We report a case of a 35-year-old Hispanic male with a past medical history of nicotine dependence who presented to the emergency department with the progressive onset of neck pain, headache and multiple episodes of non-bilious non-bloody vomiting for 2 months. He reported that the neck pain was progressive, localized, non-radiating, aggravated by movement, and upon standing from a seated position, along with intermittent vision changes over the past few months. The patient denied fever, chills, night sweats, weight loss, dizziness and his Zubrod performance status was zero.
In the Emergency Department, the patient was vitally stable. The complete blood count and complete metabolic panel were unremarkable, chest x-ray, urine analysis and blood cultures did not show infection. A neurological exam was significant for decreased active range of motion of the cervical spine with pain on palpation of the right trapezius but no appreciable erythema or mass. The exam was negative for focal weakness or paresthesia, and deep tendon reflexes were 2+. Magnetic resonance imaging (MRI) with and without IV contrast showed multiple heterogeneous intracranial masses with resultant mass effect compressing the cerebral aqueduct with dilation of the 3rd and 4th ventricles hydrocephalus and tonsillar herniation ().
Neurosurgery performed a suboccipital craniotomy, partially resected the cerebellar mass, and placed a parietal to frontal shunt catheter, which significantly reduced the size of the ventricles. Biopsy results from the cerebellar mass demonstrated cerebellar tissue involved by a diffuse proliferation of foamy histiocytes and spindle cells admixed with prominent lymphoplasmacytic infiltrate (). Immunohistochemistry showed that the histiocytes were positive for CD68, CD163, Factor XIIIa, and Fascin. They are negative for S100, CD1a and SALL4. Further testing revealed the specimen was positive for BRAF V600E/D mutation, but the assay cannot differentiate between Langerhans and non-Langerhans histiocytosis.
An evaluation for extracranial involvement was ordered and included a bone scan, PET scan, and cardiac MRI. Bone scan showed high-intensity trace uptake in the skull, mandible, predominantly distal long bones of the upper and lower extremities is consistent with widespread histiocytosis ().
PET scan showed hypermetabolic uptake within the medullary portions of the diffuse abnormal lesions of the distal femurs, tibias, and fibulas, and cardiac MRI was unremarkable. The patient was started on vemurafenib and continued to show improvement in a 3-month outpatient follow-up.


The patient was a 48-year-old man, in whom a round mass lesion was detected in the hilum of the right lung by chest radiography performed at an annual health checkup (). The image of this mass lesion had been interpreted as a normal view on chest radiography performed at his annual health checkup one and a half years previously (). The mass detected by radiography was also detected by computed tomography (CT), as a 3.5 cm low-attenuated mass with a circumscribed margin in a fissure of the right lung (). On magnetic resonance imaging (MRI), this mass lesion was displayed as a high, low and low signal mass on the in-phase of T1-weighted imaging (WI), out-of-phase of T1WI and T2WI, respectively (). The mass lesion was not clearly enhanced by fat-saturated contrast-enhanced T1WI with extracellular gadolinium contrast material (gadoterate meglumine; Magnescope®; Guerbet, Villepinte, France) (). The radiological observations were highly suggestive of a hamartoma.
The growing tumor was resected by VATS under general anesthesia with differential pulmonary ventilation. The tumor was located under the visceral pleura on the horizontal fissure of the right lung (). The size of the capsulated yellow tumor was 3.5 × 3.5 × 2.0 cm. The tumor was microscopically composed of mature adipose tissue separated by fibrous tissue of various widths. The adipocytes were of various sizes, and there was no significant nuclear atypia. Areas of lymphocyte infiltration were found to be separated by connective tissue (). These findings altogether led to a diagnosis of lipoma.


A 62-year-old Hispanic female with a past medical history of RA presented with cough, generalized weakness, and a 20-pound weight loss over six months. Her diagnosis of RA was made five years prior based on the bilateral symmetrical synovitis of the metacarpophalangeal (MCP), and proximal interphalangeal joints, a positive rheumatoid factor (RF), and a positive cyclic citrullinated peptide (CCP). Her past medical history was also significant for diabetes, hypertension, and hypothyroidism. Her RA had been well controlled on leflunomide and low-dose prednisone. Initial evaluation showed a white blood cell (WBC) count of 11,300 /mm3 and an erythrocyte sedimentation rate (ESR) 64 mm/h. A chest computed tomography (CT) scan showed a new cavitary lesion measuring 31 x 78 mm in the right lower lung lobe, a 16 x 12 mm nodular density in the left lung base with central cavitation, and several ill-defined thin-walled cavitary lesions in both lung apices measuring between 1 and 2 cm in diameter (Figure ).
Sputum cultures for Mycobacterium tuberculosis were negative. Laboratory testing revealed cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) titer of 1:160 and an elevated proteinase 3 (PR3) antibody of 4.7 units (normal <1 unit). Serial ANCA testing showed a peak titer of 1:320, with PR3 antibody of 26 units. Her first lung biopsy showed focal acute and chronic inflammation, fibrinoid necrosis, and hemorrhage. A second lung biopsy showed fragments of densely fibrous tissue with acute, chronic, and non-caseating granulomatous inflammation consistent with a diagnosis of GPA. No acid-fast bacilli, fungal organisms, or malignant cells were identified. The patient was given two infusions of rituximab 1000 mg intravenously (IV), 15 days apart with methylprednisolone 100 mg IV. Her symptoms as well as her cavitary lung lesions gradually improved. Both RA and GPA remained under good control on maintenance methotrexate (MTX) and prednisone.


A 58-year-old Indian female presented with 10 days of dyspnea and hemoptysis. She had a past medical history of RA, diagnosed at age 57 after developing bilateral MCP synovitis, elevated RF of 134 IU/mL, elevated ESR of 116 mm/hour, and hand radiographs showing periarticular osteopenia and bony erosions. Her RA was controlled on MTX, hydroxychloroquine, and low-dose prednisone when she presented with a serum creatinine of 5.5 mg/dL (baseline 1.6 mg/dL) and proteinuria. A chest CT scan showed airspace disease involving the right upper, middle, and lower lobes and left upper lobe concerning diffuse alveolar hemorrhage (DAH) (Figure ).
Anti-PR3 c-ANCA titer was elevated at 1:320. She was intubated and bronchoalveolar lavage (BAL) confirmed the presence of DAH. Biopsy of the bronchiolar wall showed chronic granulomatous inflammation and fibrosis consistent with GPA. She was given cyclophosphamide 500 mg IV, methylprednisolone IV, and plasmapheresis. She gradually improved and was eventually extubated and discharged home in stable condition. She was discharged on oral cyclophosphamide, which was later switched to azathioprine. Her RA and GPA have remained in remission on azathioprine.


An 85-year-old male was admitted to our hospital with five days of fever, hypotension, and right upper quadrant (RUQ) abdominal pain. He had a history of chronic kidney disease (CKD) receiving hemodialysis, hypertension, coronary artery disease, myelodysplastic syndrome, and chronic cholecystitis (medically managed due to extensive comorbid conditions). He also had a history of choledocholithiasis requiring sphincterotomy, stone removal, and ductal dilation. Endoscopic retrograde cholangiopancreatography (ERCP) was performed twice, approximately one year prior to presentation in June 2019 for stone removal and ductal dilation, and in December 2019 for stent removal.
Upon arrival to the emergency department, his temperature was 39.2 °C, blood pressure 139/80 mmHg, pulse rate 108 beats/min, respiratory rate 14 breaths/min, oxygen saturation 95% on room air. The patient was alert and found to have icteric sclerae, but no rash or lymphadenopathy. His lungs were clear to auscultation and heart sounds were regular. His abdomen was soft, but he had mild RUQ abdominal tenderness without abdominal distension. The laboratory data showed leukocytes 5.2 K/µL with 87.8% neutrophils, lactate 2.9 mmol/L, serum creatinine 4.11 mg/dL (unchanged from his last known baseline one month prior in the setting of CKD), serum aspartate aminotransferase 45 U/L, serum alanine aminotransferase 38 U/L, alkaline phosphatase 286 U/L, total bilirubin 1.5 mg/dL with direct bilirubin 0.8 mg/dL (elevated from baseline normal liver function tests done one month prior), lactate hydrogenase 242 U/L, and platelet 85 K/µL (decreased compared to baseline normal one month prior).
Abdominal ultrasound demonstrated a 2.7 cm gallstone impacted at the gallbladder neck.
Contrast enhanced computed tomography (CT) demonstrated a new perforated cholecystitis with perihepatic abscess and mild biliary dilation with pneumobilia suggestive of underlying bilioenteric fistula, which were new compared to prior imaging done one year prior.
Empiric antibiotic treatment with intravenous piperacillin-tazobactam and vancomycin was administered after blood cultures were obtained. A drainage catheter was placed by interventional radiology for drainage of the biliary and perihepatic abscesses. Abscess cultures revealed Edwardsiella tarda, Escherichia coli and Streptococcus anginosus. Blood cultures yielded Streptococcus anginosus. Of note, E. tarda was susceptible to cefoxitin, 3rd and 4th generation cephalosporins, beta-lactam/beta-lactamase inhibitor combinations, aztreonam, carbapenems, aminoglycosides, trimethoprim-sulfamethoxazole, levofloxacin (MIC 0.5 µg/ml), and tigecycline. It was resistant to tetracycline. Antibiotics were changed to intravenous ceftriaxone and metronidazole. On day 2, his leukocytosis initially increased from 5.2 K/µL to 20.9 K/µL, but improved down to 8.5 K/uL by day 8. The patient remained afebrile and hemodynamically stable and was discharged from the hospital 8 days after admission to complete a total 14 day course of antibiotics with intravenous ceftriaxone and oral metronidazole. CT abdomen performed 3 weeks later off antibiotics demonstrated resolution of the perihepatic abscess. Four months later, the patient returned to the hospital with recurrence of RUQ abdominal pain but without clinical signs of sepsis. CT abdomen showed acute cholecystitis and new perihepatic collections, which were percutaneously drained. Fluid cultures grew Escherichia coli and Enterococcus faecium. Blood cultures were negative. There was no growth of E. tarda, indicating that E. tarda was successfully eradicated by prior antibiotic therapy.


