Since birth, a six-year-old girl was referred to our tertiary care center with a large central chest wall defect. She was a full-term normal delivery with no other congenital malformations. The defect was noticed at birth and became more evident as she grew up. In addition to cosmetic concern on coughing, there was bulging under the skin and visible cardiac pulsation. On examination, there was a large gap (7cm) in the midline of the chest with sternal adages well apart, moving independently. : A &B. Necessary blood investigations liver and renal panel were normal. Chest x-ray showed that the sternum body had not ossified, and the medial ends of the sternum were far away from the midline The lung fields were clear. CT of thorax with the 3-D scan of the thorax showed a large sternal cleft : C & D. They already had an opinion from the surgeon of another institute who explained the defect would be covered by bilateral pectoralis major muscle flaps and bone graft. Parents were concerned about the cosmoses of their girl. A family meeting was arranged to discuss the reconstruction of the defect, and our surgical technique and material to be used for reconstruction were explained, and they consented to the procedure and photographs. Patient was placed in a supine position under general anesthesia. She received prophylaxis antibiotic, cephalosporin. A midline incision was made from the sternal notch to the xiphoid process. Sternal edges were exposed by raising the bilateral muscle flaps, and pericardium and pleura were preserved and dissected free of sternal edges. A The defect was measured, and the MMS plate was made and molded according to the defect's shape and neosternal notch was created. Holes were drilled in the sternal edges and correspondingly in the MMS plate. Wires (5 mm) were passed through the bone, and the MMS plate was fixed by twisting the wires, and the prolene mesh was sutured with 2–0 prolene to the surrounding tissues. : B & C. The anterior chest wall wound was closed by approximating the soft tissues and pectoralis major muscles. The skin was closed without the use of a myocutaneous flap.
The patient was extubated on the table and transferred to a high dependency unit for overnight observation. The patient had an uneventful post-operative recovery and was discharged home for follow up in outpatient clinic. The wound was nicely healed without any residual defect. : D.
Operative steps are shown in illustrated drawings : A, B & C.


Patient 1 is an 11-year-old girl from non-consanguineous Caucasian parents with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who underwent an allogeneic HSCT for the treatment of refractory immune dysregulation.
LRBA deficiency is a rare primary immunodeficiency characterized by the combination of a pathological susceptibility to infection and autoimmune phenomena including inflammatory bowel disease, diabetes mellitus, arthritis, autoimmune cytopenia, and interstitial lung disease. LRBA is an important regulator of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a major role in the modulation of immune responses of T cells and other immune cells []. Patient 1 is compound heterozygous for two deletions—a paternally inherited deletion of exons 3–48 and a small maternally inherited deletion in exon 23. In the western blot, LRBA protein was undetectable, demonstrating that both mutations are disease-causing (data not shown). One of the patient’s siblings also had LRBA deficiency and succumbed due to uncontrollable autoimmune cytopenia at the age of 4.
P1 developed various clinical problems in the context of LRBA deficiency. The leading clinical problem had been infant-onset autoimmune enteropathy, which resulted in failure to thrive and necessity of long-term partially and finally complete parenteral nutrition and additional tube feeding since infancy. Insulin-dependent diabetes mellitus with repeated crisis-like derailments was first diagnosed at the age of 1.5 years. Since the age of 4, P1 presented with oligoarthritis of the lower extremities. In contrast to her deceased LRBA-deficient brother, she had no history of autoimmune cytopenia before HSCT was performed. Moreover, no pathologic susceptibility to infections had been noted before HSCT, and B cell differentiation was normal without the need for immunoglobulin substitution. Because of her multiple autoimmune manifestations, P1 received long-term immunosuppressive therapy with azathioprine (since 1.5 year of age), sirolimus (since 3 years of age), intermittent systemic steroid therapies during autoimmune flare-ups, abatacept (for 6 months at the age of 6 years; discontinued due to associated fever episodes), hydroxychloroquine since the age of 8 years, and intermittent anti-inflammatory therapy with ibuprofen for knee joint arthritis.
The indication for allogeneic HSCT was based on the insufficient control of autoimmunity despite multimodal immunosuppressive therapy, persistent enteropathy, and failure to thrive despite parenteral nutrition and the expected aggravating natural course of the disease.
Following a myeloablative preparative regimen consisting of thiotepa (1 × 8mg/kg), treosulfan (3 × 14g/m2), fludarabine (4 × 40mg/m2), and anti-thymocyte globulin (3 × 15 mg/kg), the patient was grafted with bone marrow from a 10/10 HLA-matched unrelated female donor. She received 7.32 × 108 nucleated cells per kilogram of body weight, changing blood type from B rhesus positive to O rhesus positive. She experienced early complete engraftment with a leukocyte, neutrophil, and platelet engraftment on days +18, +20, and +24, respectively. Following graft-versus-host disease (GvHD) prophylaxis with methotrexate and cyclosporine A, we observed no signs of GvHD. Besides transient grade 2 mucositis, the girl had an uneventful post-transplant course. The chimerisms on days +29 and +53 in the peripheral blood showed full donor origin.
Between day +58 and day +61 after HSCT, our patient’s platelet count dropped from 142.000 to 5.000/μl, clinically compatible with an immune-mediated thrombocytopenia. We excluded thrombotic microangiopathy as a potential cause of the thrombocytopenia (normal LDH, no fragmented red blood cells, continuously controlled hypertension, no proteinuria) [] and measured a normal ADAMTS13 level and activity, no antibodies against ADAMTS13, and a stable creatinine. We performed platelet-associated antibody testing, which revealed the presence of free anti-platelet antibodies in the patient’s serum, mostly reactive against the glycoprotein complex GIIb/IIIa. Testing for platelet HLA antibodies was negative.
In the first weeks of thrombocytopenia, the only bleeding signs were skin hematomas, petechia, and mild oral mucosal bleeding. Gradually, P1 started experiencing recurrent episodes of Hb-relevant bleeding (severe epistaxis and gastrointestinal bleeding), requiring multiple packed red blood cell (PRBC) transfusions. Overall, since the diagnosis of the immune-mediated thrombocytopenia, P1 received 163 platelet and 18 PRBC transfusions.
We initiated treatment with high-dose corticosteroids (initially 2 mg/kg/day) and 4 doses of intravenous immunoglobulin (1 g/kg) from day +61 onward (Fig. a). Additionally, P1 received 4 doses of rituximab (375 mg/m2) and eltrombopag 50 to 75 mg daily, all without significant impact on her platelet count. Cyclosporine A (trough level 150–200 ng/ml), primarily administered for GvHD prophylaxis, was switched to sirolimus (trough levels 8–12 ng/ml), also without any significant response.
Given the persistence of severe thrombocytopenia despite B cell depletion with rituximab, we hypothesized that plasma cells are the likely source of the anti-platelet antibodies and initiated a plasma cell depleting therapy with daratumumab in week 8 of P1’s AIT. We administered the anti-CD38 antibody in a dose of 16 mg/kg per week i.v. The first infusion caused nasal congestion and bronchial obstruction, whereas the next infusions were well tolerated. Twenty-five days after the first dose of daratumumab and after a total of 4 administrations, the girl’s platelet count rose rapidly and the bleeding stopped. The patient’s platelet count reached 55.000/μl on day +152 after HSCT, when she was discharged, and normalized to 192.000/μl on day +159, 41 days after the first dose of daratumumab. Nine months after the cessation of treatment with daratumumab, the girl is clinically well with normalized platelet counts. One year after HSCT, we continuously see full donor chimerism and no symptoms of LRBA deficiency besides her pre-HSCT existing type I diabetes, which is well controlled. P1 experiences a gradual B cell recovery, albeit still relying on substitution of immunoglobulins.


Patient 2 was a 6-year-old boy from non-consanguineous Caucasian parents with CD40L deficiency who underwent allogeneic HSCT because of the expected natural history of CD40L deficiency with severe opportunistic infections and non-reversible organ damage.
CD40L deficiency, also referred to as X-linked hyper IgM syndrome, is a rare primary immunodeficiency characterized by an immunoglobulin class switch defect from IgM to IgG and a defect in T cell activation. CD40L acts as a costimulatory molecule which induces a variety of effects in the adaptive immune system after binding to its receptors, the most important one of which is CD40 on antigen-presenting cells. CD40L-deficient patients suffer from recurrent bacterial infections from early childhood as well as opportunistic infections, non-infectious diarrhea, and liver disease []. HSCT outcome and long-term quality of life are more favorable, if performed early and in the absence of previous opportunistic infection and/or end-organ damage [].
P2 was diagnosed with CD40L deficiency at the age of 4.5 years. He was hemizygous for a pathogenic mutation (c.686T>C; p.Phe229Ser) in the CD40L gene. The mother was identified as a carrier. Functional testing confirmed defective upregulation of CD40L on T cells after PMA stimulation in vitro (data not shown).
At age 1 he presented with a pronounced eyelid phlegmon for which he was hospitalized. Subsequently, he showed recurrent bilateral episodes of perforating otitis media. In the 3rd and 4th year of life, radiologically confirmed pneumonia with protracted recovery occurred. At the age of 3 years, P2 experienced an onset of transient diarrhea episodes, for which no infectious triggers could be identified and was therefore judged an immune dysregulatory manifestation of his disease. From age 5 onward, P2 received prophylactic treatment by intravenous immunoglobulin substitution and cotrimoxazole.
P2 underwent HSCT at the age of 6 years and was grafted with bone marrow (6.81 × 108 nucleated cells per kilogram of body weight) from a 9/10 HLA-matched unrelated male donor, following the same conditioning regimen and GvHD prophylaxis as P1. He changed blood type from O rhesus negative to O rhesus positive. During the uneventful post-transplant course, besides grade 2 mucositis, there was timely hematologic recovery with leukocyte and neutrophil engraftment on day +22 and platelet engraftment on day +20. We observed no signs of acute GvHD. The chimerisms on days +30, +43, +62, +100, and +149 in the peripheral blood and on day +149 in the bone marrow aspirate showed full donor origin.
Between day +55 and day +58 after HSCT, P2’s platelet count instantly dropped from 186.000 to 14.000/μl, and he was diagnosed with post-transplant AIT. We initiated treatment with 2 mg/kg/day prednisolone, combined with four doses of IVIG (0.4g/kg/day), and continued GvHD prophylaxis with cyclosporine A. This regimen initially resulted in a transient recovery of P2’s platelet count (Fig. b).
During the following prednisolone tapering, the patient’s AIT relapsed on day +83 with a dropping platelet count to 9 × 103/μl. In addition, P2 was then additionally diagnosed with first signs of AIHA, based on the signs of hemolysis in the laboratory analysis (hemoglobin 8.6 g/dl, reticulocytosis of 41‰, positive direct Coombs test). Further immunological studies revealed the presence of anti-E, heat, and cold autoantibodies as well as free platelet-reactive antibodies, in P2’s serum, providing immunological correlates of AIHA and AIT.
Since steroid treatment was refractory, we administered high-dose IVIG (1 g/kg/dose) in combination with rituximab (375 mg/m2/dose, a total of weekly 6 doses) starting day +87. Due to severe thrombocytopenia with platelet counts of 2–9 × 103/μl, our patient received daily single-donor apheresis platelets.
With this regimen, P2 showed again signs of response on day +98 and reached a phase with a stable platelet count and less hemolysis during prednisolone tapering. Unfortunately, on day +177 our patient relapsed again with signs of increased hemolysis, yet a stable platelet count.
We increased prednisolone again to 2 mg/kg and extended our therapy to daratumumab (16 mg/kg/dose) on day +184 with the rationale to deplete antibody-producing plasma cells after an unavailing B cell depletion. Upon the first administration of daratumumab, P2 developed transient and uncomplicated bronchial obstruction and vomiting. The following doses on days +192 und +200 were tolerated well.
On day +190, P2 experienced another acute flare of autoimmune hemolyis. Given the rapid dynamics of the AIHA, we initiated additional antibody reduction by plasmapheresis, which was performed on days +190 to +192 and +195 to +199. The patient required daily PRBC transfusions.
Despite the high frequency of plasmapheresis, the elimination of RBC antibodies was not sufficient enough and starting from day +199 P2 developed signs of a hypovolemic shock and aggravated hemolysis with Hb levels <3 g/dl. He received a salvage therapy by methylprednisolone pulses (20 mg/kg/day for 3 days), three doses of IVIG (1 g/kg/day), and one dose of eculizumab (25 mg/kg). Without any response to this therapy, P2 deceased from cardiac arrest due to acute heart failure most likely related to pulmonary embolism.


