The case of a 77-year-old woman with no family history of cancer and a prior medical history only significant for autoimmune hepatitis is here presented.
Due to the onset of constipation, she underwent colonoscopy which showed the presence of a malignant sigmoid lesion in July 2018. The finding was later confirmed by 18F-FDG PET-CT scan in September 2018.
The patient then underwent laparoscopic left hemicolectomy with nodal dissection (October 2018), with the pathological examination showing a moderately/poorly differentiated (G2/G3) stage II (pT3pN0) sigmoid adenocarcinoma with negative resection margin (pR0) and no vascular invasion (V0), microsatellite instability (MSI) not detected, RAS and BRAF wild type.
The patient was sent to clinical-instrumental follow-up with no indication for adjuvant treatments.
The first 18F-FDG PET-CT follow-up scan acquired on January 2019 showed increased FDG accumulation in two nodules at the level of the mesentery tissue and widespread pseudo nodular peritoneal thickening (left side) compatible with PC implants.
Chemotherapy was then started with FOLFOX (Oxaliplatin 85 mg/mq intravenous infusion—5-fluorouracil 2,400 mg/mq intravenous infusion over 46 h—Folinic Acid 200 mg/mq intravenous infusion) plus Panitumumab (6 mg/kg) scheme, with a total of seven foreseen cycles.
The last two cycles have been administered with a 25% dose reduction due to the onset of G1 diarrhea, G2 oral neuropathy, G2 hand-foot syndrome, and G1 stomatitis, according to CTACE v 4.0.
After seven cycles of chemotherapy, maintenance therapy with 5-FU and Panitumumab was prescribed.
The 18F-FDG PET-CT scan of May 2019 showed only a focal uptake in correspondence of a nodular formation of 12 × 8 mm with a standardized uptake value (SUV) of 20.7 in the context of the mesenteric adipose tissue in the left hemi abdomen in close proximity to small bowel loops.
The serum levels of CA 125, CEA and CA 19-9 were in the normal range.
The case was discussed in the institutional multidisciplinary tumor board that excluded surgery and addressed the patient to SBRT on the single PET positive peritoneal carcinomatosis nodule (see ).
The patient was consequently evaluated for MRI compliance [MASTER score value 1 ()] and addressed to 0.35 T 6 MV hybrid MR-Linac (MRIdian, ViewRay Inc., USA) with fully online adaptive approach.
The patient was positioned in supine position using the FluxBoard immobilization device (FluxBoard™, MacroMedics, the Netherlands) in the most reproducible and comfortable arrangement. Dedicated MRI coils were positioned under and over the abdomen of the patient. A simulation MRI was acquired according to our internal protocol.
A first 25-s true fast imaging (TRUFI) MR scan in free breathing (FB) was used to confirm patient’s correct positioning. A following 25-s deep inspiration breath hold (DIBH) sequence was then acquired (FOV of 54 × 47 × 43 cm3).
Target motion was verified with a 60-s cine-MRI on a sagittal plane (the only one currently allowed by the MRIdian system) passing through the GTV center of mass. The observed maximum amplitude was 4 mm in both cranio-caudal (CC) and antero-posterior (AP) directions.
The Gross Tumor Volume (GTV) (1.52 × 1.57 × 1 cm) included the persistent uptake in the mesenteric adipose tissue, as shown by 18F-FDG PET-CT scan. No margins for the clinical target volume (CTV) were applied (GTV = CTV). The surrounding OARs were contoured according to our institutional guidelines (RTOG).
Planning Target Volumes (PTVs) were obtained by adding a 3 mm isotropic margin to the GTV and ITV.
Considering such expansion, the PTV originated from GTV showed an 8.9 cc volume in DIBH, while the PTV obtained from ITV would have reached a 13.2 cc volume.
The patient then underwent a standard non-contrast enhanced planning CT in DIBH conditions, within 30 min since the MRI simulation on a helical CT scanner (GE HiSpeed DX/i Spiral, Boston, MA, USA, 1.5 mm slice thickness).
This planning CT scan was then co-registered with the simulation MR using deformable registration algorithms in order to obtain electron density data required for dose calculation.
A SBRT treatment plan with seven fields and 60 segments was calculated.
Dose calculation was carried out with a full Monte Carlo algorithm (MRIdian, ViewRay Inc., USA), with a statistical uncertainty of 1% using a calculation grid of 0.2 cm × 0.2 cm × 0.2 cm (–). The mean time required to obtain an initial dose distribution that solved the cost function was 1.6 ± 0.5 min ().
Planning quality was assessed using target coverage objectives and OAR constraints as recommended by the AAPM Task Group 101 report (). Small bowel loops hard constraints were set as Dmax < 35 Gy and V19.5% < 5 cc.
A fully online adaptive MRgRT workflow was chosen considering the site of target lesion, which was surrounded by numerous small bowel loops. Plan was calculated in DIBH in order to mitigate the breathing related movements on the CC axis observed during simulation imaging acquisition and to reduce target volume extension ().
A 25 s TRUFI sequence positioning MRI has been acquired prior to each delivery fraction to ensure patient’s correct positioning. The original contours were then automatically propagated on the positioning MRI of the day and manually edited within a distance of 3 cm from PTV to ensure therapy volume consistency, according to the SMART approach ().
The fluence of the original or last delivered plan was recalculated on the daily anatomy prior to each fraction, to evaluate the predicted dose distribution and the relative DVH parameters. In case of non-compliance with the set constraints, the dose distribution was re-optimized online.
Intra-fraction target motion was managed through an automatic gating approach triggered by target volume displacement (gating boundary = PTV; target out % = 5%) and verified using the online cine-MRI (four frames per second, sagittal view).
A total dose of 35 Gy at 7 Gy per fraction was prescribed to PTV, according to ICRU 83 guidelines.
All the scheduled fractions needed to be re-optimized due to significant dose distribution inconsistencies both for OAR constraints respectively and target coverage (see ).
The mean dose reduction in small bowel Dmax achieved through online adaptive replanning was 3.1 Gy (range 0.2–8.7 Gy), and the mean reduction in small bowel V19.5 Gy was 3 cc (range 0.39–8.86) comparing to the predicted dose if treated with the original plan without adaptation.
As for target coverage, the mean PTV V95% increase was 65.9% (range 32.6–94.5%) (see , right).
The dosimetric differences between predicted and re-optimized plans are reported in for each delivered fraction.
Original beam on time (as calculated by the TPS) was 3.62 minutes (min) while the predicted delivery time was 5.50 min.
Beam on time and delivery time for each following adapted fraction are summarized in .
The alignment and positioning image acquisition, contouring, plan prediction, and plan reoptimization and total delivery times resulted: 7.7 min (7–8.2); 8.2 min (7–9); 12.9 min (9.5–17); 17.3 min (16–19), respectively.
Patient’s on couch total time was 46.2 min (range 40–52).
The patient underwent the treatment without interruptions. No toxicity was observed during irradiation or at follow-up assessments, according to. CTCAE 4.0 scale ().
After SBRT, the patient was addressed to follow-up, consisting of a complete examination and recording of the clinical history, laboratory tests and restaging imaging, with no other active oncological treatments.
A first re-evaluation 18F-FDG PET-CT acquired on September 2019 (2 months after irradiation) described a slight reduction in both lesion’s dimension and standardized uptake value (SUV) (10 × 7 and 7.5 mm respectively) while a second 18F-FDG PET-CT acquired on May 2020 (10 months after irradiation) showed complete response with no other active disease sites.
The following last 18F-FDG PET-CT of September 2020 (14 months after irradiation) confirmed the observed local complete response in the absence of other disease sites.


An 80-year-old male patient with weakness of both lower extremities was admitted to the hospital for more than 1 month. The patient described progressive incomplete paralysis of both lower extremities. Thoracic MRI showed a horizontal intradural space-occupying lesion of the T4-5 vertebral bodies. T1WI and T2WI presented isosignals () and were uniformly enhanced after gadolinium-diethylenetriaminepentaacetic acid (GD-DTPA) injection (). The tumor was removed by T4-5 laminectomy under neurophysiological examination. During the operation, the tumor was found to be dark red with a vascularized surface and eroded dorsal spinal cord and nerve roots. The interface of the tumor tissue where it infiltrates the spinal cord was carefully separated under a microscope, and the whole tumor was removed () with minimal bleeding. The lower limbs could move freely after the operation. After 10 months of follow-up, the patient died of heart disease.
Postoperative histopathology showed WHO grade II HPC. Under light microscopy, the tumor tissue was rich in cells showing a rounded oval to spindle-like shape, and the intercellular stroma was rich in “staghorn” thin-walled branching vessels (). Mitotic figures were not easy to see (). Immunohistochemical staining was Ki-67(+20%), CD34(+), Vimentin(+), SSTR2(–), EMA(–), STAT6(–), D2-40(–), and GFAP(–) (). These results are consistent with the characteristics of HPC.