A 32-year-old female patient presented with a history of persistent right knee pain for over three months. There was and no history of any kind of trauma. Her medical history revealed no other medical conditions. Physical examination did not reveal any knee signs. The range of motion was normal although the patient had mild pain in excessive flexion (over 120°). The symptoms of the patient were mimicking blocking symptoms due to mechanical causes at excessive flexion and full extension. She also described an occasional audible clicking at the superolateral patellofemoral joint. The only remarkable finding was a palpable bony mass over the superolateral aspect of the right knee with tenderness and mild swelling in this area. This lump was hard as a bone, was immobile, and particularly sensitive to palpation.
Plain radiographs revealed a sessile bony mass located at the superolateral aspect of the knee joint without a stalk (Figures -). MRI scan was performed and showed a bony bulge arising from the superolateral aspect of the knee joint (within the joint capsule) with surrounding synovitis (Figures -). The imaging findings and the physical examination (especially the palpable bony mass) posed the diagnosis of solitary intra-articular osteochondroma. Due to the symptoms of the patient, diffuse and persistent pain for over three months, arthroscopic removal of the tumor was decided.
Under general anesthesia, standard arthroscopic portals were performed and the arthroscopic examination of ligaments, menisci, and cartilage was normal. Τhen with the aid of a needle the tumor was marked in the superolateral aspect of the knee joint, surrounded by a bursa, and superomedial and superolateral portals were performed.
The bursa was removed with the shaver and from the superolateral portal an osteotome was inserted at the base of the tumor (Figure ). With precise movements, the tumor was excised and finally removed with a hemostatic clamp through the portal. Finally, a burr shaver was used to abrade the bone of the femur.
The histopathological report revealed signs that confirmed the diagnosis of osteochondral lesion.
The patient started immediately weight bearing from the first postoperative day and followed an aggressive rehabilitation program with muscle strengthening. One month postoperatively the patient claimed complete relief of her symptoms and returned to her full daily activities. Radiographs at six months postoperatively showed no signs of the bone lesion (Figure ). On a follow-up seven years postoperatively, the patient remains free of symptoms without any recurrence of the tumor.


A 29-year-old male with no known past medical history was referred to the office for lower urinary tract symptoms and hematuria. He described a three-year history of symptoms including decreased force and caliber of his stream, difficulty urinating, and intermittent gross hematuria. He denied any smoking history, fever, dysuria, or flank pain. A urine sample was submitted for urinalysis, which was negative for signs of infection, and urine culture, which was also negative. He was treated with tamsulosin and was advised to return in two weeks for evaluation with in-office cystoscopy if the symptoms persisted.
The patient returned to the office two weeks later with persistent lower urinary tract symptoms. A repeat urine sample was submitted for analysis the prior day, which was again negative. He then underwent in-office cystoscopy which revealed an inflammatory-appearing mass at the bladder neck and trigone and base of the prostate gland. The urethra was normal without strictures. A computerized tomography (CT) urogram was ordered to further evaluate for any lesions due to hematuria. Transurethral resection of the bladder tumor was scheduled for the operating room.
Outpatient CT urogram was significant for posterior wall thickening with low levels of enhancement without any lesions (Figure ). Two weeks after undergoing CT evaluation, the patient returned to the operating room for cystoscopy. Cystoscopy in the operating room showed cystic lesions at the level of the prostate extending to the trigone of the bladder (Figures , ). The mass was partially obstructing the prostatic urethra. Transurethral resection of the tumor was performed, and samples were sent for pathology. Although pathology examination was negative for carcinoma, it demonstrated urothelium with florid cystitis cystica et glandularis with adequate tissue sampling proven by the presence of focal muscularis propria (Figure ).
During his postoperative follow-up in the office, the patient reported resolution of his voiding symptoms. Urinalysis demonstrated microscopic hematuria, likely due to the recent procedure, and no evidence of infection. Due to the posterior wall enhancement seen on the CT urogram, a discussion was held regarding the potential need for re-resection and biopsy. Meanwhile, the patient reported significant alleviation of his voiding symptoms after elimination of the mass at the base of his prostate.


A 23-year-old female arranged for a telephone consultation with a primary care facility in the northeast of England with the primary complaint of vertigo. Her dizziness was intermittent, and she described it as a feeling of “the world spinning around her.” This developed gradually over the course of four days prior to the consultation and was severe enough to set her balance off. By the time of the appointment, she was experiencing these symptoms four to five times a day. Each episode lasted 20 minutes on average, with the longest one lasting about an hour. These symptoms were often triggered by a change of posture, particularly after standing from a sitting position. Associated with the dizziness was a feeling of nausea; however, she did not experience any vomiting as a result of this.
In addition to vertigo, she also complained of aural fullness with the right ear affected slightly more than the left. This was accompanied by bilateral hearing loss, described as “muffled hearing,” as well as the ringing of the ears (tinnitus).
She tested positive for COVID-19 by RT-PCR 14 days prior to the appointment. She was initially prompted to test for COVID-19 due to a dry cough and runny nose for two days before testing. During the course of this illness, she also developed anosmia, ageusia, and shortness of breath. As dictated by local guidelines, she remained in isolation for ten days without feeling the need to seek medical help for her illness and therefore did not receive any medication for her COVID-19 infection. The symptoms of cough and runny nose had resolved completely; however, she continued to experience residual shortness of breath, and loss of senses of smell and taste at the time of this consultation. The symptoms of vertigo developed nine days after testing positive for COVID-19, and 11 days after the onset of her first COVID-19-related symptoms. A repeat RT-PCR three days prior to the appointment was now negative for COVID-19 (ten days after the initial positive result).
There was no history of headache, weakness, slurred speech, visual disturbances, or facial drooping. Her past medical history was otherwise unremarkable, and she was not on any regular medication. She denied any use of recreational drugs.
In light of the above history, she was called in for a face-to-face appointment on the same day for further evaluation. She was hemodynamically stable with a heart rate of 86 beats per minute, a blood pressure of 129/71 mmHg, a respiratory rate of 16 breaths per minute, saturating at 98% on room air, and was apyrexial. She was able to walk comfortably without aid into the clinic and was in no obvious distress at the time. She was fully oriented in time, place, and person. There were no motor or sensory deficits found after a thorough neurological and cranial nerve examination.
Both ears were examined and were found to be negative for any signs of infection, obstruction, or trauma. Tuning fork tests were conducted; Rinne tests were positive in both ears, and the Weber test did not lateralize to any particular side, suggesting bilateral sensorineural hearing loss. A Dix-Hallpike maneuver was performed which was negative. A head impulse test positively elicited compensatory eye movements in the horizontal plane. There was no observed nystagmus, and ocular movements were otherwise intact bilaterally. No gait abnormalities were identified and tandem walking was normal. Romberg's sign was also negative.
After a full assessment, a diagnosis of labyrinthitis secondary to the recent COVID-19 infection was made. She was treated symptomatically with prochlorperazine thrice a day for up to four weeks. She was given a leaflet for information about viral labyrinthitis, its self-limiting characteristic, and asked to therefore watch and wait for symptoms to resolve on their own within four weeks. She was warned about symptoms such as headache, visual disturbances, weakness, or slurred speech. The advice was to contact the clinic immediately if developing any of the above red-flag symptoms, or earlier than four weeks if her condition continued to deteriorate after one week despite the therapy prescribed, or in case of concerns.
She eventually made a full recovery within three weeks of the encounter with no residual symptoms persisting from either labyrinthitis or COVID-19.


A 26-year-old Guyanese male who worked at a warehouse presented with worsening left red-eye and blurry vision for two weeks. The ophthalmologist started on prednisolone eye drop, which initially controlled his eye symptoms. However, he noticed new, small skin papules on the left forearm of the tattoo that he had received five years ago. He had no significant medical history or family history of sarcoidosis. On physical examination, he was found to have a bilateral conjunctival injection, a tattoo with small bumps on the left forearm and upper arm, and no erythema or discharge was noted around the tattoo.
Results of laboratory studies, including serum calcium, were normal; additionally, the erythrocyte sedimentation rate (ESR) was 6 mm/h, angiotensin-converting enzyme (ACE) level was 55 U/L (ref 14-82 U/L), and C-reactive protein (CRP) level was 2 mg/L (normal: less than 10 mg/L).
Chest X-ray was normal, and chest CT revealed bilateral axillary lymphadenopathy with the largest node noted in the left axillary region measuring 2.1 x 1.2 cm and a 2 mm nodule noted in the right middle lobe. Skin punch biopsy showed the tattoo having sarcoid granuloma (Figure ).
Tissue culture for mycobacteria and fungi was negative. The patient was started on topical corticosteroid and then mycophenolate mofetil 2 g daily was added to the treatment, as the patient had recurrent uveitis and the patient's symptoms improved after starting mycophenolate mofetil.


A 23-year-old Guyanese male presented with left eye pain, which was burning and pricking in nature, and intermittent blurry vision. He received chest tattoos in March 2018, which became inflamed around July 2018. Shortly afterward, the arm tattoos that he received three years ago also became raised. The raised portions were in areas with black and red ink only. On physical examination, he was found to have a bilateral conjunctival injection, and there were raised plaques without erythema within black tattoo margins on the chest. He denied shortness of breath, fevers, chills, cough, or sputum production, and he did not have any significant medical history or family history of sarcoidosis.
Laboratory studies revealed ESR was 24 mm/h with no other additional abnormality. The ACE level was 32 U/L (ref. range 14-82 U/L). Chest CT showed a 2 mm pulmonary nodule in the superior segment of the left lower lobe and a 1 mm nodule in the left upper lobe, which did not show axillary or mediastinal lymphadenopathy. Skin punch biopsy demonstrated a tattoo with non-necrotizing epithelioid granulomas (Figure ).
Tissue cultures were negative for mycobacteria and fungi. The diagnosis of tattoo-associated systemic sarcoidosis was made on clinical and histological findings. The patient initially was treated with prednisolone 20 mg daily and then started on mycophenolate mofetil 1500 mg daily, as the patient had recurrent uveitis when tapered off prednisolone. After three months of this treatment, the patient's uveitis and skin lesions improved.


A 12-year-old, castrated male Chihuahua dog weighing 4.2 kg was referred to the hospital with a diagnosis of chronic coughing. The medical history of the dog included tracheal collapse. Physical examinations revealed a grade III murmur and cough. Respiration rate was 20 breaths/min. The dog was diagnosed with hyperlipidemia and mitral insufficiency whose severity was classified as II b by the International Small Animal Cardiac Health Council. Consequently, the administration of alacepril (1.5 mg/kg, SID) and a low-fat meal were initially prescribed. The subsequent treatment was continued for a period of two months. However, cardiomegaly continued to progress, whereas the frequency of coughing was not reduced. Moreover, hyperlipidemia was not improved. Abdominal ultrasonography revealed biliary debris that was gradually increasing in size. Consequently, PS (1 mg/kg, SID) was prescribed. Following PS administration, the clinical signs were evaluated, and hematologic, serum biochemical, and radiologic examinations and echocardiographic and circulation parameter measurements were performed.
Cough disappeared one week after PS administration. In addition, blood biochemical tests revealed that the total cholesterol, triglyceride, and N-terminal probrain natriuretic peptide (NT-proBNP) concentrations were significantly decreased from Day 11 to Day 211 (). An increase in creatine kinase value was not observed throughout the administration period. Additional hematologic and biochemical findings indicating renal or hepatic failures and adverse effects were not observed up to 375 days after PS administration ().
Furthermore, the radiographic vertebral heart size (VHS) decreased after PS administration, as shown in . With respect to the echocardiographic and circulation variables, decreases in heart rate (HR) and left atrium/aorta ratio (LA/Ao) were observed during PS administration, whereas LV fractional shortening (FS) and LV ejection fraction (EF) increased from Day 30 to Day 150 after PS administration (). No marked changes in the peak velocity of early diastolic transmitral flow (E), peak velocity of late transmitral flow (A), E/A ratio, and deceleration time of early diastolic transmitral flow (DTE) were observed during PS administration. Stroke volume (SV) and cardiac output (CO) decreased on Days 30 and 45 after PS administration but thereafter increased and maintained well. No substantial changes in the maximum systolic mitral regurgitation velocity (MRmax) were identified after PS administration. The maximum systolic tricuspid regurgitation velocity (TRmax) and systolic pulmonary arterial pressure (sPA), calculated using the modified Bernoulli equation (4 x TRmax2 + 10), both decreased after PS administration (). The peak velocity of early diastolic mitral annular motion (Em)/peak velocity of diastolic mitral annular motion (Am) ratio increased during PS administration compared with preadministration. E/Em decreased on Days 34 and 65 after PS administration but increased after Day 96, and a higher value was then observed ().