The index patient was a 8-year-old female patient born from non-consanguineous parents (). Eczema started at the age of 6 months and it was treated with topical steroids and emollients. Recurrent skin bacterial infections occurred, but they responded well to topical antibiotics. At the age of two, she had two episodes of parotitis treated with intravenous antibiotics. The second one was complicated by cellulitis. Vulvovaginal candidiasis occurred once, along with abscess of the outer labia. At the age of three, she had thrombocytopenia in the setting of active EBV infection (). Platelet count did not increase with high doses of intravenous immunoglobulin (IVIg), requiring oral steroids. Thereafter, EBV DNA remained detectable with viral load ranging from 2 x 102 to 5 x 103 copies/ml. During the follow-up, persistent lymphadenopathies and lymphopenia were detected. Hypereosinophilia was never observed. IgE, initially within normal range, mildly increased by the age of 6 (). Upper and lower respiratory tract infections were frequent. The most common bacterium in sputum was Haemophilus Influenzae. Bacteria were always sensitive to commonly-used antibiotics. Antimicrobial, antiviral, and antifungal prophylaxis and monthly IVIg infusion were started with good clinical improvement. Lung computed tomography performed at the age of six showed diffuse bronchial wall thickening with tree-in-bud opacities and mediastinal adenopathies. Incidentally, marked enlargement of the biliary tree was noticed, which was absent at a previous abdominal ultrasound. Liver test were normal (including alanine transaminase, aspartate transaminasase, gamma-glutamyltransferase, prothrombin time, and total bilirubin) except for mildly increased bile acids. Testing for infectious agents, including Rotavirus, Adenovirus, Clostridium Difficile, Giardia, and Cryptosporidium was negative. With respect to Cryptosporidium, fecal samples were repeatedly tested by means of microscopic analysis and chromatographic immunoassay for the detection of Cryptosporidium antigens. Marked dilation of intrahepatic bile ducts (more pronounced at the right system) and dilation of the common bile duct (up to 7 mm and without any mass forming lesion in the lumen) were then confirmed by means of abdominal ultrasound and magnetic resonance imaging (). Liver biopsy showed one dilated duct with “onion-skin” type of periductal fibrosis and portal and acinar inflammation consistent with SC (). Fecal calprotectin was mildly increased (185 μg/mg; normal up to 50 μg/mg). Upper gastroenterology endoscopy showed enlarged duodenal papilla. Histology revealed moderate chronic gastritis and mild chronic inflammation of the duodenal mucosa. Colonoscopy showed mild mucosal inflammation with mixed cell infiltrate, including macrophages, eosinophils, and plasma cells. Considering the good clinical condition, endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy of the major duodenal papilla was successfully performed with disposable duodenoscope () and no immunosuppressive treatment was initiated. Patient remained well, without any abdominal symptom.
During the follow-up, neutropenia was detected with occasionally normal neutrophil count (). Analyses of main lymphocyte population consistently displayed reduced T cell counts compared to age-matched healthy controls (HC), while evaluation of lymphocyte subsets revealed a moderate reduction of naïve T cells and memory B cells. At 7 years of age, regulatory T cells (Treg), defined as CD4+CD25+CD127low/- cells, were analyzed, resulting in a percentage that was below the detection limit of age-matched HC and in a significant reduction of their absolute count (below 2SD from mean; ). The release of new lymphocytes by the thymus, either quantified by means of T-cell receptor (TR) excision circles (TRECs) or recent thymic emigrants’ counts, was reduced in comparison to that of age-matched HC. Flow cytometric analysis of T lymphocyte proliferation by incorporation of carboxyfluorescein diacetate succinimidyl ester was assessed, displaying a markedly reduced proliferation ability at the level of CD8+ cells either upon stimulation with phytoemoagglutinin (PHA) or with anti-CD3 monoclonal antibody. Spectratyping analysis of T-cell receptor variable beta (TRBV) chain subgroups revealed a restricted T-cell repertoire. The production of new B-lymphocytes from the bone marrow, measured by means of K-deleting recombination excision circles (KRECs), was comparable to that HC. Evaluation of serum immunoglobulins indicated reduced IgM and moderately elevated IgE ().
Considering the clinical manifestations and the immunology evaluation, combined immunodeficiency was suspected, and molecular analysis performed. At the age of seven, using targeted next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA), we identified distinct biallelic variants in DOCK8, which were not present in public databases (gnomAD, ESP, and 1000 Genomes) and were exclusive to this family in our internal databases. NGS revealed a heterozygous NM_203447:c.T824A variant in exon 7 of the DOCK8 gene, resulting in a premature stop codon (p.L275*), which was confirmed by Sanger sequencing (). The father was heterozygous carrier of the variant. Single nucleotide polymorphism (SNP) array and MLPA revealed the maternally inherited deletion of exons 1 to 3 (). Both variants are supposed for their nature to lead to a null DOCK8 phenotype being pathogenetic (class 5). Flow cytometric and western blot analysis showed markedly reduced, but not absent, DOCK8 expression in patient’s interleukin-2 (IL2)-PHA expanded T-cells, CD3+CD4+ and CD3+CD8+ while DOCK8 expression was absent in monocytes. These results collectively suggested hypomorphic residual function in T-cells (). Sanger sequencing analysis performed on epithelial cells as well as on peripheral T-cells confirmed the presence of the heterozygous status for the T824A variant in all the lineages, excluding the possibility of somatic reversion for this variant, while a somatic reversion of the deletion was detected by MLPA analysis in patient’s T-cells blasts (). STAT5 phosphorylation in T-cells (both CD3+CD4+ and CD3+CD8+) was reduced either after anti-CD3/CD28 or IL-2 stimulation (). To examine the role of the novel variants in the IS, CD8+ were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies to mimic the interaction between CD8+ cells and dendritic cells. Patient’s cells exhibited a significantly reduced actin polymerization in response to stimuli, whose distribution pattern was similar to the one displayed by LFA-1 ().
Haploidentical related donor HSCT was performed at 7 years and 6 months of age. Due to donor specific anti-human leukocyte antigen antibodies, desensitization protocol included a single dose of 375 mg/m2 rituximab and plasma exchange. Conditioning regimen included 2 days of low dose cyclofosmamide, 5 days of fludarabin, 3 days of busulfan and 200 cGy total body irradiation. Graf-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (from day -1, ongoing), cyclofosfamide (on day +3 and +4) and mycophenolate (from day +1 to day +26). Neutrophil engraftment (0.5 x 109/l) occurred at day +17 (1.0 x 109/l at day +19) and platelet engraftment (20 x 109/l) occurred on day +18 (50 x 109/l at day +19). Complete donor chimerism was detected on day +25 and thereafter checked every 14 days. Main complication after HSCT was hyperacute stage 2 grade 1 skin GVHD on day +16, which required additional therapy with methylprednisolone at 1 mg/kg/day and resolved on day +18. CMV reactivation on day +34 was successfully treated with valganciclovir. The patient is now alive and well 122 days after HSCT, with no signs of GVHD. Chimerism will be checked every 14 days until day +180 and afterward once a month until 1 year after HSCT.