History
A 54-year-old transgender female presented to the ED with five months of progressive gait instability resulting in debilitation so severe that she had become wheelchair dependent. She also reported lumbar back pain and right lower extremity radiculopathy. Her history was notable for HIV+ intermittently compliant on antiretroviral medications, hypercalcemia, and chronic kidney disease. She also had undergone two body contouring procedures with mineral oil injections of her buttocks and thighs 20 years prior in the process of transitioning to a woman. Physical exam revealed right lower extremity paresis. In her right lower extremity she had 3/5 strength in dorsiflexion and 4/5 throughout the rest of the leg. There was decreased sensation in bilateral lower extremities with 4+ patellar deep tendon reflexes and ankle clonus. Her buttocks and posterior thighs demonstrated diffusely hard darkened skin, and a 10 cm x 10 cm well-circumscribed midline nodule at the level of the sacrum. A separate but similar 5 cm x 5 cm nodule was also noted in the lumbar area. Laboratory results demonstrated hypercalcemia (13.2 mg/dL), depressed parathyroid hormone (PTH) (4.8 pg/mL), slightly elevated parathyroid hormone-related protein (PTHrp) (5.0 pmol), and elevated Vitamin D 1,25 OH (248 pg/mL).
The MRI of the neuroaxis demonstrated a small amount of posterior epidural fluid from C7-T3, multilevel degenerative changes of the cervical spine, and severe spinal canal stenosis from C7-T1 resulting in cord compression and myelomalacia (Figure ,B). CT of the cervical spine re-demonstrated the cervical central canal stenosis, highlighting a circumferential calcifying process involving the ligaments and lamina (Figure ,D). Given her progressive weakness and clear cord compression due to these calcified lesions, she was taken to the OR in an urgent fashion.
Operative procedure
She was placed prone on a Jackson table in Mayfield pins. A midline cervicothoracic incision was made, and the posterior elements exposed. A standard midline laminectomy was performed, removing the entire lamina of C7 and T1, with extension to the inferior portion of C6, and superior portion of T2. The lamina was adherent to an epidural collection of calcified phlegmon which was adherent to the dura. This was carefully excised using a combination of curettes and Kerrison rongeurs until normal appearing dura was visualized at the margins of the laminectomy, and the spinal cord adequately decompressed. The phlegmon was sent to pathology and microbiology. The wound was irrigated, hemostasis achieved, and closed in layers with a drain left in place.
Postoperative course
Immediately after surgery, she demonstrated significant improvement in right lower extremity strength, numbness, and gait. By postoperative day (POD 9) she regained full strength with significant improvement in deep tendon reflexes and clonus. In addition to cervical decompression, she also underwent a lymph node biopsy. Final spinal pathology demonstrated fibrous connective tissue with nonpolarizable calcifying crystalline material associated with foreign body-type granulomatous reaction, and calcification consistent with TC (Figure ). The lymph node biopsy demonstrated lipogranuloma. She was treated with zoledronate and hydroxychloroquine and on POD 25, she was discharged ambulating independently with strict instructions for outpatient calcium level follow up.


We present the case of a 22-year-old woman without significant prior medical history who presented to our medical center after a loop electrical excision procedure (LEEP) cone biopsy at an outside hospital which showed cervical squamous cell carcinoma. The patient desired future fertility. A positron emission tomography (PET) scan did not show any evidence of distant disease. The patient became pregnant, was treated during her second trimester with cisplatin and paclitaxel, and underwent a radical cesarean hysterectomy at 37 weeks gestation with bilateral pelvic lymph node dissection. Intraoperative findings showed a clinically visible lesion on the cervix, but no visible lesions in the pelvis or lymph nodes. Resection showed residual moderately differentiated squamous cell carcinoma of the cervix, arising from severe dysplasia (Figure ) with lymphovascular invasion. The bilateral parametria were negative for squamous cell carcinoma.
Fifteen pelvic lymph nodes were identified bilaterally. Two pelvic lymph nodes (one from each right and left side) had aggregates of large, polygonal cells with well-defined cell borders and abundant eosinophilic cytoplasm with round nuclei (Figure ).
These nests of loosely cohesive cells were positive for estrogen and progesterone receptors (Figure , ), and a cluster of differentiation (CD)10 (Figure ) which is a sensitive and diagnostically useful marker for normal endometrial stroma. p63 (transformation-related protein 63) was negative (Figure ) and thus ruled out metastatic carcinoma.
The final diagnosis was endometrial stroma with decidual stromal changes in the lymph nodes. There was no evidence of involvement of the remaining specimen by endometriosis or ectopic decidual stroma.


A 46-year-old Latinx man with no significant past medical history presented with two months of persistent shortness of breath associated with subjective fever, sore throat, dry cough, general malaise, and recent onset pleuritic chest pain. The patient also complained of one month of diffuse nonpruritic skin rash, mostly involving his back, abdomen, pelvis, and bilateral upper extremities. He mentioned a recent trip to his homeland of the Dominican Republic three months prior and works at a convenience store, but he denied any known sick contacts. He also denied: high-risk sexual activity, illicit drug use, weight loss, hemoptysis, orthopnea, paroxysmal nocturnal dyspnea, or lower extremity edema.
Approximately six weeks prior to this presentation, the patient completed an empiric antibiotic course for suspected community-acquired pneumonia after presenting to the ER with a mild cough, shortness of breath, and diarrhea. At that time, the patient was febrile and chest X-ray showed bilateral interstitial infiltrates. He was otherwise stable and was discharged home with antibiotics.
On this presentation, the patient was found to be febrile with a temperature of 39.1°C. He was also tachycardic with heart rate fluctuating between 130 and 180 beats per minute and mild hypoxia with pulse oximetry of 91% while on room air; otherwise, he remained normotensive. On exam, the patient was awake and in no acute distress. He was noted to have bilateral conjunctival injection without exudates and mild oral mucositis. Neck exam was remarkable for mild bilateral cervical lymphadenopathy, but no jugular venous distention or apparent thyromegaly. Cardiovascular exam revealed tachycardia with an irregularly irregular rhythm without significant murmur or peripheral edema. Lungs were clear to auscultation. Skin exam revealed a coalescing erythematous macular rash, predominantly scattered around upper extremities, abdomen, back, and groin (Figure ). A rash with perioral distribution was also noted on the face. No joint tenderness and swelling were noted. Abdominal exam was without organomegaly. Neurology exam was unremarkable.
Laboratory results revealed white blood cell (WBC) count of 10.3 x 103/μL, hemoglobin 16.5 g/dL, thrombocytopenia of 119 x 103/μL, D-dimer of 4400 ng/mL, lactate dehydrogenase (LDH) of 253 u/L, C-reactive protein (CRP) of 74 mg/L, and ferritin of 827 ng/mL. Other abnormal laboratory findings included activated partial thromboplastin time (aPTT) 61 s, fibrinogen 664 mg/dL, creatinine 1.6 mg/dL, creatine kinase 773 u/L, alanine aminotransferase, and aspartate transaminase 76 U/L and 57 U/L, respectively. Urinalysis was remarkable for pyuria (WBC 10/HPF), moderate hematuria, proteinuria (protein 30 mg/dL), and negative for both nitrite and leukocyte esterase. On imaging studies, chest X-ray revealed a middle lobe opacity and basilar linear opacities, and CT angiography showed patchy consolidations on bilateral lung apices (Figure ). Electrocardiogram (EKG) showed atrial fibrillation with rapid ventricular response (RVR) (Figure ). Transthoracic echocardiogram showed left ventricular eccentric hypertrophy with reduced ejection fraction of 31%. Subsequent cardiac MRI revealed bilateral perihilar lymph nodes, but no suspicion for infiltrative disorders like sarcoidosis or amyloidosis.
Extensive infectious workup, which included specific testing for HIV, streptococcus, legionella, tuberculosis, syphilis, pneumocystis, histoplasma, cryptococcus, aspergillus, malaria, babesia, and strongyloides, was unrevealing. Blood and sputum cultures, viral hepatitis panel, respiratory panel, as well as acid-fast bacilli smear with culture were also negative. SARS CoV-2 rapid polymerase chain reaction (PCR) testing was negative on two occasions, but the patient eventually tested positive for SARS CoV-2 IgG antibodies. He underwent bronchoscopy on day six of hospitalization. Bronchial washings were also unremarkable; cytology was negative for malignant cells. Workup to evaluate for underlying autoimmune conditions included testing for antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, complements C3 and C4 levels, rheumatoid factor, anti-glomerular basement membrane antibody, and cryoglobulins were also unremarkable. Skin biopsy of the rash showed interface dermatitis with negative antibody or complement deposition on immunofluorescence.
The patient remained febrile for at least the first six hospital days consecutively. His health continued to decline with progressive renal insufficiency, liver injury, and thrombocytopenia but remained hemodynamically stable throughout the hospital stay. The trend in inflammatory markers continued to increase during the first six days as well. He received supportive care and completed a 10-day course of empiric treatment for community-acquired pneumonia and sepsis with cefepime combined with doxycycline. For atrial fibrillation, anticoagulation therapy was initiated with apixaban. On the eighth hospital day, the patient began to show signs of clinical improvement as evidenced by the resolution of his initial symptoms and fever. From this day forward, the thrombocytopenia, renal, and liver function continued to improve until full recovery. On day 10, the patient actually converted back to sinus rhythm as he continued his recovery. On hospital day 12, he was discharged home in stable condition with close outpatient follow-up.