A 64-year-old man, an alcoholic and smoker since adolescence, without previous comorbidities, sought dermatological care due to the appearance of an erythematous lesion on the face showing progressive growth for seven months, associated with cough with hemoptoic sputum, dyspnea, night fever, and weight loss in the last three months. Upon examination, he had a tumor lesion on the nasal tip, with a lobulated surface, an infiltrated base, which was intensely painful to the touch (). No other findings were found upon physical examination.
A biopsy of the skin lesion was performed and the histopathological study showed the dermis infiltrated by a malignant epithelial neoplasm of organoid pattern (, ). Immunohistochemistry showed reactivity with cytokeratin 40, 48, 50, and 50.6 in a Golgi pattern, chromogranin A and synaptophysin () and was negative for TTF-1 and CK 20, characterizing it as a neuroendocrine tumor. The patient underwent computed tomography of the skull, thorax and total abdomen, which showed an extensively infiltrative pulmonary mass involving the main right bronchus, in addition to multiple lesions suggestive of brain, bone, liver, and adrenal metastasis. Bronchoscopy was performed, but the pulmonary mass biopsy was considered unfeasible due to heavy bleeding during the procedure.
It was concluded that it was a pulmonary carcinoid tumor with metastases to the skin and other parts of the body. The patient was classified as stage IV and referred to the oncologist and died within one month.


A 65-year-old female developed contralateral kidney metastasis 1 year after left radical nephrectomy for clear cell RCC. The patient was referred to our department in April 2018 and was in overall good health, with a Karnofsky Performance Status score of 100%. Her medical history included diabetes mellitus, arterial hypertension, and hypothyroidism pharmacologically well controlled. Physical signs were as follows: oriented, collaborating, and autonomous walking; no neurologic examination abnormalities; blood pressure 125/70 mmHg and pulse 75/min; no fever; and regular bowel and bladder functions. Routine laboratory tests including complete blood count, renal and liver function tests, and electrolyte count were within normal range. Radical right nephrectomy had been performed in April 2016, and postoperative pathology findings confirmed a localized clear cell RCC grade 2 tumor (pT2N0M0 stage II) according to the American Joint Committee on Cancer 2017 cancer staging. No recurrence was observed during follow-up until July 2017, when total body computed tomography (CT) revealed a 24-mm enhanced mass in the left kidney in absence of other signs of metastasis in the brain, lungs, liver, abdominal lymph nodes, and bones. The patient refused biopsy, so contralateral kidney metastasis rather than asynchronous primary tumor was diagnosed based on the short time from nephrectomy—14 months—and the peripheral location of the lesion.
The patient started targeted therapy with sunitinib, administered at a dose of 50 mg orally once daily for 4 weeks of each 6-week cycle. Nine months later, the kidney metastasis had decreased from 24 mm to 12 mm. The patient's case was discussed by the urologic multidisciplinary group of our hospital, and SBRT indication for the kidney residual lesion () was shared among all specialists with the intent to consolidate the response obtained with targeted therapy. Targeted therapy was temporarily discontinued 15 days before and after SBRT. To better define the target, the patient was studied with magnetic resonance imaging (MRI).
A planning CT scan was acquired with the patient in supine position within an immobilization device, and a specially designed coordinate-system (body frame) was used for the exact localization of the tumor. An abdominopelvic thermoplastic mask was used to minimize setup motion. MIMvista, version 6.6 (MIM Software Inc) was used for volume contouring and image fusion of MRIs with planning CT. Gross tumor volume (GTV) was defined as the radiologically visible lesion volume in contrast-enhancing T2-weighted MRI sequences. Clinical target volume (CTV) was coincident with GTV, and planning target volume (PTV) was GTV/CTV plus an additional 4 mm in all directions. The spinal cord, a safety margin from the cord (cord planning rescue volume), left kidney, and small bowel were delineated as organs at risk ().
SBRT was administered using the volumetric modulated arc therapy technique in absence of free-breathing or breath-hold techniques, designed with the Monaco Treatment Planning system (Elekta AB) via the Monte Carlo algorithm. Treatment was delivered using the Elekta Synergy linear accelerator with 6-MV x-ray beam energy without a flattening filter free mode and a single arc of 340° rotating clockwise from 190° to 170°. The statistical uncertainty of the Monte Carlo algorithm was 1%, and the final dose was calculated with a grid resolution of 2 mm. The prescription dose was a total of 40 Gy in 5 fractions every consecutive day, with 95% of the PTV receiving at least 95% of the prescription dose. Dose constraints adopted were those suggested by Hanna et al (ie, Dmean was 40 Gy; V10Gy for the solitary kidney was 28%). The PTV and organs at risk doses are shown in the .
The patient did not receive premedications and had no acute side effects during treatment. No renal function test modification was observed 1 week after SBRT. Creatinine and creatinine clearance values pre-SBRT and post-SBRT remained stable (1.4 mg/dL and 38 mL/min, respectively). To prevent possible CT iodine contrast nephrotoxicity, radiologic follow-up with MRI was done 3 months after SBRT and every 4 months subsequently. At last follow-up 19 months after SBRT, MRI showed a complete response; the treated lesion was no longer detectable ().


A 25-year-old woman in immediate puerperium was admitted to the hospital with proximal weakness that has been increasing progressively until difficulty in mobility and subsequent prostration that occurs seven hours after cesarean.
There were no personal or family history diseases, current medications include ferrous sulfate, and she denied alcohol or recreational drugs. She had one previous pregnancy without complication. This pregnancy was normal, and a cesarean section was performed at 37 weeks for pelvic dystocia.
On physical examination, she was alert and oriented, and her vital signs were normal in the neurological examination with findings of proximal weakness, without alteration in the tendon reflexes and findings of alteration in long tracts or focal neurologic deficit.
Initial laboratory showed normal blood cell counts, severe hypokalemia (potassium, 1.91 mEq/L), and pH of 7.24, bicarbonate at 7.7 mmol/L with normal plasma anion gap (anion GAP: 12, 5 mEq/L) .
Urine studies showed urinalysis was normal with a pH of 6.5, without urine active sediment. Urinary K: Cr 83.7 mEq/g, urinary anion gap: 24 mmol/L, and urinary osmolar gap is positive .
Serologic testing was negative for autoimmune causes.
A renal ultrasound revealed normal-sized kidneys with marked increase in the echogenicity in the region of the renal pyramids bilaterally and symmetric consistent with nephrocalcinosis.
Treatment: She received potassium chloride initial by the peripheral vein, and 6 hours after admission, his serum potassium level increased to 2.1 mEq/L with improvement of weakness.


The patient is a 33-year-old African American male with no significant past medical history who presents to the Emergency Department for one day of hematuria. He also endorses a five-day history of myalgias, intractable headache, loss of taste, and minimal dyspnea on exertion. The patient was seen at local urgent care the night prior to presentation for the majority of similar symptoms and received testing for SARS-CoV-2 with the COVID-19 Pro-Genex test. Labs collected included complete blood count (CBC) and comprehensive metabolic panel (CMP). He was later called by the urgent care and was informed his liver enzymes were elevated. Throughout the evening, he noticed dark red color of his urine, which prompted his visit to the ED. He denies urinary frequency, urgency, and dysuria. He notes extreme myalgia, which preceded the hematuria, approximately five days prior to presentation. Myalgias had been gradually worsening. He admits to taking 400mg of ibuprofen the day prior with no symptomatic relief. There is no recorded fever at home, but he endorses chills. History is notable for moving into a new apartment the prior weekend; however, his myalgias began prior to this, and he denies significant exertional efforts. He works in a healthcare setting.
In the ED, the patient had a heart rate of 124 beats per minute, temperature of 98.3 F, oxygen saturation 98% SpO2 on room air, and respiratory rate of 20 breaths per minute. He weighs 90.4 kg. Physical exam findings reveal an ill-appearing African American male with dry lips and mucous membrane, lung sounds diminished at posterior bases, and the rest of the exam was unremarkable (Table ).
Chest radiograph demonstrates a left lower lobe infiltrate. Computed tomography of the chest without contrast shows patchy infiltrates involving the bilateral lower lobe. COVID-19 SARS-CoV-2 assay was ordered inpatient. In the ED, further labs were drawn. Droperidol 2.5mg IV once was administered for his headache, however, acute dystonia developed and diphenhydramine 50mg IV was administered with a resolution of symptoms. The patient was admitted with the diagnosis of severe rhabdomyolysis, systemic inflammatory response syndrome, elevated liver function tests, hematuria, and suspected COVID-19 infection.
The patient was aggressively started on IVF with lactate ringer at 200mL per hour after CK level returned severely elevated (the lab was drawn prior to dystonia); strict ins and outs and renal function were monitored closely. Extensive lab testing was performed to rule out potential rhabdomyolysis causes. Epstein-Barr virus (EBV), HIV, cytomegalovirus IgM, toxoplasmosis, and acute hepatitis panel were negative for viral etiology. EBV IgG was positive. Acetaminophen level and urine drug screen were unremarkable. Rheumatological work up including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), anti-Smith, SS-A/SS-B, anti-Jo 1, and gamma-glutamyl transferase (GGT) levels was negative. LDH > 4,000 U/L. CRP and sedimentation rate were elevated. Aldolase elevated 1,224.3 U/L. COVID-19 polymerase chain reaction (PCR) was positive within 24 hours of initial testing. Of note, urine myoglobin level is not reported in this report due to hospital-associated lab errors.
Nephrology and Infectious disease teams were consulted on the day of admission. Transaminitis was concluded to be secondary to rhabdomyolysis as no other acute liver etiologies could be identified. For suspected, early COVID-19 pneumonia (based on chest imaging), he was started on remdesivir 200mg IV on the first day, then remdesivir 100mg IV daily after for four days, for a total five-day course. Per COVID-19 pneumonia guidelines, he received vitamin C 500mg PO daily and zinc 500mg PO daily for five days, in addition to dexamethasone 6mg IV daily for 10 days. He was also started on a five-day course of azithromycin 500mg IV daily and Rocephin 2g IV daily for possible superimposed bacterial pneumonia with the left lower lobe infiltrate and developed symptoms of cough. Due to the elevated risk of thromboembolism with COVID-19, he received deep vein thrombosis (DVT) prophylaxis with enoxaparin 40mg subcutaneous daily during his hospitalization. CPK levels, liver enzymes, and renal function were trended daily (Figures -).
On day 2 of the hospitalization, the patient was requiring fluid management included 1/2 normal saline + bicarbonate at 200 cc/hour. He was maintained on a bicarb drip for the rest of his hospitalization with improvement in his CK level and renal function. No further worsening of respiratory status during his stay and his dyspnea resolved prior to discharge. On day 7, he was discharged home with close follow-up with his primary care provider.


