-dose of intramuscular Haloperidol (1 mg) was administrated with partial clinical response. Few hours later, the patients developed rapid and involuntary movements of the four limbs with motor restlessness and inability to remain relaxed. 2 mg of intravenous lorazepam were administrated with transient recovery. In the suspect of seizures, electroencephalogram was performed that resulted negative for epileptic abnormalities. A diagnosis of drug-induced myoclonus was suspected and an oral treatment with Clonazepam (0.3 mg × 3/day) was started with a good clinical response.
Moreover, during hospitalization, a transient pancytopenia was found at blood tests, characterized by mild leukopenia (WBC = 3.200/μl), moderate anemia (haemoglobin = 8.7 g/dl) and severe thrombocytopenia (PLT = 12.000/μl). The patient did not develop any mucocutaneous petechiae or major bleeding; only one episode of modest and self-limiting nosebleed was observed. Serum levels of folic acid, vitamin B12, LDH, haptoglobin, procalcitonin and coagulation parameters were normal; the peripheral blood smear was not pathological. During hospital stay, heparin was never administered. Pancytopenia was treated with platelets and RBC transfusions and intravenous steroids, in the initial suspect of immune-mediate disease. In the following days, progressive normalization of laboratory tests occurred, including a reduction of serum creatinine and increase in platelet count and haemoglobin level up to physiologic values. Based on blood tests and the temporal association between the administration of Haloperidol and the hematological changes, we hypothesized drug-induced pancytopenia as the most likely diagnosis.
The patient was discharged from the Geriatric Unit after 14 days of hospitalization. The patient is still alive after 30 days.


A 68-year-old man, who had been undergoing medical treatment for liver dysfunction due to chronic hepatitis C virus (HCV) infection and alcoholic liver disease, was found to have a liver tumor measuring 25 mm in segment III on abdominal ultrasonography and was referred to our hospital for further evaluation. He was on antihypertensive medication and had undergone open reduction and internal fixation with metal plates for the fracture of his left upper extremity. He was a past smoker, with a daily alcohol intake of 80 g for 42 years. Laboratory analysis revealed the following results: aspartate aminotransferase, 46 U/L (normal range: 10–40 U/L); alanine aminotransferase, 51 U/L (normal range: 5–45 U/L); alkaline phosphatase, 210 U/L (normal range: 100–325 U/L); and gamma-guanosine triphosphate, 27 U/L (normal range < 30 U/L). Serum AFP and AFP-L3 were 822.8 ng/mL (normal range < 10 ng/mL) and 75.2% (normal range < 35%), respectively. Levels of protein induced by vitamin K absence or antagonist II, carcinoembryonic antigen, and carbohydrate antigen 19-9 were within normal limits. Serological tests for hepatitis viruses showed that hepatitis B surface antigen was negative, but hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody were positive. There was no anemia or elevation of white blood cell count and C-reactive protein level. Coagulation profile, total protein, albumin, and bilirubin levels (both total and direct) were normal. Contrast-enhanced computed tomography (CT) showed a 24-mm mass in segment III of the liver adjacent to the left hepatic vein, and an 8 mm mass in segment VIII. These lesions showed weak enhancement in the early phase and demonstrated washout of the contrast in the delayed phase (Fig. ). The lesion in segment III appeared abnormal on fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) with a high standardized uptake value of 10.9, however, the segment VIII lesion did not show this uptake pattern (Fig. ). Magnetic resonance imaging could not be performed because of the presence of the metal plates in his arm. Based on the findings of HCV infection, elevated serum AFP and AFP-L3, and radiological imaging of the liver, HCC was suspected. Thus, laparoscopic left lateral sectionectomy and partial hepatectomy for segment VIII were performed.
Macroscopically, the resected specimen showed hard white nodules, not like HCC, in approximately the same location that was indicated by the imaging studies (Fig. ). Histopathological analysis showed that both tumors consisted of fibrous tissue infiltrated by inflammatory cells, mainly plasma cells (Fig. a, b). In immunohistopathological analysis, tumor cells were diffusely positive for CD31, and partially positive for CD68 and alpha-smooth muscle actin, whereas human serum albumin and glypican 3 were negative (Fig. c–g), suggesting that the tumor cells contain lymphocytes and macrophage but not cells derived from hepatocyte. And, there were some tumor cells positive for AFP in immunohistochemical staining (Fig. h). Non-tumorous liver tissues were noted to be A2F3–4 based on New Inuyama Classification []. Malignant cells, including HCC cells, were not detected. The lesions were finally diagnosed as hepatic IPT.
The patient had no postoperative complications and was discharged 7 days after surgery. AFP and AFP-L3 levels decreased to 13 ng/mL and 38.9%, respectively, 1 week after of surgery, and returned to normal levels 3 months later, to 5.5 ng/mL and < 0.5%, respectively. These tumor markers were not elevated during the 1-year follow-up.


A 34 year old man of English and Irish descent was born from a normal pregnancy and had normal motor development. He had no history of early joint contractures. He was notably tall and thin in elementary school. In middle school, he started experiencing difficulty keeping up with peers in sprinting and jumping activities. Limitations to his range of eye movements were first noticed by peers at age 23. By age 26, he had difficulty climbing stairs, while a year prior to his clinical presentation, he developed mild shoulder muscle weakness in the absence of myalgia. He had no dysphagia or dyspnea. His parents and two sisters were unaffected by muscle weakness (father was deceased but had no history of weakness). Neurological examination was notable for mild bilateral ptosis and ophthalmoparesis (Fig. a, b),
mild weakness of facial and neck flexor muscles 4+/5, as graded by the Medical Research Council (MRC) scale, symmetric muscle atrophy and weakness of the shoulder girdle muscles (Fig. c, d), brachioradialis and finger extensors (4, 4+/5), severe weakness of hip flexors (3/5 bilaterally), less severe involvement of thigh adductors and abductors, and ankle dorsiflexors (4+/5). The quadriceps were symmetrically atrophic but with spared strength. Axial weakness was suggested by patient’s inability to sit up from a supine position without assistance. He demonstrated a waddling gait and was able to walk on toes but not on heels. Tendon reflexes and sensory examination were normal. He had a high arched palate, laxity of the metacarpal phalangeal joints and mild gynecomastia (Fig. d), but no contractures. No tremor was present.