A 31-year-old man without previous medical history presented to the emergency department with acute back pain that had started suddenly during weightlifting. Initially, spinal disc herniation was suspected by the orthopedic surgeon and the patient was discharged. He returned four hours later with pain and a sense of numbness in the right leg and an absence of femoral pulses bilaterally. A thoracoabdominal computed tomography (CT) angiography (Fig. ) showed embolism to the left renal artery, splenic artery, and a massive thrombus in the aortoiliac arteries. Then the CT scan was elongated to include the lower limbs, which revealed embolism in the right superficial femoral artery. The vascular surgeon decided to perform an acute embolectomy.
Laboratory tests for C-reactive protein, hemoglobin, and thrombocytes were normal, but leukocytes were slightly elevated at 13.3 × 109/L. The coagulation samples showed PK INR level of 1.1, APTT 32 s, fibrinogen 2.5 g/L, D-dimer 1.55 mg/L, and antithrombin 1.08 kIU/L. Because this occurred during the coronavirus disease 2019 (COVID-19) pandemic, polymerase chain reaction for SARS-CoV-2 was performed and was negative.
The surgical procedure confirmed embolism of both acute and chronic appearance; soft black thrombi suggesting acute formation and white hard cylindrical (shape of the iliaca vessels) suggesting chronic forms. During surgery, a medial and lateral lower leg fasciotomy was also performed on the right side in order to prevent post-operative compartment syndrome.
Following surgery an echocardiography (Additional files –: Videos S1–S4) demonstrated left ventricular inferior hypokinesia, an ejection fraction of 30–40%, and two large thrombi in the left ventricle (Figs. and ). The ECG showed sinus rhythm with minor intraventricular conduction delay but was otherwise unremarkable. During a four day stay at the intensive care unit the patient was initially treated with low molecular weight heparin with a dose of 5000 IU twice daily (because of recent surgery) and this was slowly increased to full dose. The hormone T4 was 15.5 pmol/L, T3 2.6 pmol/L, thyroid stimulating-hormone 0.65 mIU/L, and testosterone 6.1 nmol/L. Troponin T was elevated at 75 ng/L, N-terminal pro-B-type natriuretic peptide was 310 ng/L, and anti-SARS-CoV-2(ECLIA) was negative.
At the second day after admission a cardiac magnetic resonance imaging assessed reduced ejection fraction (44%), it also showed a thrombus in the left ventricle (Fig. ) and late gadolinium enhancement of the inferolateral and septal regions (Figs. and ), which indicated recent myocarditis. Two large thrombi, previously seen on echocardiogram, were visualized in the midventricular-apical region. A more detailed patient history was taken, and the patient reported an episode of fever, chest pain, and shortness of breath two months earlier but never sought medical attention for this. This was interpreted as myocarditis likely due to viral infection.
Successful suture of the fasciotomy was performed six days after the primary surgery. The patient was transferred to an internal medicine ward. Tests for coagulopathies were taken and included haptoglobin which had a level of 1.45 g/L and homocysteine with a level of 28 µmol/L (slightly elevated). Moreover, S-anti-GBM, S-anti-myeloperoxidas, and S-anti-proteinase 3 were normal.
The patient was negative for mutations in JAK2, CALR, MPL, factor II, and V test for paroxysmal nocturnal hemoglobinuria was negative and so were the tests for protein C, protein S, antiphospholipid antibodies (anticardiolipin, anti-beta2-glycoprotein I, and lupus anticoagulant).
Magnetic resonance imaging of the brain demonstrated a non-acute infarct in the left parietal lobe. Ultrasound of the carotid and vertebral arteries were normal. A second echocardiography, performed 11 days after the first, showed slight improvement of left ventricular systolic function, but two thrombi were still present. Apixaban 5 mg twice daily was initiated, but subsequently replaced with warfarin because the thrombi remained at follow-up. ECG showed premature ventricular complex. Bisoprolol and candesartan were titrated, prescribed and the patient scheduled for further follow-up in the cardiology department. Six months after hospital discharge an echocardiogram showed improvement of left ventricular function with an ejection fraction of about 45% and resolution of the thrombi.


Has been reported in line with the SCARE 2018 criteria.
A 12-year-old medically free boy presented to the Head and Neck Clinical Department of Prince Sultan Military Medical City (PSMMC) in Riyadh in 2016 complaining of tongue swelling “at the age of 8 year old” and who had been asymptomatic since birth; , the tongue had not increased in size or changed colour, there was no history of pain, burning sensation, dysphagia, paraesthesia, bleeding from the lesion. There were no other masses in his mouth or other body areas. There was no history of allergies with negative family history of any head and neck masses or genetic disease. On examination, a smooth cystic mass was observed on the right side of the ventral tongue, with no other abnormalities detected in the nose, nasopharynx, larynx, ear or neck.
In 2018 the tongue mass started to increase in size and interfere with speech, but laboratory investigations were normal. The patient underwent a contrast-enhanced CT scan, which was inconclusive, and the MRI with infusion results are show in . The patient was admitted in December 2018 and underwent intra-oral excision of the ventral tongue mass under general anaesthesia by head and neck consultant with no complications (). The patient was discharged on the same day with antibiotics and analgesia, with instruction to consume a soft diet before advancing, and with follow-up after 2 weeks. The patient currently undergoing follow-up in the clinic; since discharge, there have been no signs or symptoms of recurrence.


The patient is a 75-year-old Caucasian female with a past medical history of major depressive disorder who presented to the emergency department for altered mental status. She was brought in by ambulance after the patient developed acute aphasia and was unresponsive to verbal commands. She had developed generalized weakness, decreased oral intake, and recurrent falls over the past several weeks. Over the previous year, she had been increasingly developing abnormal dietary habits, including obsessively eating canned peaches, dairy products such as milk and cheese, and refusing to eat any leafy green vegetables. However, her mentation remained sharp, as she was able to have meaningful and in-depth conversations, up to until her recent symptoms had developed. Her initial vital signs indicated a temperature of 86.7 degrees Fahrenheit via rectal thermometer, hypertensive at 154/60 mmHg, bradycardic at 48 beats/minute, respiratory rate of 18 breaths/minute, and saturating 99% on room air. On physical exam, she was responsive only to painful stimulation, with a Glasgow Coma Score (GCS) of 8. However, she was able to spontaneously move all of her extremities and intermittently opened her eyes. Initial laboratory values were significant for hyponatremia of 120 mmol/L (reference range 135 - 145 mmol/L), glucose of 69 mg/dL (reference range of 74 - 106 mg/dL), white blood cell (WBC) count of 1.22 1000/uL (reference range of 4.50 - 10.50 1000/uL), ammonia was within normal limits as was the thyroid-stimulating hormone (TSH) (Table ).
Initial CT scan of the head revealed a questionable hypodensity in the left middle cerebral artery (MCA) distribution in the temporal region. She was started on a forced-air warming blanket and admitted to the intensive care unit for concern for a cerebral vascular accident and hypothermia. Subsequent MRI of the brain revealed no acute intracranial findings, including no acute infarct. Mild fluid-attenuated inversion recovery (FLAIR) hyperintense foci within the supratentorial white matter was noted. Electroencephalogram (EEG) revealed continuous generalized slowing that was suggestive of moderate encephalopathy (Figure ).
Lumbar puncture revealed a mildly elevated cerebrospinal fluid total protein of 53 mg/dL (reference range of 15-45 mg/dL) and glucose of 71 mg/dL (reference range of 40-70 mg/dL). Her hypothermia resolved and she was transferred to the general medicine wards, however, her mentation did not improve. She remained unresponsive to verbal commands, responded only to painful stimuli, and appeared to develop nuchal rigidity, with a flat affect. Lorazepam was administered to treat for possible catatonia, however, her symptoms did not improve. Given her previous history of malnutrition, she was administered intravenous high-dose thiamine (Vitamin B₁). The following day, the patient’s mentation had improved significantly. She was able to answer questions and hold conversations. She still had partial confusion, but was alert and oriented to person and time. Her family confirmed that her improvement was closer to how she was behaving prior to admission. Subsequently, she suffered a series of mechanical falls as a consequence of persistent gait ataxia. Following her falls, her level of alertness and speed of cognition continued to improve. As her cognition returned she began to question the daily plans told to her by her physicians, physical therapists, and even her family. While some of what she said included confabulation, she rapidly became more oriented to the events around her. By the time she was deemed stable for discharge, she was able to clearly explain why she was in the hospital, as well as her post-discharge plan, but she was not able to recall events that took place during the three weeks leading up to her admission. Afterward, she was discharged home.


A 37-year-old Caucasian woman arrived at the emergency facility with severe respiratory distress, associated with pleuritic pain and tachycardia. She denied any previous comorbidities or use of medications, except for a nine pack-year history of smoking. The patient reported she had applied a cleaning substance to wash a stone floor in a small and closed room. After a few minutes, she came back into this room to scrub the floor, and within a short period, she started to feel discomfort and dyspnea and left the room. Her dyspnea became progressively worse in the following two days when she decided to look for help.
On admission, the patient had a respiratory rate of thirty-eight breaths per minute and diffuse wheezing and rhonchi. She was treated with three fenoterol cycles (2.5mg) and ipratropium (0.5mg) inhalation. Meanwhile, we identified she had used a cleaning substance composed mainly of hydrochloric acid (HCl). Her exams showed leukocytosis of 23.06x106/L (RR: 4.0 - 11.0 x106/L), composed of 88% neutrophils and 1.3% eosinophils; a C-reactive protein of 256mg/L (RR: below 5 mg/L), and the arterial blood gas collected with 35% of the fraction of inspired oxygen (FiO2) had a pH of 7.34 (RR: 7.35 - 7.45), the partial pressure of Oxygen (PaO2) of 74.5mmHg (RR: 80 - 100 mmHg), the partial pressure of carbon dioxide of 35.8mmHg (RR: 35 - 45 mmHg), bicarbonate of 19.2mmol/L (RR: 21 - 28 mmol/L), base excess of -5.2mmol/L (RR: -3 - +3 mmol/L), oxygen saturation of 93.6% and a PaO2/FiO2 ratio of 212. The chest radiograph showed bilateral interstitial infiltrates (). The patient met the Berlin criteria for acute respiratory distress syndrome. Despite treatment with bronchodilators and non-invasive ventilation, the patient became progressively worse, and her respiratory rate increased to 55 breaths per minute (bpm). Orotracheal intubation proceeded after ketamine, propofol, and succinylcholine, and she was set up on mechanical ventilation using parameters for lung protection with a low tidal volume. She was admitted to the intensive care unit and rapidly improved within the following twenty-four hours. A chest computed tomography (CT) scan showed diffuse asymmetric bilateral ground-glass opacities (). She was successfully extubated the next day. Non-invasive ventilation was necessary for the first 4 hours after extubation due to bronchospasm. Methylprednisolone 60mg intravenously was given for the first two days, followed by prednisone 40mg orally for four days. The patient presented a dry cough and slight limitation of physical activity. She denied any other symptoms and was discharged.
We evaluated her one year after her index admission. In the first three months, the patient continued to present shortness of breath, cough and wheezing, which could be triggered by minimal concentrations of irritants. Since her index admission, the patient had had four more admissions to the Emergency Department with respiratory complaints. Her clinical exam revealed no abnormality, and she stated she stopped smoking since the event. The spirometry data showed a forced expiratory volume in one second (FEV1)/ forced vital capacity (FVC) ratio of 0.79 (the predicted ratio for her was 0.83); reduced FEV1 (77% of predicted) and FVC (81% of predicted). There was pulmonary flow gain after bronchodilator use (Delta FEV1= 260ml and 12%), demonstrating a positive response to bronchodilator and a mild obstructive ventilatory disorder. In the body plethysmography, the total lung capacity (TLC) was 102% of predicted; and the thoracic gas volume (TGV) was 114% of predicted. The residual volume (RV) was at the upper limit of normality (137% of predicted), and there was a high RV/TLC value of 42 (135% of predicted), suggestive of air trapping. A normal diffusion capacity was seen (78% of predicted).