A 35-year-old woman was admitted to Reunion Island University Hospital for an infectious syndrome with febrile dyspnea. Her medical history was mainly a Sharp’s syndrome treated with long-term hydroxychloroquine and corticosteroids. She had not travelled abroad in the past 2 years. On admission, the patient presented with Systemic Inflammatory Response Syndrome (fever 39.7 °C, pulse 120 beats/min, blood pressure 112/66 mmHg, respiratory rate 32 breaths/min, and oxygen saturation in room air 100%). Pulmonary clinical signs were pleuritic pain, dyspnea, dry cough, and crackles. The patient had no extrapulmonary symptoms. Laboratory investigations showed biological inflammatory reaction, with a white blood cell count of 8.6 G/L (neutrophils: 7.65 G/L), lymphopenia (0.54 G/L), anemia (10.2 g/dL), and elevated C-reactive protein (76 mg/dL). On Day 1, an injected chest computed tomography (CT) scan was performed showing left basal pleuropneumonia with pleural effusion, subpleural nodular lesions, and lymphadenopathies. Three doses of spiramycin (3 M IU) were administered and antimicrobial therapy with ceftriaxone (3 g per day) was initiated. The patient was transferred to the Internal Medicine department. On Day 3, her respiratory status and biological inflammatory reaction worsened, with hyperleukocytosis of 15.2 G/L (neutrophils: 14.2 G/L) and elevated C-reactive protein (> 350 mg/dL); however, she presented no signs of septic shock. Urinary antigen tests for L. pneumophilia and Streptococcus pneumoniae were negative. Antimicrobial therapy with spiramycin (3 M IU every 8 h) was reintroduced. The patient was transferred to intensive care unit (ICU). Treatment was changed to triple antimicrobial therapy with piperacillin-tazobactam (16 g per day), spiramycin (3 M IU every 8 h), and amikacin (30 mg per kg). Complementary microbiological investigations performed in ICU on blood, urine, cerebrospinal fluid, and sputum were all negative. Respiratory multiplex PCR assay on nasopharyngeal swab (FTD Respiratory pathogens-21, Fast Track Diagnostics, Luxembourg; not targeting atypical microorganisms) was negative. A control injected chest CT-scan (Day 5) revealed multiple nodular parenchymal lesions in both lobes, as well as increasing multiloculated pleural effusion. On Day 6, the patient’s clinical condition finally improved. She was transferred to the Pneumology department for etiological investigations.
On Day 9, a specific PCR assay (FTD Atypical CAP, Fast Track Diagnostics, Luxembourg and Genesig Advanced Kits, Primerdesign Ltd, UK) on bronchoalveolar lavage (BAL) was positive for Legionella spp. (cycle threshold-Ct-34.35) and negative for L. pneumophila. The BAL culture was positive with typical colonies of Legionella spp. which were identified as L. sainthelensi or L. santicrucis using MALDI-TOF Biotyper (Bruker Daltonics, Bremen, Germany). A second control CT-scan performed on Day 10 showed the persistence of multiloculated pleural effusion and the appearance of bronchopleural fistula in the left lower lobe (Fig. a and b). Pleural fluid collected on Day 5 was retrospectively reanalyzed and tested positive for Legionella spp. (Ct 28.40). Biochemical analyses of pleural fluid showed parapneumonic pleural effusion with excudate (total protein: 49 g/L; LDH: 1156 IU/L; pH: 7.3 and glucose 2.1 mmol/L).
The French National Reference Center for Legionella confirmed the identification of L. sainthelensi by MIP sequencing []. Raw reads from whole-genome sequencing using Nextera XT technology (Illumina, ) were deposited into the European Nucleotide Archive (study Accession No. PRJEB40106).
Minimum inhibitory concentrations (MICs) determined using the broth microdilution method were similar to those reported for wild-type L. pneumophila strains (0.032 mg/L for moxifloxacin, 0.016 mg/L for levofloxacin, 0.063 mg/L for erythromycin and azithromycin, and 0.001 mg/L for rifampicin) [].
Three weeks after admission, the patient’s general health improved and she was sent home.


A 49-year-old female patient complained of fever and headache for 32 day was hospitalized in the Department of Infectious Diseases of Guangzhou Panyu Central Hospital, Guangdong, China, on October 29th, 2020. She had lived for one and a half years in Los Angeles, USA and just returned to China 2 days before. While living in the United States, she traveled around Los Angeles and trimmed plants for several times in the garden.
The symptoms included a sudden onset of fever (39 °C), severe headache, and rash on her face and back while she was in Los Angeles on September 27th. The patient went to local hospitals several times, but computed tomography (CT) showed no abnormities on her head. She received symptomatic treatments, but had not fully recovered.
When admitted to our hospital, the patient was with headaches, fevers, vomiting, and maculopapular rashes (1.5 cm × 1.5 cm) on the face and back. Her white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were slightly higher than the normal range, but her electrolytes was slightly lower. CT examinations revealed small nodules in the posterior apex of her left upper lobe and lateral segment of middle lobe of right lung, but no abnormalities in head.
The empiric combinatory therapy (ceftriaxone sodium 2 g daily and acyclovir 0.5 g q8h) for both viral and bacterial meningitis was given. A lumbar puncture was performed on day 34. The CSF opening pressure was greater than 400 mmH2O. CSF analysis demonstrated positive pandy test and negative cryptococcal antigen, gene Xpert MTB/RIF assay, and culture result (Fig. ). Drug dehydration and other symptomatic treatments were added. But there was no relief of the symptoms.
A lumbar puncture was repeated on the 39th day (Fig. ). Autoimmune encephalitis spectrum results were positive of the anti-MOG-IgG antibodies for the serum and the CSF (1:32 and 1:3.2, respectively). To further identify the pathogen, PACEseq mNGS (Hugobiotech, Beijing, China) of CSF and blood was performed on a Nextseq 550 platform (Illumina, California, USA). A total of 308 unique sequence reads were finally aligned to the C. posadasii genome in CSF, which showed a dominant abundance of 2.32% in all microbial species after excluding the human reads from the total gene pool (Fig. ). The blood mNGS showed negative of the pathogen. A targeted PCR of C. posadasii and Sanger sequencing were subsequently applied, which finally confirmed the mNGS detection of CSF (Fig. ). In addition, the tissue biopsy of the patient’s back rash indicated HE Stain, PAS stain (+), and hexamine silver stain (+) (Fig. ), which were also in line with coccidioidomycosis. Considering the abnormal signals in the bilateral parieto-occipital lobes and the meninges by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), the patient was finally diagnosed with C. posadasii infected meningitis.
The treatment was adjusted with fluconazole (800 mg intravenously daily) and ceftriaxone (4 g q24h). Other symptomatic treatments were also performed, such as mannitol (125 ml intravenously q8h) to reduce intracranial hypertension. The detailed treatments were shown in Fig. .
The patient gradually recovered over the next 7 days. The body temperature returned to normal, and the headache and dizziness relieved. Repeated lumbar puncture revealed the pressure at 200 mmH2O (Fig. ). The patient's vital signs were stable. The patient was then transmitted to Third Affiliated Hospital of Sun Yat-Sen University for antifungal treatment with altericin B combined fluconazole. One month later, the patient’s symptoms improved and was finally discharged. She was required oral fluconazole. On February 2021, reexamine of the patient found high blood fat with intrajugular venous thrombosis and head sinus. The patient was given levarabban, oral anticoagulant therapy, fluvastatin, and oral calcium supplements. After 3-month follow-up, her headache aggravated with a increase intracranial pressure. The patient then received dehydration treatments.


The patient was a 60-year-old Asian man. On April 14, 2014, the patient presented with sudden lower abdominal pain, vomiting, anal exhaustion, and poor defecation, without any apparent cause. He had no history of type 2 diabetes, hypertension, or other relevant past illnesses. A plain film of the abdomen showed incomplete intestinal obstruction. Colonoscopy revealed a right transverse colon neoplasm. Palliative resection surgery for transverse colon cancer was performed in May 2014. Immunohistochemical analysis revealed positive expression of CEA, CK19, CK20, villin, p53, and Ki67, and negative expression of HER-2, CgA, and Syn. Following these findings, a pathological diagnosis of moderate to poorly differentiated stage IV adenocarcinoma of the right transverse colon was made. On June 3, 2014, postoperative chest and abdominal computed tomography (CT) showed that the anastomotic wall of the residual colon cancer was slightly thicker, with a 2-cm superior mass (diameter of 2 cm) invading the duodenum. As first-line treatment, 15 cycles of mFOLFOX6 chemotherapy (d1: oxaliplatin 130 mg, leucovorin 600 mg, fluorouracil 600 mg iv, fluorouracil 1800 mg; d1–2 civ23h q2w) were administered between June 4, 2014, and December 27, 2014. The patient was followed up regularly until the disease was stable. A repeat chest and abdominal CT performed on November 21, 2015, showed an enlargement of the lesion above the anastomosis. Three cycles of mFOLFOX6 chemotherapy regimen were administered between December 16, 2015, and February 24, 2016. On March 25, 2016, CT revealed increased and enlarged lung nodules, suggestive of lung metastasis – this was considered as disease progression. Therefore, second-line treatment using FOLFIRI chemotherapy regimen (d1: irinotecan 280 mg, leucovorin 600 mg, fluorouracil 600 mg iv, fluorouracil 1800 mg; d1–2: civ23h q2w) was administered in 8 cycles between March 29, 2016, and November 28, 2016. On December 26, 2016, CT revealed enlarged lung metastatic nodules (compared to the previous CT findings) and new lung metastases (Fig. A, F). During second-line therapy, the patient became very thin. Following disease progression, third-line treatment with oral donafenib (300 mg bid) was administered continuously between December 28, 2016, and August 8, 2017. A repeat CT was performed on February 21, 2017 (Fig. B, G), April 18, 2017 (Fig. C, H), June 14, 2017 (Fig. D, I), and August 8, 2017 (Fig. E, J): gradual shrinkage of the lung metastatic nodules with some of them forming cavities was observed. The diameter of the peritoneal mass also decreased while showing signs of liquefaction and necrosis. This was considered as PR. The imaging effect evaluation was performed using the Response Evaluation Criteria in Solid Tumors version 1.1.[ Evaluation of all adverse events was based on the Common Terminology Criteria for Adverse Events version 5.0.[ On August 28, 2017, the patient developed constipation (degree II) and decreased appetite. Therefore, donafenib was discontinued. The patient experienced adverse events of donafenib such as bone marrow suppression (grade II reduction in white blood cells and grade I reduction in platelets), diarrhea (grade II), and low serum potassium ion concentration (degree II). However, he did not develop severe side effects (grade III or higher). The patient died on March 26, 2018. The efficacy of donafenib as a third-line treatment was PR, and progression-free survival was at least 8 months.