Creatine kinase (CK) levels were elevated (457–626 U/L; normal < 320). The electrocardiogram and echocardiography were normal. He had a reduced maximal expiratory pressure (73% of predicted) and normal vital capacity on pulmonary function testing. Concentric needle electromyography demonstrated mixed small and large motor unit potentials in proximal limb and thoracic paraspinal muscles with early recruitment, fibrillation potentials in the gastrocnemius and complex repetitive discharges in proximal lower limb muscles. Nerve conduction studies were normal. 2-Hz repetitive stimulation of the facial, spinal accessory and peroneal nerves showed no decrement. (Limited information on this patient were reported prior to the pathological characterization of the myopathy []).
Routine histological studies of the triceps biopsy demonstrated wide fiber size variability, muscle fiber splitting (Fig. a), internalized nuclei, rare necrotic or regenerating fibers and occasional rimmed vacuoles (Fig. b). The perimysial and endomysial connective tissue were increased suggesting chronicity. Several fibers, mainly atrophic fibers, contained prominent subsarcolemmal nuclei and/or large (up to 30 microns in diameter) central accumulation of eosinophilic material (Fig. c) that stained dark red in trichrome (Fig. d) and overreacted for acid phosphatase (Fig. e). At a higher magnification (Fig. f) these large central inclusions had the appearance of a filamentous tangle or a “ball of yarn” and often contained nemaline rods of various size. Immunohistochemical studies (performed as previously reported []) demonstrated that these tangles overreact for sarcomeric alpha-actinin and to a lesser degree for myotilin (Fig. g, h), but not for sequestome 1 (p62), desmin, alphaB-crystallin (Fig. i–k) or neural cell adhesion molecule 1 (NCAM 1) (not shown), all of which were diffusely increased in fewer scattered atrophic fibers. The tangles did not overreact for dystrophin. Under rhodamine optics, only extremely rare atrophic fibers showed focal large congophilia and a single non-atrophic fiber demonstrated small subsarcolemmal congophilic inclusions (not shown). Immunohistochemical studies using an antibody against human MyHC-IIA protein (A4.74, Developmental Studies Hybridoma Bank (DSHB) (University of Iowa, Iowa City, Iowa, USA) [] demonstrated paucity and atrophy of type 2A fibers (Fig. l), and MyHC-IIA positivity of the fibers harboring the filamentous tangles, as observed by optical (Fig. m) and confocal microscopy (Fig. n). Additionally, sections reacted for reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase showed a myriad of ring fibers, lobulated fibers and several atrophic fibers that were diffusely overreactive (Fig. o). NADH enzyme reactivity was preserved or increased in correspondence of the tangles.
High magnification (Fig. a) showed the filamentous appearance of the large inclusions and nemaline rods more clearly, while serial sections (Fig. b–f) confirmed that the filamentous tangles and associated nemaline rods occurred in type 2A fibers. Approximatively 1 to 9 type 2A fibers were present in each fascicle, with most fascicles harboring 4–5 type 2A fibers (as adjudged by combined findings in ATPase stains at pH 4.3, 4.6 and 9.4), but the estimated number of pure 2A fibers was complicated by the presence of fibers of poorly differentiated histochemical type. Immunocytochemical studies indeed showed presence of hybrid fibers co-expressing myosin IIX and IIA (Fig. a–d). Thus, hybrid fibers may also contain tangles. To better demonstrate the atrophy of type 2A fibers, we measured fiber size in sections immunoreacted for myosin IIA and IIX []. MyHC-IIA fibers had a mean fiber diameter of 28.0 ± 2.2 µm (Fig. ) (mean ± SEM) with rare fibers as large as 61 µm. The mean diameter of hybrid MyHC-IIA/IIX fibers was 47.7 ± 4.5 µm with extremely rare fibers of up to 98 µm. MyHC-IIA and hybrid MyHC-IIA/IIX diameters were not significantly different (p = 0.254). MyHC-IIX fiber types had a mean diameter of 77.4 ± 3.2 µm (range:13–233 μm), while type 1 fibers had a mean diameter of 101.3 ± 4.0 µm (range: 30–243 µm). MyHC-IIA and MyHC-IIA/IIX fibers were less frequent and statistically smaller than pure MyHC-IIX and type I fibers.
Electron microscopy (EM) studies were performed on previously frozen muscle biopsy tissue. Tissue samples were taken directly from the − 80 °C freezer and separated into approximately 2 mm pieces. Individual pieces were quickly placed in ice-cold Trump’s fixative, making sure they remained frozen before placing into fixative. After approximately two hours, tissue was transferred to a 4 °C refrigerator and allowed to fix overnight. Following fixation, the tissue was washed with phosphate buffer, post-fixed in 1% osmium tetroxide, washed in H2O, dehydrated through a graded series of ethanol and acetone, and embedded in epon-araldite resin. Following a 24-h polymerization in a 60 °C oven, 0.1 µM ultrathin sections were prepared and then post stained with lead citrate and uranyl acetate. Electron micrographs were acquired using a JEOL 1400 Plus transmission electron microscope (JEOL, Inc., Peabody, MA) at 80 kV equipped with a Gatan Orius camera (Gatan, Inc., Warrendale, PA). The EM images (Fig. a–c) showed large areas of disorganized myofibrils oriented in multiple planes of direction, often trapping many nemaline rods, corresponding to the large tangles with rods seen on light microscopy. Occasionally nemaline rods were observed in nuclei (Fig. d).