A 45-year-old male underwent a left upper lobectomy and postoperative pathology revealed invasive stage IIIA lung adenocarcinoma (). Targeted next- generation sequencing (NGS) with a customized panel (Geneseeq Prime panel) designed to target 425 cancer-specific genes was performed, and four somatic mutations and copy number alterations (CNAs) were identified, including EGFR-KDD of exon 18-25 [mutant allele frequency (MAF): 13.5%], EGFR amplification (4.5-fold), TP53 p.Y220C (MAF: 37.0%), and RB1 single copy loss (). The tumor mutation burden (TMB) was estimated to be 1.1 mutation/Mb. The patient received pemetrexed and cisplatin as adjuvant chemotherapy. Four months later, he progressed with liver metastasis in left lobe ().
Then, the patient was treated with Icotinib and the metastasis shrunk. Unfortunately, the drug resistance was observed only after 4 months, as evidenced by the fact that previously responsive liver lesion progressed. Left hepatic re-biopsy confirmed metastatic adenocarcinoma and target sequencing (Geneseeq Prime panel) detected the same EGFR-KDD (MAF: 4.9%) as well as mutation of TP53 p.Y220C (MAF: 0.5%) (). The TMB was calculated as 2.2 mutation/Mb.
Docetaxel and cisplatin were initiated as the second-line therapy. However, the left hepatic metastasis enlarged rapidly after 2 cycles of chemotherapy. The blood carcinoembryonic antigen (CEA) level increased from 9.5 mg/ml (before chemotherapy) to 22.7 mg/ml. Even worse, a right hepatic metastasis appeared soon afterward. Radiofrequency ablation (RFA) of liver was conducted on both of the left and right hepatic metastases, but no reduction in liver lesions was observed, and the CEA level showed a slight increase from 7.3 to 10.3 mg/ml.
Afterward, the patient started taking Osimertinib (80 mg once daily). Encouragingly, both liver lesions showed significant regression (). One month after initiation of Osimertinib, the CEA level decreased to 5.4 mg/ml, and remained at normal level for 18 months. Moreover, the progression-free survival (PFS) reached 21 months. However, the CEA level increased to 23.1 mg/ml at the 19th month after the initiation of Osimertinib treatment, and 2 months later, the patient progressed with enlarged mediastinal lymph nodes () with the CEA level of 73.9 mg/ml. Resampling and targeted sequencing (Geneseeq Prime panel) consistently identified EGFR-KDD (MAF: 33.9%), as well as EGFR amplification (6.6-fold), TP53 p.Y220C (MAF: 53.3%), and a new mutation of RELN p.G1774E (MAF: 45.4%) (). The estimated TMB increased to 3.4 mutation/Mb. In addition, the assessment of PD-L1 expression using antibody 28-8 (pharm Dx, Dako’s Platform) showed tumor proportion score (TPS) of 1%.
On these bases, the fourth-line salvage therapy using Nivolumab was prescribed and the therapeutic efficacy was considerable, as evidenced by the decreased CEA, regressed mediastinal lymph nodes, reduced metastases in both left and right liver (). Specifically, the CEA level decreased from 143.6 to 41.8 mg/ml one month later. The PFS reached 7 months and no obvious adverse effects were observed. The quality of life was in good status during the Nivolumab treatment. After that, the patient progressed with enlarged liver metastasis. Unfortunately, the patient was also infected with tuberculosis, and his condition took a sharp turn for the worse due to both tumor progression and tuberculosis. The families gave up further treatment and the patient died 4 months later.


A 4-year-old girl presented with pain abdomen for 1 day and subcutaneous nodules for 3 days. Pain abdomen was acute in onset in the left hypochondrium, intermittently present, non-radiating, and associated with abdominal fullness with no aggravating or relieving factors. Additionally, subcutaneous nodules were also present on anterior aspect of forearm, medial aspect of both thighs and over abdomen with initial bluish discoloration later followed by visible nodules which were painful and fixed and there was no discharge. Subcutaneous nodules appeared intermittently for last 3 months and recently appeared for 3 days, she had no history of headache, altered consciousness, abnormal body movements, visual disturbances, photophobia, decreased vision, nausea, vomiting, altered bowel habit, dysuria, hematuria, decreased urine output, fast breathing or labored breathing, skin rashes, joint swelling or bleeding manifestation from any sites. No history of medication taken for this illness, no recent travel history or exposure to COVID positive case or suspected individuals.
After admission; on examination the child was irritable, looked pale, there was facial puffiness, lymphadenopathy, with fever of 100.40F, respiratory rate of 42 breaths per minute, and pulse of 152 beats per minute, which was palpable, good in volume with decreased pulse volume in upper limb on left side. Blood pressure was 160/78 mm of Hg on left arm and 140/60 mm of Hg on right arm which was >99th centile for height for age i.e. stage 2 hypertension.
Keeping in the mind the differential diagnoses of malignancy, vasculitis, juvenile rheumatoid arthritis, tuberculosis, systemic lupus erythematosus, typhoid, infectious mononucleosis, brucellosis and leptospirosis needful laboratory investigation and imaging were sent. Her bone marrow showed normal picture. Rheumatoid factor and ANA were negative. Her blood cultures were negative despite of persistent fever without focus. Liver function and renal function test were within normal limits. Her mantoux test was negative. She had widened mediastinum seen in chest x ray. As per protocol of fever of unknown origin, to find out the cause of the fever; CT thorax and abdomen was advised, and the findings were suggestive of takayasu arteritis (,). It was accompanied with the positive findings of diffuse transmural wall thickening with luminal irregularity involving the aorta and its branches, aortic arch, descending thoracic and abdominal aorta up to its infra renal segments, brachiocephalic trunk, bilateral common carotid, subclavian and axillary arteries, celiac trunk, superior mesenteric artery, bilateral renal arteries, common femoral arteries and pulmonary arteries. All features were suggestive of vasculitis likely takayasu arteritis (type V). Mild stenosis involving mid segment of right renal artery and hypodensities at right renal cortex suggestive of renal infarction were also observed. Fusiform aneurysm involving aortic arch and descending thoracic aorta as well as luminal irregularities involving descending thoracic and abdominal aorta were seen. Small collection at both upper anterior wall likely haematomas as well as minimal ascites was found on imaging.
Her laboratory reports are shown (). Other reports including Peripheral blood smear showed anisopoikilocytosis, microcytic hypochromic erythrocytes, few pencil cells; leukocytosis with normal morphology; thrombocytosis; but there was no atypical cells and parasites on the smear. Her Echocardiography showed left ventricle ejection fraction (LVEF) of 60%; mild tricuspid regurgitation with mild pulmonary hypertension (32+5=37 mm of Hg) without regional wall motion abnormality (RWMA). There was no intracardiac mass or thrombosis.
She was initially managed in the line of infection and lymphoma. Later she developed fever and hemodynamic instability on the second day of admission for which she was admitted in ICU for close monitoring of blood pressure. She stayed in ICU for 24 hours and was again shifted to ward. Her cause of fever was not found. Later CECT and CT angiogram were done on day 7 of admission, which was suggestive of TA. She was then treated with antihypertensive medication, oral steroid and methotrexatefor her condition and to prevent further complications. Before discharge she stayed in hospital for 11 days and was asked to follow up after 4 weeks. She was planned to tapper down corticosteroid and optimize antihypertensive drugs on follow up.