A 46-year-old African American woman presented with a 1.5 x 1.2-centimeter painless cyst on her scalp. The patient reported having had the cyst for many years and mentioned that the cyst would undergo fluctuations in size, enlarging and shrinking intermittently. The epidermis overlying the cyst was unremarkable: no hyperpigmentation, induration, or necrosis was observed. The patient recalled no history of trauma to the lesion.
The patient has no history of any malignancies. Family history is negative for MPTT. She has diabetes mellitus, hypercholesterolemia, and hypertension, managed with metformin, simvastatin, and lisinopril, respectively. She denies any tobacco or alcohol use. The patient had undergone a hysterectomy and a patent foramen ovale closure.
She desired surgical excision of the cyst because she felt it to be a minor nuisance. No picture was taken of the cyst prior to surgical resection as there was no clinical suspicion for an MPTT. A simple surgical excision was performed that was flush with the margins of the cyst. Histopathological examination of the biopsy revealed epithelial nests with abrupt keratinization characteristic of trichilemmal epithelium. Tumor necrosis, anaplastic and pleomorphic cells, and increased mitotic figures were also observed, consistent with a diagnosis of MPTT. Margins were positive for atypia (Figures -).
IHC studies were also performed. The tumor was negative for a cluster of differentiation (CD) 34 (only blood vessels stained with CD34, serving as positive internal controls). Staining with p53, a proliferation marker, was strongly positive. Additionally, pronounced cytokeratin 17 (CK 17) expression was observed, although CK 7 expression was not detected (Figures -).
Following the histopathological diagnosis, the patient was referred to Mohs surgery for resection of a wider margin to remove any malignant tissue that may have been missed in the initial resection. A head and neck computed tomography was performed and was normal. For the next two years, we will follow-up with the patient every three months to inspect her scalp, neck, and lymph nodes; if no lesions appear within the next two years, we will monitor the patient every six months for three years, after which we plan to perform annual check-ups.


A 52-year-old Caucasian male presented to the outside facility emergency department following a syncopal episode and dysthymia. On arrival his vital signs were within normal limits. No leukocytosis. Chest radiograph and unenhanced CT brain were normal. CT abdomen and pelvis with contrast was performed which showed infrarenal abdominal aortic aneurysm measuring 8.9 × 10.3 cm ().
Additionally, on retrospect, the loop of jejunum appeared adherent to aneurysm sac, with ectopic air within the partially thrombosed aneurysm sac tracking to and in continuity with intraluminal bowel gas. Findings compatible with primary aortoenteric fistula ().
Patient underwent endovascular aortobiiliac stent graft placement on the same day at outside facility (). Fluoroscopy imaging demonstrate no evidence of endoleak and appropriate position of the aortobiiliac stent.
Five days following the procedure patient reported bright red blood per rectum with stable vitals and hematocrit. CT angiogram of the abdomen and pelvis was performed which showed normal positioning of aortobiiliac stent graft and no evidence of endoleak. The size of the excluded aneurysmal sac was stable from prior exam. There was interval worsening of ectopic air within the excluded aneurysmal sac. Findings were compatible with known aortoenteric fistula ().
Additionally, prior to transfer at our facility, CT abdomen and pelvis without intravenous contrast was performed which showed enteric contrast into the excluded aneurysmal sac, confirming known aortoenteric fistula ().
Patient was transferred to our facility for further management. Patient underwent resection of abdominal aortic aneurysm with a right axillary to bifemoral bypass utilizing bifurcated ringed Polytetrafluoroethylene, .


A 34-year-old male patient was evaluated by our laboratory on June 14, 2021 because reporting symptoms of anosmia, ageusia coupled with cacosmia, referred to a burnt and musty smell; he also reports mild dyspnea, muscle fatigue, and tiredness. The patient clinically appears to be healthy and not currently taking any medication; vital signs and physical examination were as follows: blood pressure max 125.8 mmHg ± 2.89 SD and min 76.6 mmHg ± 3.27 SD; pulse rate 63.1 times/min ± 1.85 SD; respiratory rate 16 times/min ± 1.49 SD; temperature 36.35℃ ± 0.05 SD; and SpO2 97.8% ± 0.63 SD on room air. Chest x-ray showed bilateral apical opacities on the lungs and brain CT scan showed no alterations. Laboratory tests and blood gas analysis do not reveal any abnormalities.
The patient has a complete health history and is a military doctor who was deployed to Codogno (Milan, Italy) for the first COVID-19 emergency in March 2020 and was infected with SARS-CoV-2. Following symptoms of anosmia, ageusia, fever, severe asthenia, muscle pain, disorientation, mild amnesia, and dyspnea, the patient underwent a molecular swab test on April 4, 2020, which was positive. The patient remained positive for approximately 30 days and the first negative swab was on May 5, 2020.
A preliminary OST test (validated in COVID-19 by Mazzatenta et al., ) was carried out and the results are shown in Figure . The OST test is useful for preliminary fast screening of the olfactory function and it works based on four disposable items based on Connecticut Chemosensory Clinical Research Center (C.C.C.R.C.) threshold test (Cain et al., ) and Italian population age phenotype threshold test (Mazzatenta et al., ). The OST test consists of a logarithmic scale of increasing concentrations of n-butanol. The test involves answering “YES” or “NO” to the presentation of three coloured ampoules in the following order green, yellow and red indicating the three increasing concentrations of n-butanol, and a white odourless ampoule which is the negative control test presented preliminarily. The affirmative answer to the green vial is considered normosmia, i.e. the subject has a normal olfactory threshold value; if the answer is negative, the subject moves on to the next colour. The affirmative answer to the yellow vial corresponds to an evaluation of hyposmia, i.e. an alteration of the olfactory threshold, if the answer is negative, the subject moves on to the red vial. If it answers positively it is severe hyposmia, that is an important alteration of the olfactory threshold, if it answers “NO” then it corresponds to an evaluation of the olfactory threshold of anosmia (Mazzatenta et al., ).
In Figure , the results of the olfactory threshold investigated using a modified Cain test (Cain, ; Cain et al., ) coupled with electrophysiological recordings are shown. OERPs are an international validated electrophysiological technique for the study of the olfactory system (Lötsch & Hummel, ). This assessment is an objective method to observe changes in olfactory function independent from patients’ response bias. The presence of OERP is a robust indicator of a healthy olfactory function; conversely, the absence of OERP suggests an olfactory loss (Lötsch & Hummel, ). Because, the transmission of olfactory sensory input travels from the olfactory neuroepithelium located into the nasal cavities toward the olfactory bulbs through the first cranial nerves, which here makes contact with the second-order neurons the mitral and tufted cells within glomeruli. From here, the postsynaptic fibers that form the olfactory tracts project to the primary olfactory areas, which comprise the anterior olfactory nucleus, tenia tecta, olfactory tubercle, piriform cortex, amygdale, anterior cortical amygdaloid nucleus, periamygdaloid, and entorhinal cortices. The piriform cortex is connected to thalamus, hypothalamus, and orbitofrontal cortex, and the entorhinal cortex is connected to hippocampus. The thalamus has connections toward secondary olfactory areas, as the OFC and insular cortex (Giessel & Datta, ). Consequently, OERPs are the result of sequential activation of different brain areas that begins from periphery and involves a number of brain areas. Typically, OERPs consist of a negative component, the N1, followed by two positive components, P2 and P3. The early components reflect the exogenous cortical activity related to sensory input detection and primary sensory processing, while the later OERP components reflect endogenous cortical activity related to secondary cognitive processing (Lötsch & Hummel, ). Latency (range from 530 to 800 ms after stimulus onset), amplitude (approximately between 4 and 20 µv), and shape are the main parameters of OERP components (Lötsch & Hummel, ). OERPs are the results of a grand average of 10 stimulations, recorded by a EEG power lab equipment's (AD-Instruments) following standard procedure (Invitto & Mazzatenta, ; Lötsch & Hummel, ; Tateyama et al., ; Wang, Chen, et al., ; Wang, Hari, et al., ) and are only detectable in the periphery at high concentrations (Figure ). Exhaled VOCs’ response to exponential growing concentration of n-butanol was recorded by the ORT-VOC test using an e-nose (iAQ-2000; Applied Sensor), (Cain, , Cain et al., ). The ORT-VOC test is based on the changes in metabolites exhaled during sensory stimulation compared to the unstimulated basal recording (Mazzatenta, Pokorski, & Di Giulio, ; Mazzatenta, Pokorski, Montinaro, et al., ; Mazzatenta, Pokorski, Sartucci, et al., ; Mazzatenta et al., ). The ORT-VOC test results in a slightly significant response at the highest concentration of n-butanol (OT9) (Figure ). Convergent results point to a diagnosis of quantitative anosmia.
Furthermore, olfactometric investigations were the evaluation of olfacto/olfactive, olfacto/trigeminal, and olfacto/gustatory responses with electrophysiological recordings (Figure ). OERPs for the three stimulations are only present peripherally (Figure ). No significant change for the three stimulations is for the exhaled VOCs compared to the unstimulated baseline (Figure ).
Convergent results point to a diagnosis of qualitative anosmia.
Finally, taste stimulation with suprathreshold 0.5 g/mL of sucrose, and 0.5 g/mL of sodium chloride, 0.5% of citric acid, and quinine provided a positive response.


A 57-year-old male presented to the ER with odynophagia and excessive drooling after swallowing a clove of garlic earlier that day. The patient denied any shortness of breath on presentation. He also denied any previous episodes of food impaction, dysphagia, or odynophagia. There was no prior history of upper GI endoscopy and no family history of any GI disorders. His past medical history was insignificant apart from hypertension and cervical spondylopathy status post-anterior cervical plating. The patient was hemodynamically stable with blood pressure (BP) of 139/79 mmHg, heart rate (HR) of 91 beats per minute, temperature (T) of 98 °C, and respiratory rate (RR) of 16 breaths per minute. On examination, the patient appeared to be in acute distress with an otherwise unremarkable exam. An X-ray of the neck was done in the ER, which showed mild distension of the proximal esophagus and some hypodense material in the lumen at the C6-C7 level, which could represent impacted food material (Figure ). No radiopaque foreign body was reported, and the patient was urgently referred to the gastroenterology department. On emergent esophagogastroduodenoscopy (EGD) under general anesthesia with the airway protected by intubation, food bolus impaction was identified in the upper esophagus 15 cm from the incisors (Figure ). The performing physician tried to dislodge it using standardized procedures including push technique, grasping forceps, and polypectomy snares, but due to the large size of the foreign body, those efforts were unsuccessful. We had a discussion as to whether an ENT consult would be appropriate or not, and our team concluded that since the patient was stable, breathing comfortably on room air, and as the foreign body was in the esophagus, this consult would not change the management plan. Therefore, the procedure was then deferred and a repeat EGD was planned for the next day.
On repeat EGD under general anesthesia with intubation, which was conducted less than 12 hours from the presentation, the foreign body was seen lodged at the level of the upper esophageal sphincter (UES). Initially, a cap was attached to the end of the scope, but it could not be dislodged. Rat-tooth forceps (13 mm) were then used to grasp the food bolus with no success. Next, a Boston Scientific Hydra Jagwire™ (Boston Scientific, Marlborough, MA) was maneuvered alongside the bolus into the distal esophagus. A biliary balloon catheter was inserted into the guidewire and inflated, and the catheter was dragged up, dislodging the food bolus into the oropharynx (Figure ). Using a large polypectomy snare, the food bolus was grasped and removed intact (Figures , ). No fluoroscopy was used during the procedure. After the successful removal of the foreign body, the scope was reinserted to reexamine the oropharynx and the upper esophagus with washing and suctioning. A mild stricture and significant erythema were noted at the UES. No mucosal disruption, tears, or perforation was noted. After the procedure, the patient was stable and tolerating a soft diet, and hence he was discharged home. A follow-up EGD was done four weeks later and showed a normal-appearing esophagus, with the resolution of erythema and inflammation. The patient was advised to transition to an advance diet as tolerated after the follow-up visit.