Whole exome next generation sequencing, performed in a commercial laboratory (GeneDx, Gaithersburg, Maryland, USA) identified two heterozygous variants in MYH2. The first MYH2 variant, c.3331C>T, p.Gln1111*, is predicted to result in truncation of the proximal tail region of the MyHC-IIA protein and is therefore predicted to be pathogenic. This variant has an extremely low allele frequency (3.98e−6, 1/251326) in large genetic databases (gnomAD) and shows possibly damaging (PolyPhen-2), damaging (SIFT, FATHMM, and fathmm-MKL), deleterious (LRT), disease causing (MutationTaster) effect through in silico analysis with a Combined Annotation-Dependent Depletion (CADD) score of 39. The second MYH2 variant, c.1546T>G, p.Phe516Val, affects a highly conserved amino acid within the highly conserved catalytic motor head relay loop. MYH2 c.1546T>G, p.Phe516Val is reported to have a very low allele frequency of 0.00000398 in large genetic databases (gnomAD, 1000 Genomes, and Exome Variant Server [EVS]), and shows probably damaging (PolyPhen-2), damaging (SIFT, FATHMM, and fathmm-MKL), unknown (LRT), and disease-causing (MutationTaster) effect through in silico analysis, with a Combined Annotation-Dependent Depletion (CADD) score of 25. Targeted Sanger sequencing showed that patient’s asymptomatic mother carries the c.1546T>G, p.Phe516Val variant, suggesting that the c.3331C>T, p.Gln1111* either arose from the asymptomatic deceased father or is de novo. The patient was also found to carry two heterozygous variants of unknown significance in MYO9A (c.5620A>C, p.Lys1874Gln and c.1148C>T, p.Ser383Phe), both detected also in the asymptomatic mother. No pathogenic or potentially pathogenic variants were detected in other genes so far known to cause neuromuscular diseases.
Western blot analysis for MyHC-IIA protein concentrations were performed on total protein isolated from the proband patient’s muscle biopsy and muscle from an age-matched normal control subject. Protein lysates from 15 mg (dry weight) of muscle tissue were run at a concentration of 2.0 ug/ul per lane in quadriplicate using a 66–440 kDa separation module on a Wes Simple platform (ProteinSimple, San Jose, California, USA), according to the manufacturer’s protocol. MyHC-IIA protein bands were identified with mouse anti-human A4.74 antibody (1:10 dilution) as developed by Blau HM and colleagues [] and obtained from the Developmental Studies Hybridoma Bank. MyHC-IIA band intensities were normalized to human vinculin protein (mouse anti-human antibody, 1:50 dilution) (R&D Systems, Minneapolis, Minnesota USA) in multiplexing analysis using the anti-mouse Luminol-S detection module and the Compass software (ProteinSimple). Mean MyHC-IIA protein illuminance in the affected patient sample, normalized to that of vinculin in each lane was reduced to 1.21 ± 0.15% (mean ± SEM) of that within the normal control sample (100.00 ± 9.15%) (Fig. a).
Protein structure homology modeling using the X-ray structure of cow cardiac myosin as template predicts that the p.Phe516Val substitution in MyHC-IIA destabilizes the motor head relay loop domain. Phe516 is located in a hydrophobic cavity, where it directly contacts Ile710 (Fig. b). With a valine in place of a phenylalanine at position 516, the hydrophobic cavity is disrupted and the loop domain becomes less compact. As the relay loop domain acts as a fulcrum that regulates conformational change between high and low affinity states, this structural change may in turn affect the angular and rotational movements of the motor head converter, actin-binding region and ATP binding sites.


A 57-year-old White female with past medical history of obstructive sleep apnea, nontoxic multinodular goiter, and hypertension underwent a routine mammogram, which revealed a focal asymmetry in the right breast; this was subsequently characterized on ultrasound as an irregular, hypoechoic solid mass with indistinct margins measuring 14 mm. A biopsy revealed an invasive ductal carcinoma, grade 1, ER 100%, PR 100%, HER2/neu 1+ with a Ki-67 index of 5%. The patient underwent partial mastectomy with sentinel node biopsy and subsequently received radiation therapy.
The patient was then referred to our endocrine clinic for treatment of her osteopenia, when it was noted that she had features consistent with growth hormone excess, including frontal bossing, jaw protrusion, wide-spaced teeth, deep voice, diaphoretic palms, and enlarged hands and feet. Symptomatically, she noted episodic headaches and diaphoresis of the hands but denied arthralgia or change in ring, shoe, or hat size. Biochemical evaluation for growth hormone excess at this time revealed an IGF-1 level of 535 ng/mL by LC/MS (reference range 50–317 ng/mL, Z-score > 3) and morning fasting growth hormone level of 1.57 ng/mL (reference range 0.01–3.61 ng/mL). Two-hour oral glucose tolerance testing was performed, which showed failure of growth hormone to suppress, with a nadir level of 1.4 ng/mL. Dynamic 3 Tesla magnetic resonance imaging (3T MRI) of the pituitary with gadolinium administration revealed subtle asymmetry of the right aspect of the sella without discrete lesion noted (Fig. ).
The patient opted to address her malignancy first prior to consideration of definitive therapy of her acromegaly. She was started on adjuvant endocrine therapy with anastrozole for her breast cancer but developed severe arthralgia, so was changed to tamoxifen, with prompt resolution of her headache and musculoskeletal symptoms. Two months after tamoxifen initiation, the patient’s IGF-1 levels normalized and remained within the normal reference range for over 3 years while she continued tamoxifen treatment (Fig. ). Her growth hormone levels ranged from 1.4 to 2 ng/mL while on tamoxifen therapy. Recently, the patient briefly discontinued the tamoxifen for 3 months to see if this was the cause of her diminished energy levels; her IGF-1 levels increased above the normal reference range from 249 to 446 ng/mL and her acral symptoms recurred, so she restarted tamoxifen, with successive normalization of her IGF-1 level to 205 ng/mL. Repeat imaging 3 months after restarting tamoxifen therapy again failed to reveal a discrete sellar lesion.
Given the patient’s excellent IGF-1 response to tamoxifen, she has opted for continued medical therapy rather than surgical exploration. When she completes her course of tamoxifen next year, she prefers to transition to oral octreotide for ongoing treatment of her acromegaly. Regarding her breast cancer, she has had no evidence of recurrence 4 years since the time of diagnosis.