A 31-year-old female patient was admitted to the vascular medicine department of the Hôpital Européen Georges-Pompidou for an acute ischemia of the left hand. She presented with necrosis of the intermediate and distal phalanges of the second, third, fourth and fifth fingers of her left hand.
Three days earlier, the patient turned up at the primary care center close to her home for a sudden and constant pain in her left hand. She was discharged within 2 h with painkillers. After 72 h, cyanosis and coldness of the intermediate and distal phalanges of the fingers of the left hand appeared. She then decided to consult at the Hôpital Européen Georges-Pompidou emergency department.
Left hand examination revealed the following injuries: cyanosis and coldness of the intermediate and distal phalanges of the fifth finger, necrosis of the distal phalanges of the second, third and fourth fingers, phlyctens of the intermediate phalanges of the second, third and fourth fingers and the proximal phalanges of the fourth finger (,). The hand was still painful with paresthesia, but without fingers paralysis. Upper limb pulses were present and symmetrical. Injection marks were noted at the bend of the right and left elbows. Cardiac auscultation was normal without any bruit that could evoke an infective endocarditis, and she had no fever. Electrocardiogram showed a sinus rhythm without any abnormalities.
In her medical history, she had no cardiovascular history but active smoking, as her only cardiovascular risk factor. Spontaneously, she mentioned being a drug addict, but weaned off ectasy, codein, and cannabis, and currently in a weaning off program for heroin. She had been prescribed tapered doses of buprenorphine but still used to take bromazepam and zolpidem off the counter.
The continuous Doppler confirmed the presence of flow in the left radial, ulnar and palmar arteries. A digital subtraction angiography was rapidly performed which demonstrated no run-off in the digital arteries of the second, third and fourth left fingers (). No thromboaspiration could be performed on these too small arteries. Anticoagulation with unfractionated heparin was started.
The patient was transferred to the vascular medicine department for medical therapy and further investigations. As the patient denied any recent intravenous drug injection, a complete screening for acute limb ischemia etiology was performed.
Human Immunodeficient Virus and Hepatitis B Virus serology were negative, whereas Hepatitis C Virus serology came back positive. Several analyses to find a cryoglobulinemia returned negative.
Arterial thrombophilia has been investigated in vain, with normal prothrombin time and activated partial thromboplastin time, absence of anti-cardiolipin antibodies, anti-beta2GPI antibodies, lupus anticoagulant, antinuclear antibodies, anti-double stranded DNA antibodies, anti polymorphonuclear cytoplasm antibodies. There was no antithrombin or protein S or protein C deficiency and no hyperhomocysteinemia. There was no argument for a myeloproliferative syndrome in the absence of a clinical call point (especially no mass or lymphadenopathy), the blood count was unspecialized and JAK2 mutation V617F was absent.
We also looked for an embolic arterial cause. The trans-thoracic echocardiography did not find any thrombus or any argument for an infectious endocarditis. The 24 h Holter-ECG was normal. The computed tomography performed at the emergency room did not show any atheroma on the aortic arch or atheromatous plaque on the left upper limb arteries.
Once she was arrived in our department, we started a daily treatment with iloprost, an arterial vasodilator, as well as pain medication, and local care with a protective dressing. Treatment with iloprost allowed delineation of necrosis at the intermediate and distal phalanges of the three fingers involved, and cyanosis of the fifth finger and the proximal phalanx of the fourth finger resolved. Management by an orthopedic surgical team specialized in the upper limb and hand was required for the amputation of the intermediate and distal phalanges of the three fingers involved ().
Finally, the patient acknowledged she had injected herself, 3 days before her admission, just below the fold of her left elbow with one and a half crushed tablet of zolpidem 10 mg mixed with contact lens cleaning fluid. The patient intended to do an intravenous injection, but it turned out to be an accidental brachial intra-arterial injection. The 3 days delay corresponded to the beginning of the pain and to her first consultation at the local medical center.
Antithrombotic therapy by anticoagulants was changed for antiplatelet therapy and the patient was then transferred to a vascular rehabilitation unit for complete healing of the amputation wounds. presents a timeline summary. After her discharge, the patient did not come back at follow-up consultations and was lost to follow-up despite several reminders.


We report a case of a 59-year-old male who presented with four days of productive cough with blood-tinged sputum, shortness of breath, and chills, along with some sinus congestion, sore throat, diarrhea, headache, and generalized body aches. The patient had decreased oral intake and had not been compliant with his diabetes medications. He had underlying disease significant for type 2 diabetes, essential hypertension, obesity (BMI 32 kg/m2), history of pancreatitis and diabetic ketoacidosis. His diabetes medications included insulin degludec 126 units with insulin lispro sliding scale, dulaglutide, metformin, and sitagliptin. He was a non-smoker and did not use vaping devices. The patient was working at one of the local intermediate care facilities one week prior to symptom development, and there was no history of exposure to COVID-19 positive patients or history of travel to a level 2 or 3 region.
On examination, the patient was lethargic. Initial vital signs included a temperature of 36.8°C, respiratory rate 24/min, heart rate 65 bpm, blood pressure 140/67 mmHg, and oxygen saturation 91% on room air. Lung auscultation revealed bilateral widespread crackles. Laboratory testing was significant for hyperglycemia (glucose 387 mg/dL) with increased anion gap metabolic acidosis (corrected with albumin) and concurrent normal gap acidosis, positive urine ketones, elevated hemoglobin A1C, elevated lactic acid dehydrogenase (LDH), and troponin (demand ischemia) (Table ). An initial chest x-ray showed bilateral peripheral pulmonary infiltrates. He was suspected to have COVID-19 infection. An infectious workup for influenza, rapid strep test, pneumococcal and legionella urinary antigen tests were negative.
The patient was admitted due to worsening hypoxia. He developed fever and lymphopenia (absolute lymphocyte count 795 cells/uL, range 950-3,500 uL) during hospitalization. The patient subsequently required intubation and mechanical ventilation. His acute hypoxic respiratory failure was consistent with ARDS according to Berlin definition and was classified as severe ARDS (PaO2/FiO2 ratio of 71). The patient was concomitantly diagnosed with DKA due to hyperglycemia with elevated anion gap metabolic acidosis with positive urine ketone and normal lactate. Moreover, his clinical course was complicated by hypotension, likely multifactorial - DKA, sepsis, and sedative medication. He was treated with variable rate of intravenous insulin infusion, initially started at 12 units/hour with subsequent titration down to average of 5 units/hour, fluid resuscitation (approximate 34 ml/kg actual body weight) and potassium repletion on the first day.
On the same day, his hypoxia worsened with an increase in opacities bilaterally on his chest x-ray (Figure ), so intravenous fluid delivery was ceased and norepinephrine infusion was commenced for 24 hours.
His mechanical ventilation settings followed ARDS guidelines with low tidal volume (ml/kg ideal body weight). The initial settings comprised of tidal volume 6 ml/kg based on ideal body weight, positive end-expiratory pressure (PEEP) 12 cmH2O, FiO2 75%, with lung compliance of 70 ml/cm H2O, and plateau pressure of 20 cm H2O. Mean PEEP, FiO2, lung compliance, and plateau pressure throughout mechanically ventilated period were 8.5 cmH2O, 60.5%, 55.3 ml/cmH2O, and 18.33 cmH2O, respectively. The patient did not require any prone positioning or neuromuscular blockade. After maintaining a negative fluid balance with volume restriction and furosemide administration, we were able to wean down on PEEP and extubate in 72 hours. However, with continuation of negative fluid balance, he required an additional five days to completely wean off oxygen. Intravenous insulin was continued for 46 hours then was switched to subcutaneous basal-bolus regimen (Figure ). The patient was admitted for a total of 10 days, three of which he spent in the ICU. He was discharged with insulin degludec 100 units with insulin lispro sliding scale, metformin, and sitagliptin. Dulaglutide was held due to duplication of therapy.
Infectious workup revealed positive COVID-19 from real-time reverse transcription-polymerase chain reaction. Blood culture and sputum culture were negative. The patient was treated with intravenous ceftriaxone, azithromycin, and oral oseltamivir for five days. There were no confirmed cases in his intermediate care facility before or after his discharge.


A 13-month-old male presented to our pediatric emergency department (ED) in early April 2020 with the chief complaint of fussiness, decreased appetite, and fever for five days. His mother reported that there was no resolution of his fever despite the use of antipyretics. At the presentation time, his mother denied cough, runny nose, ear pulling, shortness of breath, rash, vomiting, or diarrhea. She reported no recent travel nor sick contacts at home. Social history was remarkable for crowded and close living conditions, with five other family members sharing a two-bedroom apartment. The patient remained isolated at home since the pandemic began, but other family members had been out of the house for groceries.
He was nontoxic on physical exam, appearing but fussy and febrile with a temperature of 102.7°F (Table ). Physical exam was remarkable for dry, cracked lips with fissuring along the vermilion border and labial mucosa. His mucous membranes were dry, and there was pharyngeal erythema without exudates or tonsillar hypertrophy. The chest was clear to auscultation bilaterally. The patient had no conjunctivitis, lymphadenopathy, hepatosplenomegaly, nor edema or rash on the trunk, hands, and feet.
Laboratory findings showed a negative respiratory viral panel, a normal complete blood count (CBC) with lymphocytic predominance (Table ), elevated C-reactive protein (CRP) of 25.81 mg/dL. The comprehensive metabolic panel (CMP) revealed metabolic acidosis with a normal anion gap with ketones present in the urinalysis. We obtained blood and urine cultures, and the patient was admitted and started empirically on ceftriaxone, antipyretics, and intravenous fluids.
Due to persistent fever, a chest X-ray (CXR) was ordered, which showed bilateral interstitial infiltrates more prominent on the right peri-hilar area, which could represent atypical pneumonia (Figure ). Urine and blood cultures were negative. However, the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) polymerase chain reaction (PCR) was positive 24 hours after admission to the hospital. The patient was subsequently started on azithromycin for clinical suspicion of atypical pneumonia related to COVID-19, correlating with the CXR findings. The fever subsided after the first day of antibiotics, and the cheilitis improved during the admission. The patient was discharged home with isolation guidelines and completed five days of azithromycin and seven days of amoxicillin clavulanate for suspected clinical pneumonia.