An asymptomatic 71-year-old man presented with an abnormal lung nodule detected by computed tomography (CT) during a regular postoperative checkup for renal cancer. CT revealed a nodule in the right lower lobe and a PAPVC of the right superior pulmonary vein with the azygos vein (Fig. ). Transbronchial biopsy revealed adenocarcinoma. The echocardiogram and electrocardiogram showed normal cardiovascular activity without atrial septal defect. Although the patient was asymptomatic, cardiac catheterization revealed a pulmonary to systemic flow ratio (Qp/Qs) of 1.64, and his mean pulmonary arterial pressure (MPAP) was 16 mmHg (27/6 mmHg). Blood gas analysis revealed age-normal partial oxygen (79.7 mmHg) and carbon dioxide pressures (41.5 mmHg). Pulmonary function tests showed forced expiratory volume in the first second of 2.29 L (78% predicted) and forced vital capacity of 3.34 L (93% predicted). His lung cancer was considered to be resectable clinical T1c N0 M0 stage IA3 and right lower lobectomy was planned; however, it was considered that this could cause fatal right-sided heart failure unless the PAPVC was repaired. The possible surgical approaches of right lower lobectomy for the lung cancer and concurrent PAPVC repair were discussed preoperatively with a cardiovascular surgeon.
We were concerned that the patient might be at risk of fatal postoperative right-sided heart failure without PAPVC repair. However, he had no atrial septal defect and was asymptomatic, and we therefore concluded that it was not necessary to treat the PVPAC. Based on these considerations, we decided to only perform concomitant repair of the PAPVC if his circulatory dynamics could not be maintained during surgery or if his MPAP exceeded 25 mmHg.
The patient’s pulmonary artery pressure was carefully monitored during surgery using a Swan-Ganz catheter. His MPAP was 20 mmHg; therefore, we performed thoracoscopic right lower lobectomy, without repairing the PAPVC. The anomalous pulmonary vein was found on the anterior aspect of the right hilum. In accordance with the CT observations, we found a PAPVC of the right superior pulmonary vein with the azygos vein (Fig. ). The patient had an uneventful postoperative course. The lung cancer was confirmed as pathological stage IA3 (T1c N0 M0). Postoperative cardiac catheterization 6 months after surgery revealed a Qp/Qs of 1.19 and MPAP of 18 mmHg (31/7 mmHg). He remained well with no relapse of lung cancer at 18 months after surgery.


A 20-year-old Chinese man with a complaint of headache and fever for 5 days was admitted to our hospital. He had no specific medical history except for Ebstein anomaly corrective surgery at the age of 15 years. His family history was unremarkable. The temperature on admission was 38.1°C. Meningeal irritation signs, including neck stiffness and Kernig's sign, were absent. On admission, the laboratory test results revealed normal complete blood count, coagulation tests, erythrocyte sedimentation rate, procalcitonin, C-reactive protein, anti-streptolysin O, rheumatoid factor, tumor markers, anti-nuclear antibody (Ab), anti-dsDNA Ab, and anti-cardiolipin Ab. Serum antibodies against Epstein–Barr virus (EBV) showed a pattern of previous infection. Cranial computed tomography (CT) and CT venography were unremarkable. The initial intracranial pressure (ICP) measured was 220 mmH2O (normal range, 80–180 mmH2O) (, day 6 after symptom onset). Biochemical detection of cerebrospinal fluid (CSF) including protein, glucose, chlorine, and white blood cells showed that these were all within normal ranges. As meningitis was suspected, he was administered intravenously (IV) with acyclovir. However, the headache was not relieved after antiviral treatment. A second lumbar puncture (, day 11) revealed clear CSF with an opening pressure of 300 mmH2O. The CSF biochemical results were within the normal range. CSF cultures for bacteria, acid-fast bacilli, and fungi were also negative. Results of polymerase chain reaction (PCR) for herpes simplex virus, cytomegalovirus, human herpesvirus, EBV, and herpes zoster virus were normal. Meanwhile, he was administered IV with acyclovir, mannitol, and other symptomatic treatments.
On the 7th day after admission, the patient developed a severe headache accompanied by a rash all over the body (). Neck stiffness and Kernig's sign were positive. Fever was essentially unaffected. Routine laboratory tests were normal as before. A third lumbar puncture examination (, day 17) showed a 400-mmH2O-high cranial pressure with elevated protein (0.52 g/L; normal range, 0.15–0.45 g/L) and white blood cell count (56 × 106/L; normal range, 0–8 × 106/L), among which monocytes represented about 92%, while glucose and chlorine levels were normal. The repeated CSF culture was sterile, and the PCR for viral agents was negative. At this point, mannitol was continued, and the dosage was increased to treat elevated ICP.
On the 14th day after admission, several discrete, tender, and rubbery lymph nodes 10–20 mm in size were present on both sides at the posterior neck. Ultrasonography of the neck revealed multiple swollen bilateral cervical lymph nodes, some as large as 21 × 8.5 mm. A cervical lymph node biopsy demonstrated numerous lympho-histiocytic cells and karyorrhectic debris without neutrophils, suggesting KFD. Immunohistochemical staining showed CD68+ histocytes and CD3+ T cells, further indicating KFD (). The absence of Reed–Sternberg cells, hematoxylin bodies, and neutrophils excluded the diagnosis of Hodgkin's disease and systemic lupus erythematosus (SLE). A fourth lumbar puncture (, day 23) revealed a decreased ICP of 260 mmH2O and WBC of 32 × 106/L (monocytes 99%), while the other biochemical tests were normal. Based on the clinical manifestations and the CSF and cervical lymph node biopsy findings, the patient was diagnosed with KFD with aseptic meningitis. The treatment was adjusted to oral methylprednisolone administration (40 mg per day), which was tapered to 8 mg per day. During this period, the patient's clinical symptoms and CSF parameters (, day 52) gradually resolved. The patient was satisfied with the treatment outcome and had good compliance with follow-up. After 10 months of follow-up, no symptoms or signs of meningitis relapse or evolution into other autoimmune diseases were detected.


A 19-year-old Turkish mother in her fourth pregnancy was admitted to our institute with an ultrasound report suggestive of dilated small bowel loops at 24 weeks of gestation, which was followed up in the department of maternal fetal medicine with a pre-diagnosis of fetal bowel obstruction. The mother’ s previous obstetrical history was uneventful. There was no relationship between the parents. Repeat ultrasonography revealed a segmental distended bowel, with preserved motility and vascularization. There was no evidence of fetal anemia, and the amniotic fluid index was within the normal range. Jejunal atresia was considered as the first differential diagnosis in the fetus.
At 38 weeks of gestation, the mother underwent a planned cesarean section due to a history of previous cesarian section. A Turkish male child weighing 3600 g was delivered, with APGAR scores of 8 and 10 at 1 and 5 minutes, and pulse, blood pressure and temperature within normal ranges. The baby was immediately transferred to the intensive care unit under pediatric surgery. An infant feeding tube was secured in place. Bilious drainage from a nasogastric catheter was detected. On physical examination, the patient was alive and active. The abdomen was soft and had minimal distention. Neurological examination was normal. Septic findings were not observed in the patient. Laboratory values of the patient were within the normal range. An initial complete blood count revealed no anemia or leukocytosis, with hemoglobin of 15.2 g/dL, platelet clumping with a normal count (221,000/uL) and white blood count of 16,200/uL. There was no meconium output in the follow-up. In radiological evaluation, there was no distal gas passage on the abdominal X-ray, and air–fluid levels suggested proximal obstruction (Fig. ).
The patient underwent surgery on the first postnatal day. In laparotomy, it was observed that the small intestine was rotated two full cycles from the mesenteric root (Fig. ). Bowel blood circulation was good. Volvulus was untwisted. There was a significant difference in diameter in the small bowel segment approximately 20 cm distal to Treitz. No atresia was detected. It was thought to be due to Ladd’s bands compression (Fig. ). There was malrotation. A Ladd's procedure was performed. The patient was started on oral feeding on the first postoperative day. There was no problem in follow-up. He was discharged on the seventh postoperative day with full oral feeding. The patient is still in the first postoperative year, and the follow-up has been uneventful.