The patient is a left-hand-dominant 75-year-old female with history of prior cerebral vascular accident without residual left upper extremity deficits, Crohn's disease, hypertension, and mitral valve prolapse who underwent TEA in November 2018 for the treatment of end-stage arthritis. Total elbow arthroplasty was performed at an outside facility by another surgeon. Three months following primary surgery, the patient reported persistent swelling, erythema, and pain of the operative elbow. Per patient report, multiple aspirations were performed, but she denies being given a diagnosis for or undergoing treatment for PJI. She initially presented to us in July 2019 for evaluation with complaint of unrelenting elbow pain, erythema, and swelling. Physical exam revealed diffuse induration and erythema over the posterolateral left elbow, without draining sinus, limited ROM of the left elbow of 30-90°, and no neurovascular deficits. Radiographic imaging demonstrated signs of loosening of both humeral and ulnar components, ulnar osteolysis concerning for infectious etiology, and a new periprosthetic fracture of the medial epicondyle (). Infectious workup was completed with initial erythrocyte sedimentation rate (ESR) elevated to 47 mm/h (normal 0-30 mm/h), but normal C-reactive protein (CRP) at 0.3 mg/dl (normal 0.0-0.9 mg/dl) and no leukocytosis evident on Complete Blood Count (CBC) (white blood count 5.1 × 103/μl). Due to continued concern for infection, the patient was indicated for left elbow irrigation and debridement (I&D), removal of implants, possible revision elbow arthroplasty, and possible placement of an antibiotic spacer. Antibiotics were held prior to surgery until cultures and intraoperative frozen sections had been obtained.
Initial revision surgery was performed in August 2019. The patient was placed in a lateral decubitus position. A triceps tongue approach described by Marinello et al. was performed through the previous posterior surgical incision []. Dissection into subcutaneous tissue exposed a purulent fluid collection with signs of communication to the underlying joint (). Capsulotomy was performed confirming communication between the joint and abscess as well as notable inflamed and infected synovium and early metallosis. A total of 4 tissue culture specimens and one fluid culture were sterilely obtained. Tissue samples were also sent for a frozen section which yielded >10 WBC per high-power field. At this time, a two-stage arthroplasty with an antibiotic spacer was performed. The ulnar component was found to be grossly loose as it could be removed by hand during extraction. The humeral component was found to be moderately fixed with some implant motion at the cement interface. The humeral implant could not be removed by hand. The humeral component and cement mantel were removed with a combination of high-speed burr and cement extraction tools. However, during removal of the cement mantel, the periprosthetic fracture of the medial column propagated causing a spiral fracture of the humeral shaft. The remaining intact humeral canal and proximal ulna were again irrigated and debrided. A hand-molded antibiotic spacer was prepared, consisting of two bags of gentamicin-impregnated antibiotic cement, mixed with a total of 4 grams of vancomycin. As the surgical bed had gross infection signs, staged treatment of the infected TEA with an antibiotic spacer and closed treatment of the humerus fracture with a Sarmiento brace and bone stimulator was chosen rather than immediate fixation [, ].
Postoperatively, the patient was managed by the infectious disease service and was placed on IV vancomycin and oral levofloxacin daily for 6 weeks. All tissue and the single fluid culture (5 of 5 cultures) were positive for Staphylococcus epidermidis (Staph epi).
At 5-month follow-up, the patient had minimal left elbow pain but notable functional limitations. Computed tomography (CT) imaging (not available) and radiographs revealed a left humeral shaft fracture with incomplete union (). Infectious workup with elbow synovial fluid α-defensin, ESR (18 mm/h), and CRP (0.1 mg/dl) was within normal limits. Further staged treatment with surgical fixation of the fracture nonunion prior to TEA was offered to the patient; however, as this was her dominant extremity, she opted for alternative surgical options. Earlier surgery was delayed to allow for increased healing of the periprosthetic humerus shaft fracture. The patient returned to the OR for repeat I&D, open surgical fracture fixation with femoral strut allograft augmentation of the humeral shaft nonunion, and total elbow arthroplasty. The previous posterior elbow incision was again used; however, a triceps-off approach described by Morrey [] was utilized to allow for mobilization of soft tissue and effective proximal neurolysis of the radial and ulnar nerves. The antibiotic spacers were removed. A total of 4 tissue cultures and one fluid culture were obtained. The humerus was noted to have a stable fibrous tissue and incomplete union, but the humeral canal was patent. The femoral allograft struts were contoured with a burr, and the native humerus cortical surface was gently prepared with a burr. The allograft struts were placed along medial (146 mm), lateral (112 mm), and posterior aspects (61 mm) of the humerus similar to previously described techniques [, ]. Allograft was used to augment the incomplete union of the humerus. FiberWire cerclage cables (Arthrex, Naples, FL, USA) were used to secure the allografts near the neurovascular structures as well as a 1.7 mm stainless-steel cerclage cable (DePuy Synthes, Warsaw, IN, USA) which was utilized for a radiographic marker to monitor for early loosening. A cement restrictor was placed within the native humeral canal. PALACOS gentamicin-impregnated cement (Heraeus Medical, Yardley, PA, USA) was placed in the humeral canal and an SRS augmented total elbow arthroplasty (Zimmer-Biomet, Warsaw, IN, USA) with a 6 mm × 75 mm humeral stem, and a size of 50 mm augment was cemented in place. A 75 mm × 4 mm Nexel ulnar component (Zimmer-Biomet, Warsaw, IN, USA) was cemented in place. The elbow was reduced and components were linked (). The elbow motion was 0-130 degrees of extension-flexion and 80-80 degrees of pronation-supination without evidence of instability or implant stress. The triceps was reattached to the proximal ulna using FiberWire nonabsorbable suture (Arthrex, Naples, FL, USA) as previously described []. The patient was placed on prophylactic antibiotics with doxycycline for 2 weeks until cultures resulted. A single intraoperative culture was positive for Cutibacterium acnes at 12 days and Staphylococcus capitis at 14 days, both susceptible to doxycycline. Antibiotics were continued for an additional month, for a total of 6 weeks.