A healthy 36-year-old Caucasian woman gravida 1 was referred to our hospital at 6.3 weeks of gestation due to the presence of a cervical heterotopic pregnancy after an IVF cycle for tubal infertility with transfer of two embryos. She brought an ultrasound exam, performed at 5.5 weeks, showing the presence of two gestational sacs, one intrauterine and one cervical, each with an embryo with a heartbeat and yolk sac (Fig. ). On admission, transvaginal ultrasound confirmed the presence of two gestational sacs with corresponding embryos and cardiac activity, one located in utero (40 × 21 mm; CRL 6.9 mm) and the other in the cervix (32 × 19 mm; CRL 6.9 mm). On specular examination, the cervical gestational sac was visible in the cervical canal at about 1 cm from the external cervical os, dilated by about 1 cm. No blood loss was present. After an extensive consultation where the woman expressed her intention to do everything possible to safeguard the intrauterine pregnancy, while being aware of the risks related to the termination of cervical pregnancy, and after a multidisciplinary counseling between gynecologists and radiologists, we proposed to use MWA. After written informed consent was obtained, at 6.5 weeks, the patient received one session of MWA. Under transabdominal ultrasound guidance, the microwave antenna was introduced transvaginally inside the cervical gestational sac, and ablation was performed with 100-W output for 90 s (Emprint Ablation System with thermosphere Technology Medtronic; Medtronic, Minneapolis, MN, USA) (Fig. ). With this MW technology, the output and exposure time are evaluated based on the volume of the target lesion. It was considered that these parameters were the most suitable for obtaining better control and more accurate predictability of the ablated volume, so as to avoid nontargeted ablation. The procedure lasted 15 min overall was performed without anesthesia and with no discomfort for the patient; 1 g cefazolin was given intramuscularly at the same time. The patient did not require any pain medication after the procedure.
At the end of the procedure, the ablated gestational sac appeared as a homogeneously hyperechoic area, with a mean diameter of 1.8 cm and no flow signal at Color-Doppler US. Neither bleeding nor uterine contractions occurred after the procedure and in the following 3 days, when she was discharged. She was then followed on a regular basis and with monthly obstetric visits and ultrasound examinations that showed the persistence of nonhomogeneous, vascularized material within the cervical canal that was approximately 46 × 42 mm at 15.6 weeks and 25 × 25 mm at 33 weeks (Fig. ): however, as specular examination and cervical length were always regular, the hypothesis of a cervical cerclage was discarded. Pregnancy was otherwise uneventful.
With an elective cesarean section planned at 39 weeks, at 37.6 weeks, the patient was admitted at the hospital due to abundant vaginal bleeding with irregular uterine contractions, no cervical effacement or dilation present. An emergency cesarean section was performed in the suspicion of placenta abruption, not confirmed neither by the histological examination nor during surgery when it was seen that the blood loss came from the cervico-isthmic area, likely residual of the cervical pregnancy ablation. A live female of 2780 g, Apgar score 10/10, and umbilical arterial pH 7.31 was delivered. A Bakri balloon was placed to prevent further blood loss, which was 800 mL in total. The balloon was removed on the first postoperative day; hemoglobin concentration dropped from 12.2 g/dl before to 9.5 g/dl, 1 day after the cesarean section.
The postpartum course was regular, and the patient was discharged after 4 days, before discharge ultrasound revealed regular endometrium and endocervical canal.


A 59-year-old man (height, 167 cm; weight, 71 kg) underwent a medical check-up that revealed an abnormal radiopacity on a chest radiograph. Consequently, he underwent computed tomography (CT), which led to the diagnosis of IDPA. He visited our institution for surgical treatment. CT showed a dilated pulmonary artery measuring 64 mm (Fig. a). It also revealed a right aortic arch, featuring an aberrant left subclavian artery with an aneurysm measuring 3 cm (Kommerell’s diverticulum) (Fig. b). Transthoracic echocardiography showed normal wall motion and no significant valvular disease. Cardiac catheterization demonstrated normal pulmonary artery pressure and no stenosis in the coronary arteries. Pulmonary artery replacement was planned to prevent rupture of the dilated pulmonary artery aneurysm.
After placement of the radial artery catheter, anesthesia was induced with fentanyl (0.5 mg), propofol (150 mg), and rocuronium (100 mg). The trachea was intubated with an 8.0-mm tracheal tube using a video laryngoscope (McGRATHTM, Medtronic, Minneapolis, MN, USA) without difficulty. The mechanical ventilation settings were fraction of inspired oxygen of 60%, frequency of 12 breaths per minute, tidal volume of 6 mL/kg, and positive end-expiratory pressure (PEEP) of 3 cm H2O. The target range for end-tidal CO2 was set at 30–35 mmHg. A transesophageal echocardiography (TEE) probe was inserted carefully while confirming that there was no resistance. Anesthesia was maintained with sevoflurane (1%) and remifentanil (0.3 μg/kg/min). A pulmonary artery catheter (PAC) was inserted into the right internal jugular vein and carefully advanced under TEE monitoring in the mid-esophageal bicaval view and right ventricular inflow-outflow view. Finally, in the ascending aorta short-axis view, it was confirmed that the catheter tip was in the main pulmonary artery and that there was no malposition or flexion. After PAC insertion, the mean pulmonary arterial pressure was 24 mmHg.
The approach of the surgery was a median sternotomy. Cardiopulmonary bypass (CPB) was instituted through aortic and bicaval cannulation. Main pulmonary artery replacement was performed on a beating heart. The dilated part of the main pulmonary artery was resected. The right and left pulmonary arteries were anastomosed to the edges of a 24-mm graft, and the remaining main pulmonary artery was anastomosed to the side of the graft. The patient was easily weaned from CPB with administration of dobutamine (2 μg/kg/min) and milrinone (1 μg/kg/min). The intraoperative mean pulmonary arterial pressure was consistently maintained at around 20 mmHg. The patient was transferred to the intensive care unit (ICU) under mechanical ventilation. The patient was extubated on the day of ICU admission, with a subsequent uneventful course. Mean pulmonary arterial pressure was consistently maintained at 19–24 mmHg during the ICU stay. The patient was discharged on postoperative day 16.


A 78-year-old woman was referred to our clinic with bilateral hearing loss with sound distortion, tinnitus and auditory hypersensitivity, recurrent vertigo/dizziness induced by loud noises (Tullio phenomenon), and a diagnosis of bilateral SSCD at the temporal bone HRCT performed in the emergency room (Figures 2a–c).
Preoperative audiometry indicated severe mixed hearing loss in the right ear, with moderate conductive hearing impairment in the left ear (). A pure tone sound of 110 dB at 500 and 1,000 Hz in the right ear, and pneumatically increasing external auditory canal pressure induced dizziness without detectable nystagmus on video-oculographic (or Frenzel goggles) examination. Her tympanogram was bilaterally normal. A stapedial reflex could not be performed due to patient intolerance (dizziness). Mastoid vibration elicited dizziness without detectable nystagmus on video-oculographic (or Frenzel goggles) examination. A temporal bone 1.5-T MRI with 3D reconstruction performed two months before did not show the bilateral dehiscence (). Air conduction cervical VEMPs (cVEMPs) demonstrated a threshold of 85 dB HL on the right side and 100 dB HL on the left side. The cVEMPs were recorded from both ears using 500 Hz short tone-bursts (STBs). A video head impulse test for horizontal and vertical canals, including both dehiscent SSC, showed normal vestibulo-ocular reflex gain bilaterally ().


A 66-year-old female with past medical history of end-stage renal disease on dialysis and with hypertension, diabetes, dyslipidemia, CDI a year ago, and right internal jugular vein thrombus on Coumadin presented with diffuse abdominal pain, nausea, and diarrhea occurring approximately five to seven times per day (liquid in consistency). Her previous episode of C.diff was treated with vancomycin a year ago. On admission, other laboratory studies were normal except creatinine of 7.2 and blood urea nitrogen of 34. The patient received dialysis on the day of the admission. All the vitals were normal on admission. Stool specimen was sent, and C.diff PCR came positive. White blood cell count stayed around 5,000/microliter during the admission; therefore, it was classified as a nonsevere episode of C.diff. The patient was started on the fidaxomicin therapy as this was her first recurrence, and the initial episode was treated with vancomycin. From the next day of starting fidaxomicin, INR started declining (Figure ); it became subtherapeutic requiring more Coumadin dose reaching to 10 mg per day from baseline of 3-5 mg per day. Apart from fidaxomicin and Coumadin, the patient was on metoprolol, nifedipine, insulin, and atorvastatin during the hospital stay, none of which was proven to cause the subtherapeutic INR. The patient remained on the same low salt, low fat diet during the hospital stay, ruling out any diet-related alteration in INR. The patient remained in the hospital for almost two weeks for severe diarrhea, subtherapeutic INR, and eventually supratherapeutic INR. Naranjo et al. adverse drug reaction probability scale [] indicated a probable association (score of 7) between fidaxomicin use and patient’s decreased INR.


At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. ).
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.


A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. ). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).


A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. ). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.