A 75-year-old female underwent left total hip arthroplasty secondary to severe osteoarthritis in 1989 with a subsequent revision surgery due to pain. The patient has a history of hypercholesterolemia and no predisposing comorbidities or risk factors (e.g. rheumatoid arthritis, immune-suppressive therapy with steroids, liver cirrhosis, etc.).
In November 2018, the patient was admitted to the hospital due to the appearance of secreting sinus, subsequently treated by antibiotic therapy without any improvement. Physical examinations revealed the presence of inflammatory signs (i.e. heat, pain, and redness). Radiographs highlighted bone loosening with the migration of prosthetic components (Fig. ). Laboratory tests showed a C-reactive protein (CRP) of 4.43 mg/l and an erythrocyte sedimentation rate of 88 mm/hour.
The next day, the patient underwent revision surgery of the left hip prosthesis for a suspected PJI. After the debridement of the infected soft tissue, a Vancogenx-Space (Tecres S.p.a.) spacer loaded with vancomycin and gentamicin was fixed with Simplex™ bone cement (Stryker) with erythromycin and colistin, further enriched with 3 g vancomycin. Vancomycin (1 g/2 days) and meropenem (1 g/2 days) was used in peri-operative prophylaxis. Histological analysis depicted a chronic inflammation with fibroconnective tissue speculating an ongoing metallosis. Three periprosthetic tissue samples and the implant itself were collected intraoperatively and sent to the laboratory for culture. Aliquots of eluate obtained after treatment with 0.1% dithiothreitol (DTT, Sigma-Aldrich) were then cultured in proper conditions []. After incubation, all the samples yielded the growth of Gram-positive cocci identified as Staphylococcus capitis by means of Vitek2 System (BioMeriéux). The antibiotic treatment started the day of surgery with intravenous antibiotics (vancomycin 1 g every 12 h and meropenem 1 g every 8 h) and shifted to vancomycin alone after the antimicrobial susceptibility profile was obtained. It was suspended due to cutaneous erythema 10 days after. Therefore, based on antimicrobial susceptibility results, treatment was continued with oral trimethoprim/sulfamethoxazole (160/800 mg every 12 h for 6 weeks). During the hospitalization period, urinalysis and urine culture were routinely performed without evidencing any sign of infection due to bacteria or yeasts. Nineteen days after surgery CRP levels decreased and the patient was discharged from the hospital.
However, 3 months later, the patient was attended to the emergency room due to the presence of inflammatory signs (i.e. edema and swelling). She did not report any infectious event in the period from hospital discharge to the admission to emergency department when specifically asked. Synovial fluid was collected and sent to the laboratory for culture. The sample was plated on agar plates and inoculated into proper broths. No evidence of S. capitis was detected, however, a yeast grew on Chocolate agar and Sabouraud agar plates and after 3 days, also in BHI broth. The yeast was identified as Candida albicans by Vitek2 system. The retrieved C. albicans was susceptible to all the tested antifungal agents (amphotericin B MIC = 0.5 mg/l; caspofungin MIC ≤0.12 mg/l; flucytosine MIC ≤0.1 mg/l; fluconazole MIC ≤0.5 mg/l; micafungin MIC ≤0.06 mg/l; voriconazole MIC ≤0.12 mg/l).
Fifteen days later, the patient was hospitalized for the removal of the infected spacer. Briefly, a custom-made spacer was created with StageOne™ Select Hip Cement Spacer Molds (Zimmer Biomet) using the Refobacin® Bone Cement R (Zimmer Biomet) containing gentamicin and clindamycin and further enriched with 400 mg voriconazole. Afterward, the explanted spacer was sent to the laboratory together with biopsies of the surrounding soft tissues and the synovial fluid. The synovial fluid analysis evidenced a leukocyte count of 2926 cells/μl with 74.3% of polymorphonuclear cells. Leukocyte esterase resulted positive (score 2+). Microbiological cultures confirmed the results of the synovial fluid sample collected in the emergency room with the isolation of C. albicans with the same susceptibility profile. Again, cultures were negative for S. capitis. According to the susceptibility profile, the patient was treated with fluconazole (400 mg/day). Additionally, 1 g vancomycin and 1 g meropenem until the results of the intra-operative cultural examination were administered. The same therapeutic plan was followed once the patient was discharged from the hospital for the next 6 months. In November 2019, the patient underwent second-stage surgery, performed with an un-cemented hip revision implant (multihole acetabular component also fixed with screws and diaphyseal stem with distal femoral grip) to overcome the huge loss of bone substance as a consequence of the infection and previous interventions. The removed spacer was sent to the laboratory and the microbiological tests were all negative, hence, after 15 days the antifungal and antibiotic therapy was suspended. After 12 months of follow-up, the patient has fully recovered and no radiological signs of infection have been detected.


Presentation
The first case involves a 78-year-old female with IV bronchogenic adenocarcinoma with involvement of the left upper, right middle, and right lower lobes. She had undergone previous chemotherapy and wedge resection with lymphadenectomy of the right middle and right lower lobe tumors. The patient also had undergone SRS of the left upper lobe two years prior to presentation. Treatments had been done both at our facility and at an outside institution. Despite these therapies, she was noted to have disease progression around the site of previous stereotactic therapy. After a discussion of the patient’s case at the multidisciplinary tumor board, the decision was made to proceed with resection of the left upper lobe. Preoperatively the patient had undergone CT-guided biopsy to confirm recurrence as shown in Figure .
Intervention
The patient was taken into the operating room and during the thoracoscopic evaluation of the left chest, there was noted extensive adhesion around the left upper lobe. After mobilizing and freeing the lung there was purulent drainage from the chest wall which was cultured and irrigated. Drainage was noted to be originating from a rib fracture and a fragment of the fractured third rib was resected and sent for pathological analysis. Intraoperative image is shown in Figure . We then proceeded with wedge resection of the apical posterior segment and mediastinal lymphadenectomy.
Hospital Course and Follow Up
The patient was admitted to the step-down unit. She was maintained on cefazolin given the purulent materials encountered, however, cultures were negative. Pathology of the bone fragment revealed necrosis without evidence of malignancy. The wedge resection was consistent with well-differentiated mucinous adenocarcinoma without lymph node involvement and negative margins. Her chest tubes were removed on hospital day three and she was discharged to home on oxygen. The patient continues palliative Taxol and has been doing well as of her one-year follow-up.


Presentation
A 60-year-old female with a history of gastrointestinal malignancy had previously undergone a pancreaticoduoduodenectomy after 12 cycles of FOLFOX therapy. Follow-up PET-CT was concerning for a metastatic left pulmonary nodule. This was further evaluated with a chest CT as shown in Figure . She was started on FOLFIRI and SRS of both lung nodules. Despite these therapies, there was progression of the nodule in the left lower lobe of the lung. Additionally, there was new thickening of the distal transverse colon. After discussion at the multidisciplinary tumor board one year after her completion of SRS the decision was made to proceed with staged metastectomy of the abdominal and left pulmonary lesions. The patient noted several months of left-sided chest-wall pain treated with lidocaine patches and no identifiable musculoskeletal abnormalities on preoperative imaging. Seven days after undergoing open left colectomy with lymphadenectomy, she did proceed to the operating room with the thoracic surgery team.
Intervention
The patient was taken to the operating room and placed in the right decubitus position. Thoracoscopic evaluation was begun and there was bulging of the pleura noted adjacent to the lung lesion. Upon incision of the pleura there was a rush of necrotic material with an incidentally noted rib fracture. This was debrided and sent for both cultures and pathology. Frozen sections were performed but negative for evidence of malignancy. The standard wedge resection was then completed with lymphadenectomy. A chest tube was left in place and the patient was taken to the critical care unit for postoperative monitoring.
Hospital Course and Follow Up
The patient was noted to have an air leak postoperatively. The preoperatively placed epidural was removed on postoperative day two due to inadequate analgesia. Final pathology revealed adenocarcinoma, bowel primary, with no evidence of involvement of the lymph nodes or resected rib portion. On postoperative day three she was noted to have feculent drainage from her abdominal incision prompting laparotomy with right colectomy and ileosigmoidostomy for bowel ischemia and associated perforation. The patient had a prolonged recovery on broad-spectrum antibiotics and total parenteral nutrition (TPN) until bowel function was restored. The patient’s chest tube was transitioned to a one-way valve device for persistent air leak and discharged to home with home health care. Her chest tube was removed one month after discharge. She did develop an abdominal abscess which required percutaneous drain placement. Six months after her hospital course she was noted to have new mesenteric and hepatic lesions for which she underwent MRI-guided intensity-modulated radiation therapy. At one-year follow-up she had recovered well from her surgeries and subsequent abdominal radiation therapies and no longer had any left-sided chest wall pain.


A 90-year-old woman visited our clinic with cauliflower-like mass on her back. It was insidious in onset and gradually progressive, growing from 3 cm on the first visit to 8 cm after 9 months. Her general condition was fair, except weakness of lower extremities owing to senility. She was an ordinary housewife without any special family history and had total hysterectomy in gynecological history because of uterine leiomyoma. Cytological study revealed positive HPV in previous hysterectomy. All the vitals were stable and there was no palpable lymphadenopathy. Local physical examination revealed a verrucous and pedunculated mass on the back (). The masses were two, in which the larger was 5.0 × 4.0 cm2 on the inferomedial side and the smaller was 3.0 × 2.0 cm2 on the superolateral side. They invaded into subcutaneous layer () and were excised widely with 5 mm free margin on the basis of the surgical treatment of other SCCs () []. The incision wound could be primarily closed with Nylon #4-0 (). The gross specimen had ulcerative warty shape, and uninvolved surgical margins were confirmed. The microscopic finding showed arborescent papillomatosis with prominent fibrovascular core, parakeratosis, acanthosis and koilocytosis with nuclear pleomorphism (). Therefore, it was diagnosed as warty (condylomatous) carcinoma. The patient was fine without any complication and there was no recurrence on follow-up after 6 months ().


Patient 1 was a 57 year-old woman of French Canadian, German, and Bohemian ancestry who had neurological symptoms beginning in her 30's of progressive spasticity that led to a diagnosis of primary progressive multiple sclerosis at age 38. However, at 57 years-of-age, the diagnosis was questioned at our medical institution and she underwent a genetics evaluation for alternate pathologies resulting in progressive spastic paraparesis. General physical examination revealed tendon deposits. Neurological examination showed severe lower extremity weakness distally and mild-to-moderate weakness proximally along with profound lower extremity sensory loss below the hips, necessitating full-time use of a wheel chair. Spinal MRI revealed longitudinal T2-hyperintensity. However, in this case no lesions were present by brain MRI. Her clinical workup consisted of biochemical testing for CTX which revealed an elevation of the cholestanol precursor 7α,12α-dihydrocholest-4-en3-one (Table ) and molecular analysis of the CYP27A1 gene that revealed two pathogenic variants: c.410G > A (p.Arg137Gln) and c.1183C > T (p.Arg395Cys). Both of these variants have been reported previously (Table ), including some cases with corresponding biochemical data., , , , , , , This patient's imaging has been described previously and is consistent with rare previous reports of spinal xanthomatosis occurring both with and without brain lesions. Upon diagnosis with CTX, a regimen of chenodiol (250 mg three times per day) and atorvastatin were initiated for the patient; however, she developed transaminitis requiring her dose to be reduced to 250 mg daily. Biochemical testing was repeated after 8 months; this time including a full sterol panel (Table ).