Patient NRF178 was a 14 years old female, competitive athlete (swimming) with 6 years of active sport experience. She had no general health complaints, no history of syncope, no family history of SCD, and she exhibited good exercise tolerance. She was recommended to undergo genetic counseling and testing after an annual cardiac examination.
While resting, her ECG showed a sinus rhythm, heart rate of 61 beats/min, QT interval of up to 480–500 ms, and QTc interval of 495 ms. In response to standing up, her ECG showed a sinus rhythm, heart rate of 72 beats/min, QT interval of up to 480 ms, and QTc interval of 535 ms (). One month after reduction in training intensity, her ECG showed a sinus rhythm, heart rate of 46 beats/min (bradycardia), with a QT interval of 473 ms, in response to standing up. During the exercise test, at the 4th minute of recovery, the ECG showed a QTc interval of 495 ms. Schwartz’s score was 4.5 points, and the patient was suspected to have LQTS. To confirm this diagnosis, the patient was sent for genetic consultation and subsequent DNA testing.


This is a 60-year-old male patient, with hypertension and diabetes mellitus under treatment. He underwent heart transplantation on 2017 in Spain, and currently under immunosuppressors: Tacrolimus 1mg and Mycophenolate mofetil 0.5mg, twice daily.
He reported a recent trip to Spain two weeks before the symptoms for a check-up with his doctors, but had no contact with any known-SARS-CoV-2 infected individuals.
The patient had a history of fever, runny nose, sore throat and dry cough evolving for 8 days prior to his admission. His evolution worsened and he developed dyspnea and chest pain, motivating his visit to the emergency room.
Clinically, the patient was conscious, hemodynamically stable, with an oxygen saturation of 78% in ambient air; 96% under 15L oxygen with a high concentration mask. He also had a normal body temperature.
Biologically, he had a lymphocytopenia at 220 elements/m3, a normal troponin level of 17 ng/mL, with positive inflammation markers: C-reactive protein level at 106 mg/L, Ferritin level 679 mg/L; fibrinogen level at 8.7 mg/L, Lactic dehydrogenase (LDH) level at 370 mg/L. A SARS-CoV-2 reverse transcriptase PCR was performed and came back positive.
Arterial blood gas was performed and showed a hypoxemia with a PaO2 at 41 mmHg.
He also benefitted from a thoracic CT-scan with an extent of pulmonary damage of 75%, and a cardiac evaluation with a normal transthoracic echocardiography.
A non-invasive ventilation based on High Flow Nasal Cannula (HFNC) was started at the 2end day of his admission; the immunosuppressors were discontinued and he was put under: Azithromycin, Vitamin C 2g/day, Zinc 45mg/day, Enoxaparin 0.6UI/12h, Dexamethasone 6mg/day; Aspirin 160mg/day and antibiotics: 3rd generation Cephalosporins 2g/day and quinolones (Ciprofloxacin 200mg/12h). He also received two doses of Tocilizumab (400mg with a 10 day interval).
His antibiotics were changed to Piperacillin-Tazobactam 4g/8h, Amikacin 1,5g/day and Voriconazole 200mg/12h when nosocomial infection was confirmed by culture.
The patient unfortunately presented complications, such as acute respiratory distress syndrome in the 3 erd day of admission, and was intubated and put under intensive mechanical ventilation. The progression of the disease was very fast for his case He presented a multi-organ failure (acute kidney injury and disseminated intravascular coagulation) and a refractory septic shock in 2end days after intubation, that resulted in his death at one week of his admission.


The patient was a 69-year-old female with a past medical history of atrial fibrillation, hypertension, hyperlipidemia, and hypothyroidism. She denied any family history of neurovascular disease, AVM, or aneurysm. A right cerebellar hemispheric AVM was discovered incidentally during workup for dizziness. She had undergone neurologic work-up for intermittent vertigo 2 years before the admission, which in turn had resulted in the discovery, on brain MRI, of a right cerebellar hemispheric lesion, thought to represent a cavernous malformation (CM). At that time, she did not have any complaints of headache, motor or sensory disturbances, or loss of bladder or bowel control. Her neurologic evaluation was intact. Thus, she was being followed up by brain MRI and neurologic examination annually. The repeat MRI brain during her second year of follow up was interpreted as demonstrating an AVM rather than a CM, and she was scheduled for cerebral angiography to confirm the diagnosis.
Angiography revealed a 2.5 cm pial AVM in the superomedial right cerebellar hemisphere, abutting the tentorium. The AVM was supplied primarily through branches of a hypertrophied right superior cerebellar artery (SCA), with lesser arterial supply provided by distal branches of the right posterior inferior cerebellar artery (PICA) (). A single short superficial cerebellar vein drained the AVM into a right cerebellar tentorial vein, and then into the right transverse sinus. Two small nidal aneurysms were also identified, the largest of which measured 1.8 mm in maximal dimension. Magnetic Resonance T2 gradient echo imaging demonstrated small foci of susceptibility in the region of the AVM, presumably reflecting small areas of chronic hemosiderin deposition, but there was no evidence of recent hemorrhage. The vertebral arteries were relatively co-dominant.
After neurosurgical consultation, surgical resection of the AVM was recommended, and pre-surgical embolization was requested to minimize the risk of intraoperative bleeding.
Embolization was performed under general anesthesia. Blood pressure, heart rate, and oxygen saturation were monitored intra-procedurally. The mean arterial pressure (MAP) averaged 94.5 mmHg (range 76–117 mmHg) and no hypoxia or hypotension occurred throughout the procedure. Using ultrasound guidance, a five French shuttle guide sheath was placed into the right common femoral artery. Heparin was administered intravenously with intermittent bolus administration to maintain therapeutic anticoagulation. Activated Clotting Time was monitored, with an average value of 201 and a baseline of 135.
The sheath was advanced over a four French angled vertebral catheter into the proximal cervical left vertebral artery (VA). As noted on the diagnostic angiogram, the left VA had a variant origin, arising directly from the aortic arch, and was chosen for access due to marked tortuosity at the origin of the right VA. Five micrograms of intra-arterial verapamil was administered to prevent vasospasm, and the five French guide sheath was advanced to the mid-cervical left VA, beyond the origin of the artery of cervical enlargement, which was visualized on roadmap digital subtraction angiograms (DSA). The vertebral catheter was removed and DSA was performed through the sheath. There was good flow around the five French sheath without evidence of any contrast stagnation to suggest flow compromise or occlusion of the VA (). The AVM was unchanged compared to the angiogram 2 months earlier.
Next, a Phenom Plus delivery catheter and Apollo microcatheter were advanced coaxially over a microwire through the five French sheath, with the Phenom Plus catheter terminating in the distal cervical left VA. An Apollo microcatheter was first taken distally into the dominant SCA branch supplying the AVM, and Onyx 34 was used to embolize a portion of the AVM nidus. The Apollo microcatheter was slowly removed, and the tip detached, remaining in the right SCA. Next, a new Apollo microcatheter was taken into a second SCA branch supplying the AVM, and additional Onyx was administered. This microcatheter was removed, without tip detachment. Finally, an SL-10 microcatheter was advanced into an inferior branch of the right SCA supplying the AVM, and a small amount of Onyx was administered before removing the microcatheter.
The remaining branches of the right SCA supplying the AVM were not easily catheterized. Embolization had resulted in an approximately 50% reduction in the size of the AVM nidus, so a decision was made to terminate the exam. Post-embolization intracranial and cervical angiography demonstrated patency of the arteries of the posterior circulation and the extracranial and intracranial segments of the left VA. The artery of cervical enlargement and the ASA remained patent at completion of the procedure. The sheath was removed, and hemostasis achieved. A Cone beam CT demonstrated expected post-procedural changes.
The patient was extubated and transferred to the intensive care unit. She was slow to awaken from general anesthesia, but was oriented, following commands, and moving all extremities antigravity immediately post-extubation.
On evaluation 3 h post-procedure, she was sleepy but easily aroused by voice, and could follow simple commands. Her neurologic examination at that time was intact. Additionally, she had bilateral upper extremity strength of at least 4/5 and intact light touch sensation throughout. Over the next 2 h, her condition mostly remained unchanged, with mild weakness of bilateral upper extremities on examination that was suspected to be limited by the element of effort and of position, given otherwise normal findings. She was reported to have general weakness at approximately 8 h after the procedure. Her situation did not improve after 2 h and required a repeat of examination and further evaluation.
Her examination, approximately 10 h post-embolization, revealed strength of 3–4/5 in both upper extremities. Her lower extremities strength remained 5/5, with normal pinprick and vibration sensory exam throughout. Her vital signs were within normal limits and stable, and her examination was otherwise unremarkable. However, concern for ischemia prompted a Magnetic Resonance Imaging (MRI) brain, which suggested diffusion restriction in the upper cervical spinal cord, although this was sub-optimally evaluated due to motion artifact. A cervical spine MRI was obtained next and demonstrated T2/STIR hyperintense signal at the C1 level, corresponding to the region of restricted diffusion reported on MRI of the brain, raising suspicion for possible cord infarction. The patient's upper extremity weakness continued to progress over the subsequent 8 h despite maintaining MAP >75 mmHg, and stable vital signs, and she developed new intermittent lower extremity weakness, but light touch sensation remained intact in all extremities. Clinical examination at this point was consistent with acute SCI. A second cervical MRI revealed more extensive abnormal signal centered at the C2 and C3 levels with associated cord expansion. Additionally, new signal abnormality had developed at the C5–C6 level, without associated cord expansion (). Her limb weakness continued to progress. On evaluation 1 day post-procedure, she had a strength of 1/5 and 2/5 in proximal and distal muscle groups of both upper extremities, respectively, with a strength of 2/5 in both lower extremities. Pinprick and temperature sensation were decreased at the approximate level of C2–C4 throughout the lateral torso and both upper extremities, while vibration and proprioception remained intact in all extremities. These findings reinforced the diagnosis of acute SCI. demonstrates the timeline of the events within 24 h after the procedure. A second brain MRIat this time showed evidence of T2/FLAIR hyperintense signal and increased diffusion restriction in the right cerebellar hemisphere at the site of Onyx embolization. As a result of the SCI, she developed hypercapnic respiratory failure requiring urgent endotracheal intubation and mechanical ventilation. She eventually required tracheostomy placement for anticipated prolonged ventilator weaning along with percutaneous gastrostomy placement. She was successfully weaned off the ventilator and resumed oral intake by 3 weeks, and underwent acute inpatient rehabilitation for a total 4 months, and is now residing at home with significant assistance.