Postoperatively, the patient improved significantly and at 12 months after the second-stage revision surgery had no pain in her elbow. The Mayo Elbow Performance Score (MEPS) at nine months was 90 points (range 0-100). Her active arc of motion was excellent: 10°-130° (), and X-ray showed stable TEA components without signs of failure or loosening or resorption of the strut allograft (). The patient is scheduled for a follow-up at 2 years from her revision surgery.


Mr. A was a 22-year-old man with a diagnosis of schizoaffective disorder and neurodevelopmental disorder not otherwise specified (NOS) according to DSM-5 criteria [], admitted for the first time in our department, after several previous hospitalizations, for the reexacerbation of a hypomanic episode with dysphoric features and psychotic symptoms.
The patient, a healthy carrier of beta-thalassemia, did not suffer from any other current or past medical conditions and had no family history of psychiatric disorders.
At admission, on psychic examination, the patient presented a slight stutter and logorrheic language with hyperphonic tone. Mimicry was slightly overexpressed with verbal and motor stereotypes. He was euphoric with mild motor restlessness and with reduced need for sleep. Slight acceleration of thoughts with poorly structured paranoid and persecutory ideas.
His longitudinal evaluation revealed that he was born preterm (34th week of gestation due to liver dysfunction from preeclampsia) and acquired walking after the 15th month. Since childhood, the patient has showed some language (expressive and receptive), learning (dysorthography, dysgraphia), and behavioral problems (impulse-control), and since adolescence, he has experienced mood swings, obsessive thoughts (fear of dying and sexual issues), compulsive accumulation, stereotyped language, aggressive attitudes (self-injurious tics), and specific phobias (elevators, fear of drowning, swimming, and cataclysmic events) with serious impairment of personal autonomy and school performance.
In those years, the patient regularly performed several personalized multidisciplinary therapeutic programs in different neuropsychiatric institutes with partial clinical benefit.
In the last three years, Mr. A reported a period of euthymia, achieving the high school diploma and occasionally working as a waiter. However, four months before our consultation, the patient showed mood swings with irritability, nervousness, verbal aggression, and paranoid and persecutory ideas towards parents and colleagues, and he underwent two hospitalizations in other clinics with poor clinical benefit. When he was admitted to our inward, he was taking zuclopenthixol (20 drops/day) and diazepam (15 mg/day).
Lithium sulfate was introduced on the first day, zuclopenthixol and benzodiazepines were gradually suspended until the third day, and aripiprazole (5 mg/day) was given on the fifth day. Approximately 8 hours after aripiprazole, the patient began to experience protracted and bothersome hiccups that lasted for the following 8 hours. The doctor in charge was called by the nursing staff and decided to give him gabapentin (100 mg) that led to a complete hiccup resolution in about 60 minutes.
Since hiccups were considered as an adverse event of aripiprazole, this drug was immediately stopped and replaced by risperidone and clozapine. The patient remained in our hospital for the next 18 days, and he experienced no more hiccups.


Mr. G was a 20-year-old man, working in the family business, admitted to our department for the onset of a major depressive episode (according to DSM-5 criteria []) with suicidal thoughts and progressive impairment of social and academic functioning.
The family history was positive for anxious spectrum disorders in both maternal and paternal lineages. He referred previous cannabis and alcohol misuse. The patient did not suffer from any medical conditions.
On psychic examination, he was not very talkative, and if questioned, he used short and concise sentences reporting experiences of self-devaluation and inadequacy. Mr. G described a sense of apathy, anhedonia, and a not-better-specified “emptiness.” He referred low energy levels, hypersomnia, difficulties in attention and memorization, poor prospects for the future, suicidal thoughts, and anxiety fluctuations with recent cardiorespiratory and neurovegetative critical episodes. The psychomotricity was slightly slowed. He denies recent alcohol and substance use.
Neurological physical examination did not detect any signs of stiffness or tremor with regular peripheral-induced reflexes.
His longitudinal evaluation revealed no complications at birth, pregnancy, and delivery with regular neuropsychomotor development.
The onset of the psychopathological picture seemed to date back to the age of 14 when the patient experienced a drop in mood with anhedonia, loneliness, feelings of self-devaluation and inadequacy, irritability, anguish, thoughts of death, fluctuations of anxiety levels, and self-cutting. For this reason, he decided to begin a psychotherapeutic treatment with clinical benefit. At the age of 16 years, Mr. G started taking alcohol and cannabinoid for recreational-disinhibitory purposes.
When he was 18, the patient reexperienced depressive symptoms with structured anticonservative ideation and progressive impairment of social and scholastic functioning (he quit the school). He underwent psychiatric evaluations, and several psychopharmacological associations were prescribed including antidepressants, antipsychotics, benzodiazepines, and mood stabilizers with partial clinical benefit. Considering the persistence of the symptomatology, he consulted us, and he was hospitalized in our clinic. At the admission, he was taking valproic acid (50 mg/day, blood levels: 37 μg/mL), perphenazine (4 mg/day), and sertraline (50 mg/day).
On the second day, carbolithium 300 mg/day was added, sertraline was increased to 75 mg/day, and perphenazine was stopped. On fourth day, after increasing carbolithium to 600 mg/day, aripiprazole 5 mg/day was introduced, and the patient reported improvement in mood and anxiety. Aripiprazole was increased to 7.5 mg on the sixth day, and on the subsequent day, about 5 hours after having taken the daily dose of aripiprazole, the patient began to experience hiccups and decided to contact the medical staff (about three hours after the onset). In this case, two doses of 100 mg gabapentin were administered to stop hiccups at a distance of about 2 hours due to the ineffectiveness of the first dose. About 35-40 minutes after the second dose, a complete regression of hiccups was obtained. The medical team stopped aripiprazole, and the hiccup never showed up again.