A 39-year-old woman with a family history of breast cancer in her mother and ovarian cancer in her maternal grandmother noticed a lump in her left breast and consulted her primary care doctor. Because of the examination, the possibility of breast cancer was considered, and she was referred to our hospital for detailed examination.
A 1.4-cm tumor was palpated in the upper-outer region of left breast, an enlarged lymph node was not palpated, and there was no nipple discharge.
According to mammography (Fig. ), an equal density mass with a margin showing a circumscribed irregular shape was observed in the outer upper quadrant of the left breast at one o’clock in the anterior portion, and calcification was found inside of the mass. By ultrasonography, a 1.4 × 1.4 × 1.0-cm clear and rough, microlobulated marginal heterogeneous mass was observed in the outer upper quadrant of the left breast, along with calcification and enhanced posterior features (Fig. b).
Invasive ductal carcinoma and adjacent chondroid metaplastic breast cancer were diagnosed by needle biopsy. Positron emission spectroscopy-computed tomography revealed a tumor of maximum standardized uptake value of 7.7 in the outer upper quadrant of the left breast, with no lymph node metastasis or distant metastasis.
Based on these results, we diagnosed the patient with left breast cancer, cT1cN0M0, Stage I.
We performed left mastectomy + sentinel lymph node biopsy + tissue expander insertion as well as silicone implant replacement surgery approximately 6 months later.
In the outer upper quadrant of the whole breast resection specimen, 1.5 cm of metaplastic carcinoma (Fig. a), a component of chondroid metaplasia (Fig. b), and a component of ductal carcinoma (Fig. c) were mixed. Breast cancer invaded the fat tissue, the nuclear grade was 3 (atypia: 3, mitosis: 3), and the surgical margin was negative. Lymph node metastasis was not observed. The results of immunohistochemistry analysis were as follows: estrogen receptor: negative (0%), progesterone receptor: negative (0%), HER-2: negative (0), and MIB-1 index: 70–80%. These results suggested triple-negative breast cancer (TNBC).
As a postoperative course, we conducted genetic counseling because of the young onset of TNBC with a family history of both breast cancer and ovarian cancer. She wished to undergo genetic testing, and thus we evaluated BRCA1 and BRCA2. The results confirmed the presence of the pathogenic mutation c. 188 T>A (L63*) in BRCA1. Four courses of doxorubicin+ cyclophosphamide therapy were performed as postoperative adjuvant chemotherapy. In addition, after disclosing the genetic test results, periodic surveillance of ovarian cancer was started. She did not want to undergo contralateral mastectomy; therefore, surveillance of the contralateral breast was started. The patient has asthma and cannot be evaluated by contrast-enhanced magnetic resonance imaging, and thus mammography and ultrasonography are performed once per year. Currently, she has been alive without relapse for 2 years post-surgery.


A 42-year-old man presented with a 6-year history of mild evening fatigability in all four limbs followed by slowly progressive gait imbalance and recurrent diplopia, despite an unremarkable cerebral and orbital magnetic resonance imaging (MRI) as well as negative anti-acetylcholine receptor antibody serology, repetitive nerve-stimulation and single fiber electromyography. During the last 3 years, he had progressively developed limb incoordination, slurred speech and dysphagia, and lost approximately 20% of his body weight. His family history was positive for rheumatoid arthritis, Sjögren’s syndrome, pancreatic cancer, but negative for ataxia, myasthenia gravis, neuropathy, tremors, and dementia. His medical history was significant for allergic asthma, increased blood pressure, and left retinal macular degeneration. At the time of presentation to our Institution, the general physical examination was unremarkable apart from bilateral xanthelasma, vitiligo on the dorsal aspect of hand fingers and yellowish papulae on both feet and the left pectoral region. Neurologic examination revealed acalculia (mini mental state examination: 23/30), horizontal gaze nystagmus, normal fundoscopic and pupillary examinations, slow start, hypermetric saccades mainly in the horizontal plane and mild bilateral neurosensorial hypoacusia. Romberg’s sign was present, and a marked ataxic gait, tight-rope walking inability, dysdiadochokinesia, arms dysmetria, tremor, dysarthria, rhinolalia, and motor hindrance of the hands were also observed.
A biopsy of one of the skin papulae showed nodular infiltration of the dermis by mononuclear histiocytes (CD163+, CD68+, CD14+, CD4+, CD1a−, CD207−, S100−, phosphorylated extracellular signal-regulated kinases+). Several histiocytes showed a foamy cytoplasm (Fig. ).
Extensive laboratory workup including complete blood count, complete metabolic panel, hormonal profile, inflammation markers, immunoglobulins, anti-Yo antibody, coeliac disease serology, interferon alpha, angiotensin-converting enzyme, Quantiferon, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and syphilis testing was unremarkable, except for persistent monocytosis. Low levels of both testosterone and circulating T regulatory lymphocytes were found, and high levels of vascular endothelial growth factor (× 2 upper limit of normal-ULN) and anti-thyroid peroxidase (× 2 ULN), in the presence of anti-nucleus Antibodies (Abs; titer: 1:640) with positive anti-dense fine speckled 70 Abs. To rule out a possible diagnosis of cerebrotendineous xanthomatosis or Gaucher’s disease, plasma cholestanol and chitotriosidase levels were measured, resulting normal and slightly increased (1.8x), respectively. Genetic analysis of spino-cerebellar ataxia (SCA)1, SCA2, SCA3, SCA6, SCA7 and SCA36 genes did not reveal any mutations, nor was the Friedreich’s ataxia (FRDA) trinucleotide repeat disorder identified. MRI of the brain revealed atrophy of the midbrain, cerebellum, superior and middle cerebellar peduncles (Fig. a, b). Hyperintense signals were observed in T2 and fluid-attenuated inversion recovery (FLAIR) sequences within the pons, cerebellar white matter, dentate nuclei (DN), and globi pallidi in the absence of any contrast enhancement (Fig. c, d, g). Both the retro-orbital space and the pituitary gland appeared normal. Susceptibility weighted imaging (Fig. e, f) demonstrated paramagnetic compound accumulation in the DN, caudate nuclei, and globi pallidi. Spectroscopy MRI showed a reduction of N-acetyl aspartate in the DN and globi pallidi (Fig. g, h). Whole-body bone scintigraphy with 99technetium-methylene diphosphonate (99Tc-MDP) showed intense, abnormal radiotracer activity in the distal femurs and whole tibiae bilaterally, with additional areas of weak uptake in the ulnae, radii, right mandible, and left maxilla (Fig. a, b). This pattern of skeletal colonization was further confirmed by fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging (Fig. e), and high resolution computed tomography (CT) of the femurs and tibiae consistently showed the presence of granulomatous lesions characterized by central demineralization and peripheral osteosclerosis (Fig. c, d). A brain 18F-Florbetaben PET was carried out to detect the presence of β-amyloid, but was unrevealing, as were CT scan of the thorax and abdomen and MRI of the heart.
The presence of xanthelasma, the biopsy findings, cerebellar degeneration and skeletal findings raised the diagnostic suspicion of ECD. Genetic testing of the formalin-fixed paraffin-embedded skin lesion identified the V600E, GTC > GAG mutation of the BRAF gene, further corroborating the diagnostic suspicion. To rule out a concomitant diagnosis of Rosai-Dorfman-Destombes disease [], a sternal fine-needle biopsy of bone marrow was performed and demonstrated the absence of emperipolesis. Immunostaining for S100 was negative, whereas a Kirsten rat sarcoma (KRAS) mutation was found in 1% of nucleated marrow blood cells.
Given the extensive CNS involvement, the patient was started on the BRAF inhibitor Vemurafenib at 960 mg bid. After 15 months, the patient is continuing on the same treatment. Multiple dose adjustments have been necessary in this timeframe as a result of the poor individual drug tolerance. Asthenia, weight loss, and palmoplantar fibromatosis have been the main adverse events. Clinically, the patient has benefited from the BRAF blockade, with disappearance of the xanthelasma and a progressive improvement of the cerebellar symptoms. Nonetheless, the CNS and skeletal findings have remained substantially unchanged, as demonstrated by follow-up imaging. The possibility of combining an anti-MAP2K1 agent with Vemurafenib was recently refused by the patient.


A 66-year-old female presented with easy fatigability and jaundice. Investigations at admission revealed a serum bilirubin of 6.8 mg/dl with no evidence of cholangitis. Clinical variables have been delineated in Table . Contrast enhanced CT (CECT) and magnetic resonance cholangiopancreatography (MRCP) showed an irregular enhancing wall thickening of the sub hilar region extending distally. She had preoperative biliary drainage by endoscopic nasobiliary drainage (ENBD). Endoscopic retrograde cholangiography (ERC) with multiple biopsies for tumor mapping revealed that the adenocarcinoma of common bile duct including intrapancreatic bile duct that was extended to the left hepatic duct (LHD) (Fig. ). Hence, tumor was designated as DSBDC with Bismuth-Corlette type IIIA, which involved the right anterior bile duct (RAD) and junction of the right posterior bile duct (RPD) and the LHD, and extended to the intrapancreatic bile duct. Once her serum bilirubin dropped to < 3 mg/dl, CT with drip infusion cholecystocholangiography (DIC-CT) was done. 3D integrated visualization reconstructed by CECT and DIC-CT data revealed that she had independent configuration of the right antero-ventral portal branch and antero-dorsal portal branch (Fig. ) []. The right antero-ventral bile duct (RAVD) confluent to the right hepatic duct (RHD) and the right antero-dorsal bile duct (RADD) independently confluent to RPD with a supra-portal course. Therefore, images showed tumor extended to the RAVD, but the RADD was intact because it was confluent to the distal side of the RPD. A modified central hepatectomy including resection of the segments IV and I, and right antero-ventral segment was done concomitantly with PD, and R0 resection was achieved. CT volumetry findings have been discussed in Table . Postoperative functional assessment of liver is included in Table . She underwent staged pancreato-jejunostomy 6 months later. She is doing well without recurrence at 17 postoperative months.