A female patient in her 60s presented to a hospital emergency department with a 24-hour history of vomiting. She had a two-week history of right upper quadrant abdominal pain and severe frontal headache. She did not report diarrhoea or weight loss and had no history of neck stiffness, photophobia, rash, or limb weakness. She had been generally well since arriving in the United Kingdom (UK) from China 18 months ago. She had no relevant medical history of chronic disease and she was not formally employed. No other family members had been unwell recently, and she reported no foreign travel since arriving in the UK.
Blood tests on admission showed a mild leucocytosis, with a white blood cell (WBC) count of 10.6 × 109/L (neutrophils 9.5 × 109/L, lymphocytes 0.7 × 109/L, and eosinophils 0.1 × 109/L), and severe thrombocytopaenia (platelets 17 × 109/L). Liver function tests were deranged with increased bilirubin 21 μmol/L, alanine aminotransferase 169 IU/L, and alkaline phosphatase 337 IU/L. Coagulation was abnormal with a prothrombin time of 10.4 seconds and a fibrinogen level >9.3 g/L. Other biochemical tests were unremarkable, with normal sodium (140 mmol/L), potassium (3.1 mmol/L), and creatinine (63 μmol/L) and a mildly raised urea (9.3 mmol/L). The C-reactive protein concentration was very high at 250.6 mg/L. A urine dipstick was negative for leucocytes, nitrites, and blood, but showed high (2+) glucose and very high (3+) ketones.
The patient was treated as presumed biliary sepsis with intravenous amoxicillin and clavulanic acid (co-amoxiclav; 1.2 g intravenous three times daily). She was admitted to the acute medical unit and blood was sent for microbial culture. An ultrasound of the abdomen showed multiple solid, mixed echogenicity lesions in both lobes of the liver, the largest of which measured 41 × 34 mm, a normal gallbladder, and nondilated common bile duct. A computed tomography (CT) scan of the brain was reported as normal.
Twelve hours after admission, the patient became less responsive with a Glasgow Coma Scale 7/15 (E2 V2 M3). Venous blood gas showed metabolic acidosis (pH 7.12; HCO3 8 mmol/L), hyperglycaemia (glucose 29.1 mmol/L), and marked ketosis (ketones 7.0 mmol/L). She was intubated for airway protection and started on an intravenous insulin and fluid resuscitation regime for diabetic ketoacidosis. She was given empirical treatment for presumed central nervous system infection with cefotaxime 2 g IV four times daily and aciclovir 10 mg/kg IV three times daily. A repeat CT scan of the brain was reported as normal, and she was admitted to the intensive care unit (ICU). A CT scan of the chest, abdomen, and pelvis showed bilateral pneumonia, appearances suggestive of an abscess within the left lobe of the liver, and moderate intra-abdominal free fluid (). A blood film showed marked thrombocytopaenia with no fragments or clots. One pool of platelets was transfused in order to enable a lumbar puncture to be performed to collect cerebrospinal fluid (CSF).
The CSF was turbid and yellow (), with a very high opening pressure of >57 centimetres of CSF (above the maximum recordable level of the manometer). Both the CSF protein and WBC count were markedly elevated at 11.8 g/L and 50,000/m3 (85% polymorphs and 15% lymphocytes), respectively. The CSF glucose was low at 1.0 mmol/L, and the red blood cell count was 640 cells/mm3. The sample was positive for xanthochromia, but no organisms were seen on Gram stain or acid-fast stain. Blood and CSF cultures subsequently grew K. pneumoniae, which was reported as sensitive to cefotaxime and gentamicin. The CSF was PCR negative for M. tuberculosis, herpes simplex DNA, Zika virus RNA, and enterovirus RNA. A blood HIV test was negative. The HbA1c level was 100 mmol/mol, suggestive of persistently high blood glucose levels in the preceding months, consistent with a new diagnosis of diabetes mellitus. Following admission to the ICU, the patient was found to have fixed and dilated pupils and, following brainstem testing, a decision was made to withdraw care. The patient died 18 hours later.
The blood culture isolate was cultured onto Columbia Blood Agar (Oxoid, UK) and incubated overnight at 37°C. A single colony was picked and subcultured overnight. The antimicrobial susceptibility of the isolate was determined using the N350 card on the VITEK2® instrument (bioMeriéux, France). DNA was extracted and sequenced on a MinION (Oxford Nanopore Technologies); details are shown in Supplemental Material.
Basecalling was performed using Guppy v3.4.4 with three approaches: a fast option with default settings, a high-accuracy option with a methylation-aware model, and a high-accuracy option with a custom model trained on Klebsiella genomes. All read sets were trimmed, filtered, and assembled using Flye v2.7 [], and draft assemblies were further polished with Racon v1.3.1 [] and Medaka v 0.7.1 to generate final consensus assemblies (available in FigShare, doi: 10.6084/m9.figshare.11770908; see details in Supplemental Material).
Species confirmation and Klebsiella-specific genotyping including multilocus sequence typing (MLST), AMR, and virulence determinants were performed using Pathogenwatch (), Kaptive (), and Kleborate () []. Reference genomes of common hypervirulent or antimicrobial-resistant K. pneumoniae (Supplementary ) were downloaded from NCBI and compared to the consensus assemblies by estimating pairwise genome distances using Mash [] and then constructing a neighbour-joining tree in R.
The blood culture isolate was hypermucoid () and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as K. pneumoniae. It was resistant to ampicillin but was susceptible to all other antimicrobials tested. Sequencing via MinION yielded (after basecalling and demultiplexing) ∼2 million high-quality reads totalling ∼6 Gbp, giving ∼1150-fold coverage of the genome. Average read length was 3.2 Kbp, maximum read length 70.6 Kbp, and N50 6.0 Kbp. All three assemblies resolved two circular molecules: a 5.4 Mbp chromosome and a 228 Kbp plasmid.
The genome sequence confirmed the species identification as K. pneumoniae. Distance-based phylogenetic analysis showed the novel isolate clustered with the ST23 (sequence type) K1 hypervirulent clinical isolates SGH10 [] and NTUH-K2044 [] and was closest to SGH10 which is representative of the dominant globally distributed liver abscess-associated subclade CG23-I (). Genotyping analysis of nanopore-only data is complicated by basecalling error rates >0.1% []. Nevertheless, the genome sequence assembled from reads basecalled with a K. pneumoniae-trained custom model was identified as a single-locus variant of ST23, with virulence-associated features typical of CG23-I []: capsular serotype K1, the genotoxin colibactin (clb/pks), acquired siderophore systems yersiniabactin (ybt), aerobactin (iuc1), and salmochelin (iro1), plus rmpA and rmpA2 (associated with hypermucoidy). The assembly derived from default basecalling identified the presence of the loci but yielded less precise genotypes (see Supplementary ). The iuc1, iro1, rmpA, and rmpA2 were located in the 228 plasmid, which showed full-length homology with pSGH10, a type I K. pneumoniae virulence plasmid (KpVP-1) typical of ST23 [].


The patient was an 84-year-old man with a height of 176 cm and a body weight of 80 kg who was scheduled for minimally invasive posterior spine fusion (T9–L3) for the treatment of a lumbar compression fracture. He had a history of hypertension, atrial fibrillation, and chronic kidney disease and was taking amlodipine and apixaban (5 mg twice daily). Preoperative serum examination indicated moderate loss of kidney function, which was confirmed by a serum creatinine level of 1.05 mg/dL and an estimated glomerular filtration rate of 52 mL/min/1.73 m2. Preoperative coagulation tests indicated prolonged values for both APTT and PT-international normalized ratio (40.1 s and 1.7, respectively). Although temporary interruption of apixaban is commonly recommended for the perioperative period (usually 48–72 h before surgical procedures, such as spine surgery, with high bleeding risk) [], the patient continued apixaban until the night before surgery, according to the instruction of his cardiologist.
We considered it necessary to evaluate the residual anti-Xa effect of apixaban for the estimation of perioperative bleeding and potential need for transfusion; therefore, we implemented the use of ClotPro in combination with the conventional blood tests performed at our hospital’s central laboratory. ClotPro uses RVV as the reagent to activate coagulation. Because RVV specifically cleaves factor X to Xa, clotting time (CT) is prolonged by anti-Xa drugs, such as apixaban, in a dose-dependent manner [, ]. We examined blood cell count, PT, APTT, and plasma fibrinogen level at four time points: after anesthesia induction, at the end of surgery, on postoperative day (POD) 1, and on POD 6. We simultaneously performed the ClotPro assay, an ecarin chromogenic assay (ECA), to detect the effect of direct thrombin inhibitors such as dabigatran [], and a fibrinogen concentration assay. Blood samples for outsourced chromogenic anti-Xa assay were collected at the same time points.
Anesthesia was induced with propofol and rocuronium, and was maintained with desflurane and continuous infusion of remifentanil. The results of coagulation tests after anesthesia induction indicated delayed thrombin production (Table ) (Fig. ). All members of the surgical team recognized the residual effects of apixaban, and we prepared fresh frozen plasma for excessive bleeding. Fortunately, the volume of bleeding was 440 mL, and we did not perform a transfusion. Considering the balance of the risk of postoperative bleeding and the result of the RVV test on the morning of POD 1, which was in the normal range, we resumed apixaban at a decreased dose of 2.5 mg twice daily on POD 1. The CT for the RVV test on POD 6 was prolonged to 93 s, which was shorter than the preoperative value (167 s) (Table ). Although the patient had minor subconjunctival hemorrhaging after the resumption of apixaban, he was discharged without major bleeding or thrombotic complications.


A 27-year-old woman with adverse pregnancy history came to our center for genetic counseling. A review of her medical history revealed that she had terminated her pregnancy at 24 weeks 1 year ago due to holoprosencephaly. The fetal ultrasound diagnosis showed an abnormal cerebellar morphology, a single ventricle, unclear cavum septi pellucidi and brain middle, significantly narrowed intraorbital distance, and a single-nostril nose. The CNV-Seq results of the fetus were seq[hg19]18p11.32p11.21(120001-11580000)×1.
The woman was 159 cm tall with a round face and a thick neck. She had mild language development delay. She can communicate with people normally and live on her own. The woman graduated from a junior college. Currently, she worked full time in the restaurant business. The woman had no family history of genetic disease. Her brain magnetic resonance imaging scan showed a normal brain structure. Thus, the karyotype and chromosome microarray analyses were suggested.