Mr. R was a 41-year-old unemployed man with a diagnosis of BDI and a previous polysubstance use disorder (SUD) (DSM-5) []. The patient performed his first hospitalization in our clinic due to the onset of a depressive episode with mixed features.
The patient does not suffer from any other medical illness.
At the admission, the patient was partially accessible to intrapsychic experiences. High reactivity, irritability, and nervousness emerged. He expressed apathy with low interest for work and for social relationships. There are nuanced self-reference and paranoid ideas. He presented an inversion of the sleep-wake rhythm. He described anxiety infradian fluctuations which worsened at evening.
The neurological examination, the routine blood tests, and the toxicological urine test were normal and showed no recent substance use.
The family psychiatric history was positive for mood disorders in the paternal lineage.
The parents described him as extremely vulnerable to life events with high interpersonal sensitivity. Since adolescence, he alternated periods of dynamism, extroversion, and productivity with others of work and social withdrawal.
The onset of the psychopathological picture was traced back to the age of 25, when Mr. R experienced depressive mood with a tendency to isolation and paranoid and persecutory ideas. With family aid, he underwent a first psychiatric consultation, and he took antidepressants (n.s.) with significative clinical improvement.
The following years, the patient achieved a degree in agricultural science and, shortly thereafter, received a teaching job. When he was 34, after the end of a romantic relationship, he experienced a depressive episode again with death thoughts, paranoid ideas, and social and work impairment.
He decided to consult a psychiatrist who prescribed various psychopharmacological associations and progressively regained mood stability and global functioning.
About 6 months before the hospitalization, he presented a reexacerbation of depressive symptoms with paranoid and persecutory ideations toward colleagues, and thus, he decided to contact our clinic.
At the admission, he was taking valproic acid (1000 mg/day), olanzapine (20 mg/day), and biperiden hydrochloride (2 mg/day). Olanzapine was gradually stopped and carbolithium (600 mg/day) was introduced. Aripiprazole (5 mg/day) was added on the third day and increased up to 7.5 mg/day the next day.
Approximately 8 hours after the second aripiprazole, the patient reported the onset of a persistent hiccup. He tried different physical countermeasures, such as holding breath and drinking water while pinching the nose, but none were effective to stop it. Therefore, we decided to administer him 100 mg of gabapentin, and considering the lack of response after about two hours later, an additional 100 mg of gabapentin was given. In less than 60 minutes from the second dose, hiccup regression was observed.
The aripiprazole was discontinued, and the hiccup did not recur again.


A 67-year-old woman presented for an evaluation of her skin. Her past medical history was significant for adult-onset diabetes (for which she takes metformin), BRCA2 mutation at C3362C>G, chronic lymphocytic leukemia, and NF1. She is one of 12 children; her family history is remarkable for three brothers who also have NF1 and five siblings, without NF1, who have cancer: breast cancer (two sisters, one of whom is also BRCA2 positive), chronic lymphocytic leukemia (one sister), colorectal cancer (one brother who is positive for a microsatellite instability mutation), and lung cancer (one sister).
Chronic lymphocytic leukemia (of the B-cell type) was diagnosed when she was 60 years of age. She was subsequently treated, at age 65 years, with four weekly infusions of rituximab, which--at the time of treatment--was considered to be the first-line therapy for chronic lymphocytic leukemia. She achieved a good clinical response and is currently being followed regularly by her oncologist.
Cutaneous examination showed numerous soft nodules (neurofibromas) on her neck, arms, chest, and legs. Small, two to four-millimeter brown macules (freckling) were present in her left axillae and extending onto her left arm, adjacent and beneath her left breast, and on the left scapula area of her upper back (Figure ). She had no larger brown patches (café-au-lait macules). There were several pigmented hamartomas (Lisch nodules) on the iris of both eyes (Figure ). These clinical features, in addition to positive family history, confirmed her diagnosis of NF1.


The patient was a 39-year-old woman. She was diagnosed with right hydronephrosis with right back pain and deteriorated renal function, and she was referred to our department from Rheumatology. Her medical history included congenital left renal hypoplasia, Sjogren's syndrome, and hyper phospholipid antibody syndrome. Serum creatinine increased from 0.66 to 0.93 mg/dL. CT revealed partial right hydronephrosis, which was suspected to be an incomplete ureteral duplication (Fig. ). Since right back pain was severe and renal function was impaired, a double-J ureteral stent was immediately placed on lower pole before renogram. Retrograde pyeloureterography diagnosed incomplete ureteral duplication and UPJO of the lower pole in right kidney (Fig. ). After ureteral stenting, right back pain was relieved, and renal function improved promptly.
She then underwent laparoscopic right pyeloureterostomy. The adhesion around the right kidney and ureter was severe, and it was difficult to dissect around the ureter. After an intricate para-ureteral tissue dissection, the ureter corresponding to upper renal pole and dilated renal pelvis of the lower pole were exposed. A lateral incision was made approximately 1.5 cm in the ureter to the upper pole and dilated renal pelvis of the lower pole (Fig. ). Both ends were adapted with 3-0 absorbed thread to form a support thread, and knot stitches were similarly applied with 3-0 absorbed thread from the posterior wall. After the posterior wall was approximated, anterior wall was sutured with a 3-0 absorbent thread to complete anastomosis (Fig. ). The operation time was 5 h and 32 min, pneumoperitoneum time was 4 h and 57 min, and blood loss was 14 mL. She was discharged on the third postoperative day without any complications. The ureteral stent was removed 1 month after surgery. There was no occlusion pattern in the furosemide renogram (Fig. ), and hydronephrosis and renal dysfunction were improved (Fig. ).


A 70-year-old Caucasian male presented with complaints of diarrhea for the last 4 months. He had associated fecal urgency and incontinence at times. He was having 4-5 bowel movements a day ranging from semisolid to watery stools. He denied any history of fevers, abdominal pain, vomiting, weight loss, night sweats, or skin rashes. He denied any recent travel history or exposure to anyone with similar symptoms.