A 56-year-old man with no past medical history was referred to the Oral Medicine and Oral Surgery department at the university clinic of dental medicine, Monastir, Tunisia, with the chief complaint of a painless swelling in the left buccal mucosa for about 5 years. The patient had neither known drug allergies nor history of surgery and/or trauma related to the lesion area.
Extraoral examination revealed the presence of a solitary swelling in the left cheek covered by normal looking skin in color and texture, as well. The swelling was nontender and freely mobile to the skin, on palpation. No submental nor submandibular lymphadenopathy was detected (Figure ).
Intraoral examination showed a poor oral hygiene and a nodule in the left buccal mucosa covered by a healthy mucosa. The mass was soft and non-mobile on palpation (Figure ).
Due to these clinical findings, the initial diagnosis was benign tumor of either the oral mucosa (including vascular lesions) or the salivary gland.
An ultrasonography was required. It revealed a well-defined walled hyperechoic heterogenous lesion measuring 34 × 31 × 21 mm with posterior ultrasound reinforcement in the left buccal mucosa. Vascular lesions were excluded on Color Doppler analysis. At this stage, the diagnosis of epidermoid cyst of the left buccal mucosa was evoked (Figure ).
Under local anesthesia and with intraoral access, the lesion was completely removed. An horizontal incision in the buccal mucosa was conducted exposing a cyst immediately underlying the mucosa. The enucleation was carefully done. Accidentally, when a partial rupture of the wall was happened, a yellow liquid was observed (Figure ). The surgical wound was closed using a 4.0 silk suture, and the specimen was stored in 10% formol for further anatomopathological study (Figure ). The postoperative period was uneventful and healing was good.
Histopathological examination of the surgical specimen revealed a cystic cavity. The cyst wall is composed of keratinized stratified squamous epithelium with keratin debris and no skin appendages (Figure ). This wall contains a foreign-body giant-cell reaction (Figure ).
These findings were suggestive of epidermoid cyst.
The outcome was favorable after 1 year of follow-up. No evidence of recurrence was recorded.


A 34-year-old male presented with persistent pain in the upper abdomen was admitted to our hospital on June 14, 2019. He had no back pain, vomiting, jaundice, weight loss, loss of appetite. He had a history of splenectomy because of a traffic accident and appendectomy because of appendicitis. He had no history of diabetes, chronic pancreatitis, obesity, and no family history of cancer. He had a long history of heavy smoking (approximately 24 years*15 cigarettes/day) and alcohol consumption (approximately 22 years*100g/day). Physical examination revealed multiple palpable left axillary lymph nodes with 2cm*2cm in maximal size.
Abdominal contrast-enhanced CT scan revealed a 10.0*4.3-cm mass on the pancreatic body and tail with blurred borders with bilateral adrenal multiple metastases and multiple swollen lymph nodes in the mediastinum, left axilla, abdominal cavity, retroperitoneum and mesentery (). There are no definite masses in either lung. His serum CA 19-9 level was elevated at 219.6 U/mL (normal <33 U/mL).
Left axillary lymph node biopsy was performed on July 3, 2019 and the pathological examination revealed poorly differentiated adenocarcinoma infiltration in fibrous tissue. Immunohistochemical (IHC) staining indicated that the cells were positive for CA19-9, CK18, CK19, CK7, AE1/AE3, MUC5AC, and negative for CDX-2, CK20 and MUC6. Ki-67 showed a 10% proliferative rate. For the sake of reducing patients’ damage, we have not obtained the results of the patient’s primary tumor through puncture and other methods. However, the patient had upper abdominal pain, a mass in the pancreatic area with swelling of peripheral lymph nodes on imaging, and low enhancement with uneven enhancement on enhanced CT, which were consistent with the manifestations of pancreatic cancer. The puncture pathological section of the patient’s lymph node metastasis showed adenocarcinoma. The results of immunohistochemical marker detection and the elevation of tumor markers CEA and CA19-9 all indicate that the tumor originated from the digestive system. Based on the above information, the tumor is in line with pancreatic cancer.
First-line chemotherapy with XELOXIRI (irinotecan 260mg d1, oxaliplatin 140mg d2, and capecitabine 1.0g in the morning and 1.5g in the evening po. d1-d7)every two weeks was administered from July 5, 2019. The toxicities were acceptable. However, after 3 cycles of treatment, CT performed on August 15, 2019 showed that the primary tumor and metastases enlarged significantly (). His serum CA 19-9 level was also elevated at 477.8 U/ml. Then, second-line chemotherapy with nab-paclitaxel 200mg d1 & d8 and gemcitabine 1600mg d1 & d8 every three weeks was administered for 2 cycles from August 22, 2019, the patient developed grade 1 alopecia (according to NCI-CTC v.5.0). However, the symptoms of abdominal pain worsened and the tumors progressed significantly (CT scan on October 8, 2019, ) and serum CA19-9 increased slightly to 449.90 u/ml.
Subsequently, next-generation sequencing (NGS) (panel of 520 cancer-related genes) was performed on the tumor tissue from left axillary lymph node. There were no mutations in EGFR, KRAS, BRAF. The tumor mutation burden (TMB) was 0.8 mutations/Mb and microsatellite status were stable (MSS). However, primary/reciprocal ALK fusion (EML4(exon 6)–ALK (exon 20)/ALK (exon 20)-EML4(exon 17)) was detected. Other genetic changes include ARID1B (c.821_823delCCG, 5.34%) and KEAP1(c.425C>T, 8.40%). ALK fusion was further confirmed by Fluorescence in situ hybridization test (FISH) and immunohistochemistry (IHC) ( A H&E; B IHC; C FISH; D NGS).
Since October 14, 2019, the patient received 250mg of crizotinib twice daily. Apparent clinical remission was achieved. The palpable left axillary lymph nodes shrank quickly after 3 days of treatment. The patient’s abdominal pain disappeared and CT showed the tumor shrank significantly after 1 month (). The adverse event was grade 1 diarrhea. The treatment lasted for 8 months. On June, 2020, the patient complained of headache, decreased vision in the left eye and disturbance of balance in the left limb, CT and MRI on June 22, 2020 showed a progression in brain metastasis (). Interestingly, the extracranial lesions () and serum CA19-9 remained durable responses. Then, Alectinib 600mg twice a day was administered from 23 June, 2020. The above symptoms relieved rapidly and no adverse events occurred during the treatment. The brain lesions shrank significantly (MRI scan on August 14, 2020, ). However, after continuing the treatment for nearly 10 months, on April 13, 2021, the patient’s reexamination of the brain MRI showed that the right cerebellum () and left frontal lobe lesions increased in size. The brain metastases were progressing, but the extracranial lesions were still stable (). The patient underwent a circulating tumor DNA (ctDNA) test on April 26, 2021. As a result, 10 gene mutations were found: AMER1 p.S794*, ATR p.E2626*, CCND2 p.A109D, CHEK1 p.S193Y, CREBBP p.S1599R, ERCC4 p.T660K, IL7R p.H279N, MRE11A p.A147D, SETD2 p.R87M, SETD2 p.M1080_E1081delinsI*, ctDNA testing has not yet prompted the basis for medication. Therefore, on the basis of continuing the application of alectinib, the patient received brain radiotherapy from June 1 to July 3, 2021. In the latest examination, brain lesions () and other parts () of the disease are stable, and the patient is currently being treated with alectinib.
The patient’s treatment process and changes in tumor markers are shown in , , respectively. Due to COVID-19 epidemic, the patient’s tumor markers from January 2020 to November 2020 haven’t been successfully collected.