A 53-year-old African-American male patient with end-stage renal disease due to hypertension underwent deceased donor kidney transplant from a 49-year-old donor. Both virtual and physical cross-match were performed before the transplant. The Lich-Gregoir antireflux method for ureteroneocystostomy was performed. The procedure was uncomplicated, and the patient was discharged on postopt day 5. As induction, immunosuppressive therapy standard 3 doses of thymoglobulin (1.5 mg/kg) were administered. He was started on tacrolimus, mycophenolate mofetil, and steroids as maintenance immunosuppression. On postopt day (POD) 24, he underwent scheduled removal of the ureteric stent with flexible cystoscopy. The patient was discharged soon after the procedure. On POD 26, two days after the removal of the ureteric stent, he presented with abdominal pain, anuria, and acute kidney injury. His creatinine was 4.20 mg/dl from 2.94 mg/dl a day earlier. An immediate ultrasound showed significant hydronephrosis of the transplanted kidney with an increase in resistive indices. A noncontrast CT scan of the abdomen and pelvis was suggestive of a blood clot mid to distal ureter and a large collection around the transplanted kidney (). Imaging results were consistent with obstructive uropathy. The patient immediately underwent percutaneous drainage of seroma (triglyceride and creatinine levels did not reflect lymphocele or urinoma) and an urgent nephrostogram along with percutaneous nephroureteral stent placement (PCNU) (). On postprocedure day 1, PCNU was capped and patient voided. The patient initially complained of hematuria which gradually improved during the course of four-day inpatient stay. Serum creatinine decreased appropriately. On the day of discharge, patient denied pain and was ambulating and voiding. On POD 37, the patient underwent a repeat nephrostogram, and PCNU was converted to a percutaneous nephrostomy tube. On POD 44, the patient underwent a repeat nephrostogram for tube exchange and aspiration of ureteral filling defects. Well-formed blood clots were removed by employing suction and basket extraction technique, and also a distal ureter stricture was identified (). On POD 72, the patient underwent a repeat IR nephrostogram with balloon dilatation of mid to distal ureteral stricture and placement of a double-J ureteral stent (). Again, a large blood clot was retrieved from the transplanted ureter. Nephrostomy tube was removed with the internalization of stent. The patient has since recovered with the above complication and procedures contributing to prolonged morbidity. The allograft is functional with baseline creatinine and urine output. The patient continues on oral antibiotics for the prevention of infection. We reviewed the cause for initial ureteric injury and most likely it resulted from the kinking of the stent inside the ureter, and during removal with cystoscopy, it resulted in laceration of the ureteric epithelium causing hematoma formation and blocking the urine outflow.


A 42-year-old male was admitted to the Acupuncture and Moxibustion Department of Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine for low back pain accompanied by numbness and weakness of lower limbs for half a year. After acupuncture and moxibustion treatment failed to demonstrate significant results, the patient was transferred to The Second Orthopedics Department. The patient also complained of a history of nightly spermatorrhea that lasted for > 10 years and experienced urine incontinence, meeting the diagnosis for pudendal numbness. The patient had been treated in the Urology Department of several hospitals, but with poor results. After an MRI of the lumbar spine, we identified the potential cause: two quasicircular T2 signal shadows were observed in the S1–2 sacral canal, the larger one was ~ 2.0 × 2.8 cm in size (Fig. ). Thus, we decided to surgically remove the TC.


In October 2020, a 38-year-old Hispanic woman with no preexisting health conditions noted the onset of what she was certain to be her usual allergy symptoms, including itchy eyes, sneezing, sinus drainage, and headache. She was generally healthy and was aware of standard COVID19 precautions being a working healthcare professional. As a precautionary measure she took an additional temperature measurement, which came to be normal. Overnight, she noticed a new onset of fever, severe body aches, and pronounced fatigue. The next day she was tested for both influenza A/B and COVID-19 via antigen test, with a negative flu result but a positive COVID-19 result. For verification, she also took a COVID-19 polymerase chain reaction test that also resulted in a positive for infection. She was prescribed conventional therapy at the time, including a cocktail of three vitamins (vitamin D-3 2,000 IU daily, zinc 50 mg daily, and vitamin C 500 mg daily), hydroxychloroquine 200 mg twice daily for six days, and Tylenol 500 mg two tablets every four to six hours as needed. She had an at-home recovery and reported her predominant symptoms during the acute phase as fatigue, headaches, body pain, and shortness of breath.
After most of her symptoms were resolved, she continued to have periodic episodes of fatigue and headaches, along with random shortness of breath while at rest and during activities for months beyond the acute phase of the illness. She also noted the presence of “brain fog,” as if lacking the same clarity that she had prior to her illness. These symptoms persisted for three months before the patient underwent EECP for one-hour sessions, three times per week. The patient underwent a non-standard EECP regimen of three days per week for five weeks due to convenience. This therapy was chosen based on EECP’s unique mechanism of action and the known cardiac and extra-cardiac effects. After one week, her “brain fog” had improved, with shortness of breath improving after 1.5 weeks. The patient reported returning to pre-COVID-19 health and fitness after approximately five weeks of EECP treatment.


The 13-year-old girl presented in our outpatient department with a complaint of right-sided neck swelling for four months. It was insidious in onset, painless, and was gradually progressive. There was no history of fever, restriction of head neck movement, or sudden change in size. Her parents gave a history of hydrocephalus at birth, for which she was operated on at 6 months of age. There was no history of headache, vertigo, or any neurological deficit. History of any head-neck trauma prior to the swelling was negative. The previous surgery details were not available, and thus, the knowledge of shunt material used or whether it was tied to the pericranium was not known. There was no history of any shunt revision surgery after the first operation.
On examination of the patient, the swelling of 12 cm × 4 cm was observed on the right lateral neck (Figures and ). The swelling extended from the right mastoid tip, along the sternocleidomastoid muscle to one finger below the clavicle on the anterior chest wall. The swelling was tortuous with no dilated veins present over it. The skin over the swelling was normal, with no signs of inflammation or puckering seen.
On palpation, it had a normal temperature and was nontender. It was well defined, cystic, compressible but not reducible or fluctuant. A cord-like structure was felt running from the postauricular region to the swelling. The cord was hard in consistency not fixed to underlying tissue, as was mobile side to side. No pulsations were felt in and around the swelling. The transillumination test was positive with a brilliant glow of the swelling () with the shadow of a cord-like structure. No bruit was heard on auscultation.
The ultrasonography (USG) of the neck revealed the intracervical part of the VP shunt with perishunt large fluid collection. Fine-needle aspiration was done in our outpatient department, under aseptic measures which revealed clear colourless thin aspirate. The fluid sent for biochemical analysis confirmed CSF with glucose: 73 mg/dL and proteins: 45 mg/dL. The fluid was also sent for culture and sensitivity, which gave no growth at 48 hours.
The patient was advised for a computed tomography scan (CT) to look for the position of the shunt intracranially and possible changes in the brain due to increased intracranial pressure following shunt dysfunction. Because of the availability of CT, its high sensitivity in comparison with plain X-ray, and better delineation of neck mass, the plain X-ray (shunt series) was not asked for in our case. On the CT brain, there was no evidence of shunt intracranially, its proximal end lying just external to the cranium was present (), and hydrocephalus was present (). The CT neck revealed a cystic lesion, within the right sternocleidomastoid with a radiopaque shunt lying within ().
The patient was then referred to the neurosurgery department for VP shunt revision surgery. After written informed consent was obtained from the parents, the shunt was replaced and successfully sutured to the pericranium on the same side in the posterior parietal part of the cranium and the peritoneal cavity. The pseudocyst resolved, with no recurrence in one-year follow-up.


A previously healthy 3-year-old Turkish girl was admitted to our pediatric emergency unit with fever, a running nose, and ear pain, with no past medical history of note. She was fully immunized, including four doses of Hib and 13-valent pneumococcal conjugate vaccines. At present, her body temperature (tympanic) was 38°C, and her physical examination revealed purulent postnasal discharge, bilateral hyperemic and bulging tympanic membranes, normal lung and cardiac sounds, comfortable abdomen, and regular neurological evaluation. She was diagnosed with acute OM, and cefdinir was given orally for seven days.
Two weeks after the end of oral antibiotic treatment, the patient presented to our hospital again with fever complaints, a tendency to sleep, and purulent discharge from the right ear. Her physical examination showed a toxic-sleepy child with purulent discharge from the right ear, without neck stiffness or a Kernig's sign. A full septic screen was performed revealing a C-reactive protein level of 310 mg/L (normal range <11), white cell count of 15.9 × 109/L (normal range: 5.0–12 × 109/L) with neutrophilia, procalcitonin of 7.6 ng/mL (normal range <0.15 ng/mL), and normal liver and renal function tests. Urinalysis and chest X-ray were normal.
She was hospitalized, and ceftriaxone was ordered with a daily dose of 100 mg/kg. Her temporal computed tomography showed soft tissue densities causing obliteration in the right maxillary sinus with near-obliteration of right mastoid cellulitis. Her cranial magnetic resonance imaging also showed effusion in right mastoid cells and marked mucosal thickening in the right maxillary sinus (). Brain parenchymal structures were normal. Based on these findings, the ear-nose-throat division suggested follow-up with parenteral antibiotics. Lumbar puncture was performed; cerebrospinal fluid (CSF) opening pressure was normal, and the appearance was clear. CSF microscopy examination, Gram staining, and acid-resistant bacillus staining were all clear for cells and organisms. CSF biochemical examinations revealed a CSF glucose of 68 mg/dL (with blood glucose: 85 mg/dL) and CSF total protein of 10 mg/dl. The CSF sample was sent for a multiplex PCR examination. Vancomycin and acyclovir were added to her treatment. There was no growth in the patient's blood, urine, CSF, or throat cultures.
On the sixth day of antibiotic treatment, the child's mother reported that she had a headache. The patient wanted to lie on her right side, her right eye could not look to the right, and she complained of headache and earache. In her repeated contrast cranial CT imaging, bilateral mucosal thickening was observed in the bilateral maxillary and ethmoid sinuses, without aeration in the right mastoid cells and the middle ear was observed. The findings were consistent with OM and mastoiditis.
In her MR angiography study, a compatible appearance with the hyperintense acute stage thrombus was observed in T1-weighted images in the right transverse sinus and sigmoid sinus (). There was no pathological signal in the nervus abducens trace. She underwent urgent right mastoidectomy and right ventilation tube insertion into the ear. The Pediatric Hematology Department recommended starting enoxaparin (2 mg/kg/day) after sending a thrombosis panel study (factor II, factor V, and PAI-1 mutation were normal; MHTFR 677 mutation and MTHFR 1298 mutation were heterozygotes, protein S and protein C levels were normal; homocysteine and lipoprotein A were also in expected values).
Meanwhile, her detailed ophthalmological examination revealed right papilledema, and diazoxide therapy was started. During her follow-up, her fever decreased; her CSF multiplex PCR was negative for herpes simplex virus type 1 and 2, as well as Streptococcus pneumoniae, enterovirus, and Neisseria meningitidis PCR results, but the H. influenza result was positive. Based on these findings, acyclovir treatment was stopped, and vancomycin and ceftriaxone continued for four weeks.
We further analyzed the CSF sample using the following procedures; Haemophilus influenzae DNA isolated from the patient's cerebrospinal fluid with meningitis was sent to the General Directorate of Public Health, National Respiratory Pathogens Reference Laboratory (USYPRL), for molecular serotyping. The diagnosis of H. influenzae was confirmed by applying the type-specific real-time PCR method targeting the HPD genes encoding protein D of H. influenzae in USYPRL. Then, serotyping was performed by real-time PCR using serotype-specific primary-probes targeting a, b, c, d, e, and f capsular serotypes of Haemophilus influenza [, ]. No positivity was observed with serotype-specific primers. Thus, the DNA obtained from the case of CSF belonged to nontypeable H. influenzae.
On the 14th day of heparin treatment, her cranial angiography was repeated, and close to complete resolution of the thrombus was observed (). She was discharged with heparin for three months, and her control cranial MR angiography was normal.