On physical examination, his abdomen was soft and nontender. There was no apparent hepatomegaly or splenomegaly. The rest of the cardiovascular, respiratory, and nervous system examinations were unremarkable. Initial laboratory evaluation showed a hemoglobin of 15.5 g/dL (14–18), WBC of 8.3 K/uL (4.5–11), leucocyte fraction of 45.7% (15–50%), platelet count of 187 K/uL (140–440), creatinine of 0.9 mg/dL (0.7–1.3), AST of 34 U/L (13–39), ALT of 25 U/L (4–33), ALP of 102 U/L (34–104), albumin of 4 g/dL (3.5–5.7), and globulin of 3.1 g/dL (1.5–4.5).
Further workup was done for finding the etiology of the chronic diarrhea. Work up for infection, including parasitic infection and bacterial infections including Clostridium difficile, was negative. He underwent colonoscopy for further evaluation. This revealed a normal mucosa but diffuse submucosal nodularity through the large intestine (). Biopsies were taken from multiple sites, and histopathology of the biopsied revealed multiple aggregates for small mature lymphocytes in the submucosa (). There was no large cell transformation. Histopathology was negative for CMV colitis. Immunohistochemical stains revealed neoplastic lymphocytes positive for PAX5 (), BCL-2, dim BCL-6, CD5, partial CD20, and CD23 and negative for CD3, cyclin D1 (), and CD10. A diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma was made.
The patient then underwent CT chest, abdomen, and pelvis with IV contrast for evaluation which revealed extensive bilateral axillary, hilar, abdominal, and pelvic lymphadenopathy. He subsequently underwent bone marrow biopsy histopathology which revealed hypercellular bone marrow, with 50% involved by lymphoid cells; flow cytometric immunophenotyping studies revealed monoclonal B-cell lymphoid population with kappa light chain restriction with CD5 and CD23 coexpression consistent with CLL. The patient did not have any abnormal cell clone harboring deletion of 11q, 13q, or 17p. His Rai staging was Stage I and Binet staging was Stage B, putting him at intermediate risk. The patient was referred to oncology that started him on obinutuzumab and venetoclax chemotherapy for the CLL.
The patient went into remission from his CLL on treatment with chemotherapy. The patient improved significantly, and the diarrhea resolved. On 3- and 6-month follow-ups, the patient experienced significant symptomatic improvement with resolution of chronic diarrhea.


We describe the case of a 93-year-old woman who came to the ED with two days of syncopal episodes, altered mental status, and chest pain. The patient had a past medical history of hypertension, renal cell carcinoma requiring left nephrectomy, thyroid cancer requiring thyroidectomy, and subsequent hypothyroidism. The patient was evaluated by the Internal Medicine team and was found to be very weak and confused with a heart rate (beats per minute) ranging from the 120s to 130s. She also had episodes of sinus arrest and elevated troponins. She was admitted to the medical intensive care unit (ICU) with symptomatic sinus node dysfunction and tachycardia-bradycardia syndrome.
Upon admission, an ultrasound-guided right internal jugular catheter was placed without any reported complications or difficulties. Cardiology was consulted and the patient was started on an isoproterenol drip with plans for pacemaker placement. During the procedure, the central line was noted to be pulsatile and crossing the midline. Immediately after pacemaker placement, the Vascular Surgery team was consulted for evaluation and management of iatrogenic intra-arterial central catheter placement.
Upon vascular evaluation, a chest X-ray (CXR) was reviewed (Figure ); and the central line was noted to have an unusual track with the tip projecting medially. To confirm the diagnosis of intra-arterial catheter placement, blood gases were obtained; and the line was evaluated for waveform and blood pressure. These studies showed clear arterial parameters confirming the presumed diagnosis. Ultrasound evaluation was inconclusive due to patient habitus. After discussing the risks and benefits of removing the line at the bedside versus in the operating room (OR), the patient was immediately taken to the OR.
The patient was placed under general anesthesia and intubated. The patient's position was similar to that used for a carotid endarterectomy with the head slightly extended and turned towards the left. The catheter was left undisturbed and prepped in the operative field. An incision was made anterior to the sternocleidomastoid muscle (Figure ). The right neck was explored. The jugular vein was encircled with vessel loops for proximal and distal control. The common carotid artery, which was felt to be the likely site of the arterial catheter, was in fact intact and free of disease. Unexpectedly, the catheter was noted to enter and exit the internal jugular vein. It did not injure the carotid artery but traveled deeper into the neck and chest, posterior to the right clavicle. The dissection was carried deeper and proximal to the clavicle. It was apparent that the catheter was entering the superior aspect of the right subclavian artery just lateral to the origin of the vertebral artery (Figure ). The proximal and distal subclavian artery beneath the clavicle was mobilized sufficiently to encircle with a vessel loop. The vertebral and internal mammary arteries were identified and controlled with vessel loops. Under systemic anticoagulation, the subclavian artery was clamped proximally using a Martinez clamp; and the catheter was withdrawn from the puncture site. The entry site was closed using interrupted 5-0 polypropylene sutures. The jugular vein was repaired using interrupted 6-0 polypropylene sutures. A #10 Blake drain was placed, and the incision was closed in a standard fashion. Following surgery, the patient was transferred to the ICU, intubated.
On postoperative day (POD) 1, the patient was extubated. The neck incision was dry and without a hematoma. The drain had minimal output and was removed. On POD 2, the patient developed respiratory insufficiency requiring bilevel positive airway pressure (BiPAP). She had persistent altered mental status. The family requested Do Not Resuscitate (DNR)/Do Not Intubate (DNI) orders, but all other medical care was still provided. Neurology and Endocrinology teams were consulted, and the patient was diagnosed with metabolic encephalopathy as well as hypothyroidism with myxedema coma (thyroid-stimulating hormone [TSH]: 120 μU/mL). Treatment with intravenous levothyroxine was initiated. The Neurology team recommended further imaging evaluation with CT, MRI, and electroencephalogram (EEG); but the family declined further testing. On POD 5, the patient’s respiratory insufficiency and altered mental status worsened. The patient expired on POD 7.