The proband is a 35-year-old male with a 10-year history of sprains and muscle ruptures. He reported six left knee sprains since the age of 17 and two ruptures of the right rectus femoris muscle at the age of 29 and 30, respectively. The patient did not mention any strenuous activity that could explain the ruptures. Given the presence of weakness and discomfort in the shoulder girdle, an ultrasonography of the left superior arm was performed, showing calcifications of the tendon of the supraspinatus muscle.
At the age of 31, the patient reported a rupture of the right biceps femoris muscle that occurred in the attempt to dismount his motorcycle. These episodes were followed by a series of spontaneous muscle ruptures of the right biceps femoris and other muscles not related to any exertion.
At the age of 30, the patient started complaining about generalized muscle pain and progressive hyposthenia in his proximal lower limbs. The x-ray of the hip bones was normal. The neurological examination and the electrophysiological studies of the limbs were negative. A spinal MRI revealed several disc herniations for which the patient had undergone surgery, without pain relief. Since the muscular pain was invalidating, an opioid therapy was started leading to partial remission.
Due to the lack of an underlying diagnosis, even after a series of clinical evaluations, the patient came to our attention.
On physical examination, the proband was slender and considerably taller than his parents (185 cm vs. 160 cm of the mother and 161 cm of the father). He reported a growing spurt at the age of 16, with a gain of 22 cm in 1 year (from 160 to 182 cm of height). Other findings were pectus excavatum, arm span of 187 cm (arm span/height ratio: 1.01), flat feet, and cutaneous striae on the hips and the thighs.
On the clinical suspicion of Marfan syndrome, the Marfan Systemic Score (Dietz, [updated 2017]) was assessed and a score of 4/23 was obtained, making this diagnosis unlikely. Moreover, the ocular examination was normal and the ultrasound of the abdomen did not reveal any vascular abnormality. Serum IGF1 levels, assayed to rule out a pituitary adenoma as the cause of the patient's growing spurt, was normal.
Further examinations were performed to investigate the cardiovascular system. An ECG revealed right branch block and left branch hemiblock with a right axis deviation (−120°). An echocardiography showed mild mitral regurgitation and delayed diastolic relaxation. These findings were confirmed during the following 3 years of cardiologic follow-up, without significant variations.
Vascular echo-Doppler showed normal structure and diameters of the aorta and the supra-aortic trunks, as well as of the upper and lower limbs’ arteries.
After coming to our attention, the patient started presenting paroxysmal hypertensive episodes. Further workup, aimed at ruling out pheochromocytoma, revealed normal plasma and urinary metanephrines and no pathologic accumulation of fluorodeoxyglucose (FDG) at the PET scan examination. Repeated Holter monitoring blood pressure showed that daytime values of heart rate and blood pressure (bp) were set at the upper normal levels and there was a significant variability in daytime blood pressure rates with a physiological reduction at night (this pattern is defined as “dipper status”). One year later the variation between daytime and nighttime bp levels further increased (i.e., “extreme dipper”). A therapy with lisinopril failed to guarantee a complete pressure control, so the patient was referred to cardiological follow-up. A switch to carvedilol caused the onset of faintings (min bp: 40 mmHg), so lisinopril was reintroduced. The opioid therapy for chronic pain is still ongoing.
Although the family history was totally negative for collagen-related diseases, the recurrence of sprains and the evidence of cutaneous striae on clinical examination were suggestive of a collagenopathy with cardiac involvement.
Therefore, we considered the possibility of a cardiac-valvular form of EDS, so we performed a panel analysis of genes associated with inheritable heart diseases. Genomic DNA was extracted from peripheral blood samples using standard procedure. Briefly, the exonic and flanking splice junction regions of genes of interest were captured using the TruSight Cardio kit (Illumina) and sequenced on a MiSeq Illumina system with 150bp paired-end reads. Reads were aligned to human genome build GRCh37/UCSC hg19 and analyzed for sequence variants using a custom-developed analysis tool (Sana et al., ), selecting collagenopathy genes to create a virtual panel. Mean coverage was 285x and >30x for each target region.
On note, FBN1 gene was included in the panel and was normal, furtherly disproving the initial suspect of Marfan syndrome. The analysis showed the presence of the heterozygous variant c.3478A>G (p.Ile1160Val) in COL3A1 (NM_000090.3).
This variant has never been reported neither in literature nor in the major genetic databases (gnomAD, ExAC). Following ACMG2015 criteria, the mutation was classified as a variant of uncertain significance. It is predicted as neutral by some bioinformatics tools (Provean, Polyphen 2, Mutation Assessor and Mutpred) and damaging by others (SIFT, Mutation Taster and CADD).
In HGMD database, 708 COL3A1 mutations, mostly missense, are listed. Several missense mutations associated with vEDS have been described in the 10-amino acid regions upstream and downstream isoleucine 1160 (Figure ), suggesting the presence of a potential hot-spot region at this level. This residue of isoleucine is highly conserved, particularly in mammals (Figure ).
Further workup was aimed at investigating the pathogenicity of the variant.
The segregation analysis, performed only in the mother (father died at 59 years of lung cancer), was negative, partially supports the de novo origin of the variant.
Afterward, a skin sample of the patient was achieved to perform a functional study on the fibroblasts. The fibroblasts cultures were grown and maintained in Dulbecco modified Eagle's medium (DMEM) with 10% fetal calf serum. Type I, III, and V collagens were purified from medium and cell layer as described by Valli et al. () and then separated by gel electrophoresis. Gels were processed for fluorography using standard procedures and submitted to quantitation by using the program Image J released from National Institute of Health, USA. The reference range of type III/I collagen ratio has been determined by measuring this ratio in samples collected from healthy subjects over a period of 3 years. This analysis showed delayed electrophoretic mobility of type III collagen (Figure ). A decreased amount of α1(III) chain, as confirmed by the densitometric scan of the fluorogram, was also detected.
In the hypothesis that the electrophoretic abnormalities were due to post-transcriptional modifications of the mRNA we analyzed the mutation through “Human Splicing Finder” (Figure ), which predicted the creation of a cryptic donor splice site (CCCGTTGGA).
The employment of this cryptic site may result in the synthesis of shortened chains with consequent alteration at a post-translational level, especially in the trimer folding process. Although the prediction made by the software was weak, alternative splicing have been considered as an additional cause of the electrophoretic delay and further mRNA analysis on fibroblasts of the patient has been performed.
Further mRNA analysis on fibroblasts of the patient shows no modifications on mRNA length through electrophoresis and Sanger analysis revealing no splicing defects.
Nevertheless, adding the finding of the protein study as a parameter in the computational analysis, the variant can be classified as likely pathogenic according to ACMG2015 criteria.
A muscular MRI of neck, upper, and lower limbs with axial and coronal T1 and T2-STIR weighted sequences (Figure ) was performed to seek the consequences of type III collagen abnormality on the muscle tissue level. This investigation did not show a selective pattern of muscle involvement, but only diffuse slight signs of fat substitution, mainly in gluteus and soleus muscles, bilaterally. No signs of fat substitution in the other muscle districts examined were reported, neither muscle edema could be detected.


An 82-year-old male with baseline function of daily jogging and a past medical history of chronic kidney disease presented with right knee pain and dysfunction. He had failed two attempts at primary quad tendon repair, first with suture anchors 4 months prior to presentation and subsequently with transosseous tunnels one month later. At presentation, he had a palpable defect just proximal to the superior patellar pole and was unable to actively straight leg raise (MRI and X-ray shown in ).
His passive ROM was 0-120, and active ROM was 70-120° (i.e., 70° extensor lag). His Knee Society Score (KSS) was 35. The patient was able to ambulate with his knee locked in extension with a compensatory circumduction gait.
At the 12-month follow-up after mesh reconstruction (described below), he was ambulating without assistive devices and had an active knee range of motion (ROM) of 5-120°. He had resumed light running activities and achieved a KSS of 73.


A 58-year-old male with a remote history significant for a left, traumatic above-knee amputation presented with right knee pain and dysfunction 1 year following primary QT repair complicated by a fall and rerupture postoperatively. He previously ambulated unassisted with a prosthesis. The patient was wheelchair-bound and had passive ROM of 0-120° and active ROM between 75 and 120°. His KSS was 31. His preoperative X-ray was significant for patellar baja and no fracture ().
At the 12-month follow-up after extensor reconstruction (see below), he had returned to unassisted ambulation with his prosthesis. His passive ROM was preserved, and his active ROM had improved to 10-120 degrees and achieved a KSS of 71.


A 29-year-old Spanish male diagnosed with cystic fibrosis (mutation ∆F508 of the CFTR gene), complicated by exocrine pancreatic insufficiency, bilateral bronchiectasis and repeated respiratory infections, was admitted to the emergency department. The patient reported 12 h of profuse diarrhoea with up to 10–15 liquid stools without mucus, blood or other pathological products, and had abdominal pain, sporadic nausea and vomiting, fever of 39 °C and shivering.
The physical examination showed a body temperature of 38.6 °C, blood pressure of 63/30 mmHg, heart rate of 150 b.p.m. and data for peripheral hypoperfusion with delayed capillary refill. The patient also showed dry mucous membranes, decreased abdominal sounds and generalized pain with no signs of peritoneal irritation. The laboratory results revealed: white blood cell count 8400 cells µl−1 (90 % neutrophils), C-reactive protein 23.13 mg dL−1, procalcitonin 302.68 ng ml−1, glycaemia 240 mg dL−1, serum creatinine 3.41 mg dL−1 and glomerular filtration rate 29 ml/min/1.73 m2. The venous blood gas analysis was: pH 7.25, HCO3 14 mmol l−1, pCO2 31 mmHg and lactate 9.80 mmol l−1, indicating metabolic acidosis. Amylase and liver function tests were normal. The diagnosis was mixed septic and cardiogenic shock with an abdominal focus, and secondary acute renal failure.
In the emergency room, intensive volume replacement was started, administering up to 2000 ml of saline solution. Empirical antibiotic therapy with ceftriaxone IV and metronidazole IV was also started. As the patient did not respond, he was transferred to the intensive care unit (ICU).
Upon arrival in the ICU, the APACHE II severity score was 32 and the SAPS II score was 53, and the patient required orotracheal intubation with mechanical ventilation for 4 days. In addition, he received continuous serum perfusion, norepinephrine (0.25 µg/kg min−1) and continued with antibiotic therapy. Transthoracic echocardiography showed severe biventricular dysfunction and dobutamine 10 µg/kg min−1 and vasopressin 0.7 µg/kg min−1 were added. Despite this, the patient remained in shock with multiorgan failure, so that femoro-femoral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) together with an intra-aortic balloon pump (IABP) were put in place for 8 days. Antimicrobial therapy was changed to meropenem plus metronidazole plus amikacin.
Samples for stool culture, toxin detection and blood cultures were taken and sent to the Microbiology Laboratory prior to antibiotherapy.
Toxigenic was first detected in stool samples with the C. diff Quik Chek complete enzyme immunoassay (Alere, Waltham, MA, USA), and then confirmed by PCR GeneXpert C. difficile (Cepheid, Sunnyvale, CA, USA). The BACT/ALERT Virtuo system (bioMérieux, Marcy-l’Etoile, France) gave a positive signal in two blood cultures after 24 h of incubation, and Gram staining showed Gram-negative bacilli. After sowing on blood agar plates and 24 h of incubation at 37 °C in both aerobic and anaerobic atmospheres, some greyish bacterial colonies were isolated, which were identified as by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (Bruker Daltonics, Billerica, MA, USA), with a score of 2.326.
Simultaneously, the stool culture grew non-lactose-fermenting colonies in selective / agar (SS) after 24 h of incubation at 37 °C (bioMérieux, Marcy-l’Etoile, France). The MicroScan WalkAway system (Beckman Coulter, Brea, CA, USA) identified them as , which was confirmed using Shigella Antisera Poly (BD Difco, Franklin Lakes, NJ, USA) for identification of somatic (O) antigens. The susceptibility results, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint v. 8.0, were: ceftriaxone <1 µg ml−1 (S), meropenem <1 µg ml−1 (S), ampicillin >16 µg ml−1 (R), ciprofloxacin >2 µg ml−1 (R) and trimethoprim/sulfamethoxazole >2/38 µg ml−1 (R).
Finally, the MicroScan Walkaway system identified in the blood culture as S. sonnei, with the same susceptibility pattern as in stool. Identification was confirmed by agglutination with Shigella Antisera Poly.
Immunological tests were performed, which showed HIV-negative and normal lymphocyte populations. The main findings were IgA 651 mg dl−1 (70–400), IgG4 262 mg dL−1 (3–210) and complement activity 104.17 U ml−1 (41.68–95.06).
The patient was treated with vancomycin 500 mg 6 h−1 administered by nasogastric tube, meropenem 2 g 8 h−1 i.v. in extended infusion, a single dose of amikacin 1 g i.v. and metronidazole 500 mg 6 h−1, also administered by nasogastric tube, following Centers for Disease Control and Prevention (CDC) guidelines for the treatment of infections []. On the ninth day of admission, the haemodynamic, renal and infectious status of the patient improved and ECMO, IABP and vasoactive support were removed. After 14 days of admission in the ICU, the patient was transferred to the internal medicine unit. Although he was clinically stable, he had ischemic necrotic lesions on the distal phalanges of the hands and feet associated with hypoperfusion during septic and cardiogenic shock. Meropenem and metronidazole were removed and vancomycin was continued. The patient evolved favourably and was finally discharged 44 days after admission; nevertheless, amputation of various phalanges in the feet and hands was necessary because of the risk of necrotizing soft tissue infection.