A 17-year old boy with a history of autosomal recessive polycystic kidney disease (ARPKD) started haemodialysis when he was 4 years of age. At the age of 8 years, he received a diseased donor kidney transplant. After 8 years he lost this graft due to chronic transplant rejection and haemodialysis needed to be restarted. Two years later, a second kidney transplant was executed by means of a heart beating donor. Notably, this donor had a repeated HLA mismatch of B14. However, levels of donor specific antibodies against B14 were not detected in his last pre-transplant serum sample.
According to our local guideline, induction after transplantation was initiated with basiliximab. Tacrolimus, mycophenolate mofetil and prednisolone were given as maintenance immunosuppression therapy. Because of altered graft function (creatinine 394 μmol/L and oliguria (0.3–0.8 ml/kg.h), unresponsive to furosemide), tacrolimus was discontinued 4 days post transplantation. Day 11 post-transplant, graft function deteriorated even further (creatinine 415 μmol/L, blood urea nitrogen 36 mmol/L). After a renal biopsy was performed, methylprednisolone pulses were initiated and low-dose tacrolimus was restarted. In addition, on day 12, plasmapheresis was started for five consecutive days in order to treat a possible humoral rejection. The graft biopsy demonstrated a type 2A acute rejection (BANFF classification: C4d positive, diffuse interstitial infiltrate, extensive oedema, focal interstitial hemorrhage, mild tubulitis, mild acute glomerulopathy and mild endovasculitis) []. Polyoma virus in plasma was negative, and no viral inclusions were found in the biopsy. Due to his underlying ARPKD, leucopenia and thrombocytopenia were present.
Donor-specific human leukocyte antigen (HLA) antibodies against B14 in plasma increased significantly. Creatinine initially decreased from 425 μmol/L to 215 μmol/L but increased again to 376 μmol/L on day 18 (Fig. ). Therefore, intravenous immunoglobulin G (IVIG) was administered. Graft function improved and tacrolimus was doubled at day 15 to a dose of 1 mg (0.02 mg/kg).
A second graft biopsy, on day 18 post-transplant, showed severe cellular rejection. There were minor signs of humoral rejection as a mild influx of inflammatory cells in the capillary lumen was observed and donor specific antibodies (DSA) against B14 mildly increased. In order to treat this severe steroid resistant cellular rejection, with a mild humoral component in the biopsy and mild DSA against B14, anti T-cell therapy was indicated.
A splenectomy as well as rituximab therapy were both considered but not deemed suitable. Splenectomy to treat antibody-mediated rejection (AMR) remains debatable as antibodies are not solitary being produced by the spleen, but also in lymph nodes and bone marrow. This, combined with the increased risk of infection with capsuled bacteria, argued against splenectomy. Rituximab on the other hand, targets CD20, mainly present on memory B-cells. However, plasma-cells responsible for antibody production lead to CD138 expression and do not express CD20. The leuco- and thrombocytopenia present in this patient resulted in the choice to treat this patient with alemtuzumab instead of rATG, as less side effects were expected compared to other anti-T-cell therapies.
Alemtuzumab was administered subcutaneously at a dose of 30 mg. One hour prior to administration, 500 mg methylprednisone was given together with 2 mg clemastin to prevent allergic reactions and 500 mg acetaminophen to prevent development of fever and/or headaches. In order to prevent raised levels of uric acid due to a tumour lysis syndrome, 200 mg allopurinol was given as a prophylaxis and hyper hydration protocol was applied (1,5–2,0 L/m2 per 24 h). Except for a minor headache 4 h post administration, no side effects occurred. Two days later, tacrolimus was discontinued due to high potassium levels and the second dose of alemtuzumab was administered.
Seven hours after this second dose, patient complained about a headache similar to the day before and he developed a fever up to 38.5 degrees Celsius. Within 5 h, his clinical status deteriorated significantly. The patient became dyspnoeic (oxygen saturation 87%) with 3 L of 100% oxygen and he started coughing. He was in agony, tachypnoeic (45–50/min) with a 15 L non rebreathing mask and his heartrate increased to 150/min with a mean arterial pressure of 95 mmHg.
Furosemide 80 mg was administered intravenously without effect and the patient was transferred to the paediatric intensive care unit (PICU) and immediately intubated due to acute respiratory failure. He deteriorated within hours into severe acute respiratory distress syndrome (ARDS) with signs of pulmonary oedema (foamy bloody secretions). Mechanical ventilation with maximal settings with nitric oxide (20 ppm) and abdominal positioning as well as maximal inotropic treatment with adrenalin (max 0,7 μg/kg/min), vasopressin (max 0,04 IE/min), dobutamine (max 33 μg/kg/min) and noradrenalin (max 2,1 μg/kg/min) were required. Ascites (3 L) was drained to lower ventilatory pressure before transferring the patient into supine position. Cardiac ultrasound showed diminished hypertrophic left ventricle contractility without signs of backward failure, a normal right ventricle and a collapsed inferior vena cava. There were no signs of fluid overload. Fluid resuscitation with crystalloids, packed cells and thrombocytes was initiated. Extracorporeal membrane oxygenation was not possible due to lack of appropriate vascular access. Continuous Renal Replacement Therapy (CRRT) was started 6 h after admission to the PICU as acute kidney injury and general oedema developed due to capillary leak syndrome. Yet, this failed to improve his clinical status. As opportunistic infections as a cause for the deterioration could not be excluded, antibiotics, ganciclovir and fluconazole were given. Unfortunately, the patient was too unstable to perform a broncho-alveolar lavage for culture diagnostics. Continuing this maximal supportive therapy, the patient stabilized after 12 h and inotropic and vasopressive support could be tapered and ventilation and oxygenation gradually improved. After 5 days on mechanical ventilation, he was successfully extubated and could be discharged from the PICU to the ward after an additional 8 days. He returned home in relatively good condition 33 days after his kidney transplantation with a serum creatinine of 111 μmol/L.


A 50-year-old female patient, known case of hypertension (HTN) and taking normatin as a medication, was in her usual state of health until 6 months prior to admission when she started to complain from headache, tinnitus and vertigo. She sought medical advice and was treated as otitis media (according to the patient).
Before ten days from her admission to our hospital, she had episodes of imbalance while she was walking and recurrent vomiting.
Once again, she sought medical help and, after a brain CT and a brain MRI were done, the doctors found a left cerebellar tumor (). In the upcoming days, she was referred to our hospital in April 2019 for further evaluation and surgical management.
The patient came to our hospital by her own (using public transportation) because there were no facilities for the tumor management in other places and there was no need to being transported by ambulance.
We did a physical examination focused on a neurological examination due to her symptoms and diagnosis. The patient was conscious, oriented and alert, with a Glasgow coma scale (GCS) of 15/15.
The cranial nerves were intact, and she was positive for cerebellar signs. She also was positive for the Romberg sign, had an ataxic gait and could not perform the tandem gait.
The patient then underwent surgery in which a midline suboccipital craniectomy with microscopic gross total resection (GTR) of the left cerebellar tumor and a cranioplasty under neuromonitoring was performed successfully.
The surgery was smooth and without intraoperative complications with an estimated blood loss of 500 cc.
After the surgery, the patient was transferred to the ICU in good conditions with stable vital signs, conscious, oriented, alert and a GCS of 15/15. The cranial nerves were intact, she was able to move all limbs freely and the wound was dry and clean. Afterwards, she was discharged in good conditions, with stable vital signs and no complications or sequela.
According to the histology department, the specimen that they received in formalin consisted of a multiple pieces and fragments of a grayish tissue measuring in aggregate 7.5 × 5 cm grossly. Further microscopic investigations of the histologic sections showed a biphasic tumor with a mixture of neurocytes and lipidized cells in which the neurocytes were arranged in density cellular sheets of monotonous cells with scanty and often clear cytoplasm, rounded to oval nuclei and salt-and-pepper chromatin. Lipidized cells were clustered and resembling mature adipocytes.
Rare mitotic figures were noted and were investigated. The tumor cells were positive for synaptophysin and neuron specific enolase (ESN) immunostains, focal for glial fibrillary acidic protein (GFAP) and negative for epithelial membrane antigen (EMA).
With all these histological findings, it was concluded that the sample was consistent with a cerebellar liponeurocytoma, WHO grade 2.
After a month from the operation, the patient came to the out-patient clinic for follow-up in which we could see that she was in good conditions, with no complains and the cerebellar signs were gone. Since there was no residual tumor left after the surgery and there were no symptoms showing us cerebellar involvement, there was no need for our patient to take radiotherapy once she was discharged.
Since the patient did not come to us again, we suspect that she is not complaining from any other symptom in the neurosurgical field.