A 76-year-old gentleman with a past medical history of hypertension, type 2 diabetes mellitus, and coronary artery disease with coronary artery bypass graft in 2006 presented with a sudden onset of inability to speak. His wife reported that the day prior to his admission to our facility, he was complaining of flu-like symptoms. He drove himself to his primary care physician on the morning of admission and was prescribed amoxicillin. A few hours later, she found him on the floor. He was aphasic at that point.
Upon arriving to our emergency department, the patient had an altered mental status with a Glasgow coma scale of 12, his vitals showed a temperature of 100.8°F, heart rate of 120 beats per minute, and a respiratory rate of over 20 breaths per minute, and his oxygen saturation was 82% on room air. He had global aphasia with incomprehensible sounds as he was not following commands and produced incomprehensible sounds. Neurological examination showed sluggishly reactive, equal pupils 2 mm in diameter. Oculocephalic reflex was present. Corneal reflex was intact and so was the gag reflex. Motor examination showed generalized weakness, and deep tendon reflexes were absent throughout. Sensory exam showed no deficits. Coordination and gait could not be assessed due to the patient's condition and lack of cooperation with examination. Otological examination showed well-formed external auricles bilaterally, and there was no right-sided post-auricular erythema or fluctuance. Right external auditory canal was patent with moderate cerumen impaction, and the tympanic membrane was intact with thickening and evidence of fluid in the middle ear. There was no evidence of cholesteatoma or retraction pocket, and malleus and incus could not be visualized. No neurological focal deficit was noted. Chest auscultation revealed fine crackles on the left inter-scapular and infra-scapular zones.
Pertinent findings on laboratory tests included leukocytosis with a white cell count of 23.6 K/mm3 (87.5% PMNL [polymorphonuclear leukocyte]), an elevated procalcitonin of 15 ng/mL, lactic acidosis, creatinine 1.78 mg/dL with a GFR (glomerular filtration rate) of 37 mL/min/1.73m2 with no known history of chronic kidney disease, a mildly elevated troponin of 0.208 ng/mL, elevated pro-BNP (proB-type natriuretic peptide) at 3,500 pg/mL, and a urinalysis negative for infection. Electrocardiography showed sinus tachycardia with a right bundle branch block. Blood, urine, and sputum cultures were drawn. The patient underwent multiple imaging studies; chest X-ray showed left lower lobe heterogeneous opacity and consolidation, a computed tomography (CT) scan of the head did not show any acute abnormalities, and a CT angiography of the head and neck showed suspicion of right-sided otomastoiditis with intracranial extension. Bilateral lower extremity venous duplex scans were negative.
The patient met sepsis criteria and was therefore given the appropriate sepsis bundle including intravenous fluids and broad-spectrum antibiotics (vancomycin, cefepime, and metronidazole). He was placed on non-invasive mechanical ventilation (BiPAP) and was admitted to the intensive care unit.
The lactic acidosis resolved with the administration of intravenous fluids boluses. However, the patient’s hypoxia worsened rapidly and intubation with mechanical ventilation was necessary. Magnetic resonance imaging (MRI) of the brain was ordered, which showed evidence of right-sided otomastoiditis with intracranial extension (as shown in Figure ), cerebellopontine angle epidural abscess, and possible cerebral abscess (as shown in Figure ); FLAIR (fluid-attenuated inversion recovery) signal abnormality was noted in the sulci of the frontal lobes, and restricted diffusion was noted in the sulcus of the right parietal occipital junction, which was concerning for developing meningitis. Otorhinolaryngology team was consulted and the patient underwent myringotomy with middle ear pus drainage followed by myringotomy tube placement.
Otic ciprofloxacin drops were started, and the patient was taken to the operating room for mastoidectomy with drainage of epidural abscess. Blood, urine, sputum, and ear drainage cultures did not show bacterial growth. The patient deteriorated and developed septic shock. Infectious disease service was consulted, and recommendations were made to keep the same antibiotic regimen as mentioned previously. A repeat MRI of the brain showed residual abscess. Neurosurgery service was consulted and proceeded to perform a right sub-occipital craniectomy. No frank purulence was noted. Recommendations were made to keep the patient on the antibiotics for three weeks after the neurosurgical intervention. The patient finally became stable and was extubated and transferred out of the intensive care unit after a 14-day stay.


Patient 1 was a girl aged 9 years and 5 months, with a de novo ATP1A1 c.2797G>A [p.Asp933Asn] variant. Her motor development was normal. Her Wechsler Intelligence Scale for Children showed a Full Scale IQ (FSIQ) score of 71 at 7.5 years old, in the borderline range. She had poor executive functioning, and her learning ability, logical ability, and memory were significantly inferior to those of her peers. She began to experience sleep disorders when she was 2 years old, which manifested as waking up suddenly and crying after 3–4 h of sleep every night and the sleep disorder has relieved since her 8 years of age. In addition, she had poor emotional control, as easy to emotional collapse and cry constantly, but no epilepsy. Her brain MRI and serum Mg2+ concentrations were normal. Her birth history and family history were normal.


Patient 2 was a boy aged 2 years and 10 months, with a de novo ATP1A1 c.2590 G>A[p.Gly864Arg] variant. He had severe developmental delay, manifesting as sitting independently but unstably, he couldn't say any words and only made a babbling sound by the time of our follow-up. He began to develop epileptic seizures 5 months after birth, characterized by a tonic seizure in one limb and, later, evolving into generalized tonic–clonic seizures. EEG showed widespread slow waves and spike slow waves during sleep and wide 3–4 Hz slow waves, especially in para-midline and midline regions, during waking and sleeping stages (). He was diagnosed as developmental and epileptic encephalopathy. His brain MRI and serum Mg2+ concentrations were normal. The child has taken a total of three antiepileptic drugs including diazepam, levetiracetam, and topiramate, the latter two are currently used, but the seizures have not been controlled. He was born at 36 6/7 weeks of gestation with normal delivery. His family history was unremarkable.