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Purpose Reported outcome after multiple staged surgical treatment of infected nonunion is scarce. We, therefore, asked: (1) What is the clinical outcome in infected nonunion patients after multiple staged revision surgery? (2) Are different pathogens evidenced after surgical treatment in patients who have undergone more or less surgeries? Methods All enrolled patients were surgically treated for long bone-infected nonunion between January 2010 and March 2018. Besides patients´ demographics outcome in terms of bony consolidation and major complications defined as death during inward treatment, amputation and recurrence of infection during follow-up of at least 12 months were assessed. Microbiological findings were assessed and compared between two groups with less than five versus five or more surgical revisions. Results Bone consolidation was achieved in 86% of the patients while complications such as femoral or transtibial amputation, recurrence of infection or even death during inpatient treatment could be evidenced in six patients (14%). In patients who underwent multiple-stage surgery for five or more times, germ changes and repeated germ detection was more common than in patients with less surgeries. Conclusions Surgical treatment of infected nonunions poses a high burden on the patients with major complications occurring in about 14% of the patients using a multiple staged treatment concept. Future prospective studies comparing outcomes after limited with multiple staged revision surgeries are necessary.

Objective To describe a rare case of pheochromocytoma presenting with hypoglycemia. Methods We describe a rare case of pheochromocytoma presenting with a hypoglycemic seizure. Our article includes our differentials, work up, and management. Results Our patient had non–islet-cell tumor hypoglycemia that was non-insulin mediated, as noted by low insulin levels. His hypoglycemia was likely multifactorial and mediated by different mechanisms. We describe the rare case and review the causes of tumor-induced hypoglycemia. Conclusion Pheochromocytomas can rarely present with hypoglycemia and are associated with a poor prognosis.

Background: The novel coronavirus (SARS CoV-2) has caused significant morbidity and mortality in patients with diabetes. However, the effects of diabetes control including insulin use remain uncert...

Purpose AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. Methods In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. Results 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275–1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499–1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114–1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142–0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. Conclusions This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

Patient: Male, 62-year-old Final Diagnosis: BCGitis Symptoms: Fever • general fatigue Medication: — Clinical Procedure: Bone marrow biopsy • liver biopsy Specialty: Infectious Diseases • General and Internal Medicine Objective: Rare coexistence of disease or pathology Background: Bladder cancer (BC) is the second most common cancer involving the urinary system. In non-muscle-invading BC, transurethral resection of a bladder tumor followed by intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) is the usual treatment. Disseminated (or systemic) BCG infection (BCGitis) represents the most severe adverse effect of intravesical BCG therapy, presenting with high-grade fever, with or without symptoms in the urinary tract, leading to severe sepsis and death if left untreated. The treatment of choice consists of isoniazid, rifampicin, and ethambutol (with or without corticosteroids) for 6 months, and the recovery rate is extremely high. Given the fact that these drugs are hepatotoxic, treating a patient with liver cirrhosis is challenging. Case Report: We present a patient with a medical history of BC treated with transurethral resection and intravesical BCG therapy, presenting with fever, transaminasemia, and generalized weakness. Liver and bone marrow biopsies revealed liver cirrhosis and granulomas in both organs. A diagnose of BCGitis was made and the patient was treated with isoniazid, rifampicin, and ethambutol; rifampicin was substituted with moxifloxacin after 1 month due to worsening of liver laboratory results, and moxifloxacin was substituted with levofloxacin later on due to tonic-clonic seizures. The patient was treated for 4 more months with levofloxacin and for 7 more months with isoniazid and ethambutol, with no other adverse effects, preserving liver function and achieving cure of BCGitis. Conclusions: We present the case of a cirrhotic patient presenting with fever and deterioration of liver laboratory results, found to have BCGitis, and discuss possible difficulties in diagnosing and treating such patients.

Background Immune‐checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune‐related endocrinopathies, especially hypophysitis and thyroid dysfunction. Methods To assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune‐checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow‐up. Results The total incidence of endocrinopathies was 11.8%, 13.4% due to anti‐PD1/PDL1, 5% due to anti‐CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty‐one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow‐up. Endocrinopathies occurred after a median of 22 weeks (range: 4‐156) from treatment initiation. Of note, sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism. Conclusions Our cohort demonstrated an increased incidence of hypophysitis with anti‐PD1/anti‐PDL1 in contrast to the rarity of primary thyroid dysfunction with anti‐CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy., A prospective observational study was conducted to assess the incidence and the spectrum of endocrinopathies in 339 melanoma patients treated with immune checkpoint inhibitors. Sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy, while only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism.