A 67-year-old male presented with jaundice. Investigations revealed a serum bilirubin of 12.4 mg/dl with evidence of cholangitis. Clinical variables have been delineated in Table . CECT showed an irregular wall thickening of the distal bile duct region which extended proximally. MRCP suggested distal bile duct stricture with dilatation proximally. He had preoperative biliary drainage by ENBD, and endoscopic tumor mapping using multiple targeted biopsies revealed adenocarcinoma extending intrapancreatic bile duct to the configuration of right and left hepatic ducts. Additionally, high grade dysplasia was evident from the LHD, RAD and root of RPD. Hence, tumor was designated as DSBDC with Bismuth-Corlette type IIIA hilar component. However, ERC shows the distal side of the RPD was not involved (Fig. ). 3D integrated images using CECT and DIC-CT data revealed that RPD join to LHD with supraportal course (Fig. ). CT volumetry findings have been discussed in Table . CHPD, which consist of the segments IV and I, and the right anterior sector, was performed with R0 resection. Postoperative liver functional assessment and pathological findings of resected specimens have been included in Table . He underwent staged pancreato-jejunostomy 4 months later, and doing well without recurrence at 19 postoperative months.


In November 2019, a 37-year-old man with no underlying disease presented with pain, a rash, and swelling in the right thigh. Two days prior, he was stung by a sea anemone while scuba diving in Cebu, Philippines. He was administered a tetanus injection at a hospital in Philippines. We made the diagnosis based on the characteristic shape of the wounds, which were caused by a sea anemone tentacle, and the patient’s statement.
On admission, generalized swelling and redness were observed on the right leg. A 20 × 15 cm wound and a purpuric, reticulated patch were observed on the right thigh (Fig. a). His blood pressure was 100/60 mmHg, and his body temperature was 36.6 ℃. His white blood cell count was 17,900 cells/mm3, hemoglobin level was 13.9 g/dL, platelet count was 303,000/mm3, blood urea nitrogen (BUN) level was 51 mg/dL, creatinine level was 5.12 mg/dL, aspartate aminotransferase level was 370 IU/L, alanine aminotransferase level was 209 IU/L, and serum creatine phosphokinase level was 401 IU/L (1-171 IU/L). Urine blood was + 2 positive, and RBC count was 0–1/HPF. Rhabdomyolysis was suspected, and subsequently, fluid therapy was initiated.
On day three, his platelet count rapidly decreased (36,000 cells/mm3); and renal dysfunction (BUN and creatinine concentrations were 85 and 9.86 mg/dL, respectively) gradually worsened. Oliguria was confirmed along with worsening pulmonary edema. Therefore, we initiated conventional hemodialysis.
On day four, his body temperature was 38.4 ℃ and C-reactive protein (CRP) concentration was 5.097 mg/dL. We suspected sepsis due to cellulitis and initiated broad-spectrum antibiotics. His white blood cell count was 10,760 cells/mm3, and leukocytosis was better than that at the time of the emergency visit. Fever was observed only once (38.4 ℃), and subsequently, his body temperature was normal. His blood pressure was also stable. Blood culture test results were negative; therefore, cellulitis was confirmed without diagnosis of sepsis. We also excluded disseminated intravascular coagulation since the results in our case fulfilled only two of the four Korean Society of Thrombosis and Hemostasis disseminated intravascular coagulation (DIC) criteria. DIC can be diagnosed when three or more of the following diagnostic criteria are satisfied: (1) Positive fibrin degradation products or D-dimer, (2) Platelet count < 100,000 cells/mm3, (3) Fibrinogen concentration < 150 mg/dL, and (4) prothrombin time (PT) ≥ 3 sec or activated partial thromboplastin time (aPTT) ≥ 5 sec []. In our case, the D-dimer and fibrinogen concentrations were 5.48 µg/mL (0-0.5 µg/mL) and 542 mg/dL, respectively, and PT and aPTT were 12 sec (0.4–13.3 sec) and 29.6 sec (23.2–39.4 sec), respectively.
The hemoglobin levels decreased to 7.4 g/dL with progressive thrombocytopenia and renal dysfunction. His blood lactate dehydrogenase (LDH) level was 3,354 IU/L (150–550 IU/L), and his haptoglobin levels decreased to 10 mg/dL (50–320 mg/dL). Schistocytes were observed on the peripheral blood (PB) smear, and the patient complained of a mild headache. We suspected thrombotic microangiopathy syndrome based on microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Thrombotic thrombocytopenic purpura (TTP) could not be ruled out until ADAMTS-13 results were available. Therefore, we performed a plasma exchange until ADAMTS-13 results were obtained. Complement sampling was performed prior to plasma exchange. The concentrations of serum complement 3 and complement 4 were 109.9 mg/dL (90–180 mg/dL) and 35.6 mg/dL (10–40 mg/dL), respectively, antinuclear antibody was negative, concentrations of antineutrophil cytoplasmic antibody was 0.21 U/mL (≤ 0.9 U/mL), anti-glomerular basement membrane antibody was 0.8 U/mL (< 20.0 U/mL), and ADAMTS-13 was 46.9%. Since TTP was excluded based on normal ADAMTS-13 level, we discontinued plasma exchange. After discontinuation of plasma exchange, the platelet count began to increase. The genetic test results associated with atypical HUS were normal. Genetic testing was performed at the Department of Laboratory Medicine, Samsung Seoul Hospital. A total of 18 genes (C3, C4BPA, C4BPB, CD46, CFB, complement factor H (CFH), CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, LMNA, THBD, MMACHC, PLG, ADAMTS-13) were tested. No clinically significant variants were detected in any of the 18 genes, including the CFH gene that accounts for about 22% of atypical HUS. Based on the above results, the patient was diagnosed with HUS caused by a sea anemone toxin. We continued conventional treatment that included hemodialysis, blood transfusion, and antibiotic administration. The wound turned necrotic, and it was debrided and dressed with betadine-soaked dressings (Fig. b).
On day 10, the hemoglobin level and platelet count normalized. In addition, the urine volume gradually increased, and hemodialysis was discontinued. The serum creatinine level was 7.2 mg/dL, LDH level decreased, and haptoglobin level normalized.
On day 21, the CRP level was 0.874 mg/dL. Therefore, we discontinued antibiotic administration. The wound was healing (Fig. c), and there was no pain or swelling on the right thigh. Even after discontinuing hemodialysis, the serum creatinine level continued to decrease and serum hemoglobin level remained stable (Fig. ). Additionally, the serum haptoglobin level, LDH level, platelet count, and schistocyte count on the PB smear were stable (Figs. and ). We continued wound dressing, blood tests and kept him under close observation. Finally, he was discharged on day 28. Six months after discharge, his serum creatinine level, hemoglobin level, and platelet count were normal.


Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.
Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% []. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.
She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m2 in the supine position to 1.9 L/min/m2 after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table ). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table ) (Figs. , , , , and ). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.


A 68 years old male had undergone total mesorectal excision 10 years before a skeletal metastasis of the lower leg was diagnosed. The patient was otherwise healthy except mild hypertension and there was no familial accumulation of endocrine or malignant diseases. Histology from the primary surgery showed a 5 cm intermediately differentiated adenocarcinoma of the rectum with no signs of neuroendocrine biology. The tumor was CK7 negative and CK20 positive. Distance to the nearest circumferential margin was 3 mm, and end resection margins were clear. There was no infiltration in the removed lymph nodes nor signs of distant metastases, thus the final TNM status was pT3N0M0. Total calcium was normal (2.37 mmol/L). Carcinoembryonic antigen (CEA) dropped from 18.0 μg/L preoperatively to 1.5 μg/L after surgery. No neo-adjuvant or adjuvant radiochemotherapy was given during the primary treatment. He underwent standard follow-up regimen with bloodwork, rectoscopies, ultrasound of the liver and chest x-ray for 4 years without any signs of relapse. CEA values were stable under 2.0 μg/L and only 1.0 μg/L when follow-up was completed.
Ten years after surgery, the patient presented with a tumor in the lower leg. X-ray and magnetic resonance imaging showed a 4.4 cm osteolytic lesion of the fibular head, in addition to a 4.7 cm tumor in the left lung and paratracheal pathological lymph nodes. Biopsies of the fibular head confirmed adenocarcinoma negative for CK7 and positive for CK20, and the pathologist concluded metastasis from the rectal cancer. The histological pattern was similar to the previously resected rectal tumor (Fig. ). CEA had now increased to 15.4 μg/L. He was treated by radiation therapy to the leg (8 Gy × 1) and commenced chemotherapy (fluorouracil, irinotecan, calcium folinate and bevacizumab). His lung pathology stabilized during this treatment and he reported less pain from the leg after the radiation therapy. However, the fibular tumor progressed radiologically and was 7 cm in diameter when it was resected 15 months after discovery. Resection margins were uncertain, and he developed a wound infection with a chronic fistula to the skin.
Three months later, the patient presented with hypercalcemia after being normocalcemic during all previous follow-up. Due to rapidly growing inguinal and retroperitoneal lymph nodes, he started treatment with fluorouracil, leucovorin, and oxaliplatin (FLOX). CT-scan showed stable disease after three cycles of therapy. Bloodwork revealed that CEA had increased markedly to 380 μg/L. He developed severe hypercalcemia with free ionized calcium reaching 1.81 mmol/L (total calcium 3.33 mmol/L), concurrent with peaks in CEA and PTH levels (Fig. ). Creatinine and estimated GFR was normal, phosphorus was low (0.62 mmol/L), and 1,25-dihydroxyvitamin D was low (24 nmol/L). He had no arrhythmias or other clinical symptoms related to the hypercalcemia. Fluid therapy and zoledronic acid had only short-lasting effect on the calcium levels. PTHrP was negative, but intact PTH was elevated to 54.4 pmol/L (normal range 1.1–7.5 pmol/L). The lab used a standard two-site immunoassay for measurement of the 84 amino acid long PTH, requiring binding in both the N and C terminals for detection. The high PTH led us to consider primary hyperparathyroidism as a differential diagnosis. Ultrasound of the neck and parathyroid scintigraphy with 900 MBq of 99mTc-methoxyisobutylisonitrile (MIBI) showed no signs of parathyroid adenomas. The diagnostic challenge was to distinguish primary hyperparathyroidism from ectopic PTH production in a colorectal bone metastasis or potentially another tumor.
To investigate if the tumor of the fibular head was responsible for the PTH elevation, we biopsied the tumor and stained for PTH. No significant staining was observed, using monoclonal antibody immunohistochemistry. Because such a large tumor can contain different clones of cells, a negative biopsy does not rule out that PTH could be produced from a part of the tumor not represented in the biopsy. Also, PTH immunohistochemistry on bone biopsies could be false negative for unknown technical reasons. We therefore measured blood PTH levels while excluding the lower right leg from the circulation by use of a blood pressure cuff on the thigh (modified Casanova test [], Fig. a). PTH levels measured in blood samples from the arm fell rapidly during the 20 min of right leg ischemia, consistent with local PTH production from the fibular tumor (Fig. b).
We concluded that the diagnosis was hypercalcemia caused by PTH secretion from the bone metastasis in the fibular head, and focused further treatment against the fibular tumor. The osteoclast inhibitor denosumab 120 mg was administered subcutaneously and further radiotherapy was given to the lower leg (3 Gy × 10). This made free calcium level stabilize at values around 1.40 mmol/L, and PTH was also attenuated (Fig. ). The patient received further cycles with FLIRI/bevacizumab until a year before his death. Six months before the patient died, another surge in PTH and calcium levels arose. Now, the patient received another course of radiotherapy (4 Gy × 5) towards his fibula, followed by a drop in PTH levels and normalization of calcium levels. No adverse events or side effects were reported by the patients or treating clinicians. The patient did not develop further episodes of severe hypercalcemia during the remainder of his life and died approximately 24 months after the first incident of severe hypercalcemia, due to disseminated disease involving skin, lymph nodes, lung, pancreas and brain.
As immunohistochemistry failed to show PTH in the fibular bone metastasis, we analyzed messenger ribonucleic acid (mRNA) from the same biopsies post mortem. Despite the long interval from biopsy to RNA extraction (5–16 years), we were able to extract total RNA from formalin-fixed paraffine embedded (FFPE) tissue sections and quantified PTH by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). We found evidence of PTH transcription in both the original rectal specimen and in the fibular biopsy taken after onset of hypercalcemia, but not in the fibular biopsy that was taken before onset of hypercalcemia, nor in ipsilateral inguinal lymph node metastasis (Fig. ). This is consistent with development of clinically significant PTH production within the fibular metastasis, after local recurrence and radiation therapy to the lower leg.


A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. . Laboratory results are shown in Table . Details of affected organ systems, diagnostics and therapies are listed in Table .
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table ).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. ) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected.
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. ). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. ). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.


A 28-year-old female with no significant past medical history was apparently healthy until presenting to the emergency department with 1 week of worsening diffuse abdominal pain. Her intermittent pain had suddenly worsened over night which prompted her hospital visit. This sudden escalation in pain was also accompanied with multiple episodes of vomiting. She had been constipated with no bowel movement for the entire week prior to presenting to the hospital. The patient stated to have a well-balanced diet and live an active lifestyle for most of her life.
Upon physical examination, the patient was in serious distress due to pain. Her vital signs were within normal limits. Her abdomen was very tender to palpations in all four quadrants. Rebound tenderness was also present. These signs and symptoms were of major concern, as they pointed towards the patient having developed peritonitis. A computed tomography (CT) of the abdomen and pelvis was conducted and was highly suggestive of a sigmoid colon volvulus. The CT showed a largely dilated colon with a pathognomonic “whirl” pattern present (see Fig. ).
Clinical suspicion for potential bowel necrosis was high given the patient’s peritoneal signs and sudden worsening of symptoms. Therefore, the patient underwent an emergent laparotomy. A sigmoidectomy of the distended portion of bowel was performed (see Fig. ). The remaining proximal and distal ends were inspected to be clean and a primary anastomotic continuity of the bowel was created. Intra-operatively, we noted an abnormally redundant sigmoid colonic mesentery.
The pathology report of the resected specimen revealed necrotic bowel with evidence of ischemic changes and focal ulcerations. Ischemic changes seen on microscopy included mucosal sloughing, mucosal hemorrhages, and fibrin deposition (see Fig. ). The patient recovered without complication with return to enteral nutrition and resumed bowel function. She was subsequently discharged on post operative day number five.


A 29-year-old male patient was brought to the emergency department (ED) by his family after witnessing swallowing multiple sharp metallic nails a day before the presentation. Upon assessment, he was completely asymptomatic. He had no history of abdominal pain, nausea, or vomiting. He didn’t report any changes in his bowel habits. The patient was noted to have some bizarre behaviors indicating poor judgment and low intellectual ability. Additionally, he was believed to have a regular follow-up in a psychiatric institute a couple of years back; however, he was not on any regular medication at the moment of presentation. Moreover, the family reported a history of substance abuse. On examination, his vital signs showed a pulse rate of 78 beats per minute, blood pressure of 117/78 mmHg, a temperature of 36.8°C, and oxygen saturation of 99% on room air. Local examination revealed a soft and lax abdomen with mild tenderness at the epigastric area. Laboratory investigations showed hemoglobin 15 mg/dl (13.5-17.2), white cell count 14.6 C 103/μL (4.0-11.0), neutrophils count 9.27 C 103/μL (2.0-7.0), lymphocytes count 3.64 C 103/μL (1.0-3.0). Chest and abdominal X-rays were obtained and showed multiple metallic nails in the left upper quadrant and lower abdomen, with no evidence of air under the diaphragm (Figures -).
A decision was made to take the patient for an exploratory laparotomy considering the patient’s clinical status and abdominal X-ray findings. Exploration was performed through a midline laparotomy incision, revealing no gross evidence of perforation. A gastrotomy was performed, and a total of 52 nails were extracted from the stomach (Figure ).
The bowel was then examined from the duodenojejunal junction to the ileocecal valve. Multiple nails were palpable at 100 cm proximal to the ileocecal junction. An enterotomy was performed, and 14 nails were extracted (Figures -).
The gastrostomy and the enterotomy were closed in two layers using an absorbable suture. After further examination and with the aid of the C-arm fluoroscopy, a cluster of nails was found at the vicinity of the ileocecal junction. Therefore, an appendectomy was performed, and a total of seven nails were extracted through the appendicular stump. Finally, intraoperative C-arm fluoroscopy was performed for assessment and showed no remaining nails within the abdominal cavity (Figure ).
Thus, a total of 73 nails were extracted successfully (Figure ).
The patient had an uneventful postoperative course. The nasogastric tube was removed on the second postoperative day, at which he started tolerating oral feeding. The patient was discharged home on the ninth postoperative day and was followed in the outpatient department for three weeks. He developed a mild wound infection, for which he was treated with oral antibiotics and regular wound dressing. Psychiatric consultation was sought during the patient’s hospital course. He was started on atypical antipsychotic medication (olanzapine), to which he responded very well. Eventually, he was referred to a specialized psychiatric institute.


A 51-year-old male known with diabetes, hypertension, ischemic heart disease, chronic kidney disease, upper gastrointestinal bleeding, and morbid obesity was referred for a CT brain by the ophthalmology department as part of the workup of proptosis. The patient had no clinical features to suggest Graves' disease or Cushing's syndrome. The TSH (15.3 pmol/L) as well as the 08:00 serum cortisol (345 nmol/L) were normal.
The CT brain showed bilateral proptosis measuring 29.9 mm from the anterior aspect of the globe to the interzygomatic line, and the posterior aspect of the globe was 6.3 mm anterior to the interzygomatic line (). Marked prominence of retroorbital fat was evident. The globe, extraocular muscles, skeletal structure, and vessels were normal. Importantly, there were no ocular, intraconal, or extraconal masses. The rest of the intracranial structures, including the pituitary gland, were normal with no features of hydrocephalus.