Simple Summary Despite recent improvements in cure rates, pediatric acute lymphoblastic leukemia (ALL) patients remain at risk to develop relapse disease or suffer from therapy-associated side effects. Over 5% of adverse events appear in the central nervous system (CNS) and can impact survival or quality of life of the patients. Inherited genetic variations are possible predictive factors for these adverse events. This retrospective study aimed to investigate if inherited genetic variations in genes encoding drug-metabolizing enzymes and drug transporters localized in the blood-brain barrier are predictive for CNS events. Our results suggest that certain ABCB1, ABCG2 and GSTP1 gene polymorphisms influence CNS toxicity and CNS relapse. A more effective drug-clearance could lead to less toxicity but contribute to a higher chance of relapse and vice versa. Genetic variants in ABCB1, ABCG2 or GSTP1 genes are promising candidates for personalized medicine. Abstract Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

Objective To assess the predictive value for infection with multidrug-resistant organisms (MDROs) of reasons for empirical prescription of restricted antibiotics (rABX), in a setting with high resistance rates. Methods We prospectively studied all rABX prescriptions in a 550-bed tertiary teaching hospital from April 15 to June 14, 2018 and from September 1 to October 30, 2018. Prescribing physicians had to justify their decision by choosing one or more prespecified reasons. Results We reviewed 172 empirical prescriptions of rABX, which accounted for 67.2% of all rABX prescriptions. Stated reasons for empirical prescription of rABX were recent hospitalization (72.7%), escalation due to non-response to previous antimicrobials (47.7%), treatment for severe sepsis/septic shock (45.9%), escalation due to recurrence or deterioration (22.1%), prior MDRO infection (12.8%), and prior MDRO colonization (7.6%). Empirical treatment for septic shock or severe sepsis was the only significant predictor of MDRO isolation (OR = 5.26, 95% CI: 1.5–18.4, P = 0.009), while recent hospitalization had a high negative predictive value for MDRO (97.4%). Fourteen per cent of microbiologically documented infections were associated with MDROs resistant to the prescribed rABX. Conclusions Empirical treatment for severe sepsis or septic shock was the only independent predictor of MDRO isolation. Recent hospitalization had a high negative predictive value for MDRO infection. The isolation of pathogens resistant to the prescribed rABX suggests that in a setting with widespread antimicrobial resistance, it could be difficult to reduce the empirical use of rABX without risking inadequate treatment.

The patient is an 85-year-old man with multiple comorbidities, including hypertension and coronary artery disease with recent myocardial infarction who underwent cardiac catheterisation. During the procedure, the patient developed profound hypertensive crisis with flash pulmonary oedema, requiring significant intervention for blood pressure (BP) control. His crisis was also marked by wide excursions in his BP. The patient was found to have a large left adrenal mass measuring 9.4×8.7×8.1 cm, with biochemical testing confirming the suspicion of pheochromocytoma. Alpha-blockade was started prior to availability of lab results due to high index of suspicion. Surgical removal, the mainstay of treatment, has yet to transpire as he has no family, and due to his underlying dementia, he was not felt to have capacity for decision-making at the time of diagnosis. The case elucidates the vast presentations of this tumour, the means of diagnosis and the difficulties of treatment.

Summary Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation., Graphical abstract, Highlights • A multicohort study identifies 52 previously unknown osteoarthritis genetic risk variants • Similarities and differences in osteoarthritis genetic risk depend on joint sites • Osteoarthritis genetic components are associated with pain-related phenotypes • High-confidence effector genes highlight potential targets for drug intervention, A multicohort genome-wide association meta-analysis of osteoarthritis highlights the impact of joint site types on the features of genetic risk variants and the link between osteoarthritis genetics and pain-related phenotypes, pointing toward potential targets for therapeutic intervention.

Introduction: Kounis syndrome (KS) is defined as acute coronary syndrome (ACS) in the context of a hypersensitivity reaction. Patients may present with normal coronary arteries (Type I), established coronary artery disease (Type II) or in-stent thrombosis and restenosis (Type III). Hypothesis: We sought to investigate the clinical presentation, underlying pathophysiology, diagnosis and medical management of patients with KS. Methods: We searched PubMed until 1/1/2020 for case reports of KS. Patients with age Results: Out of the 269 unique patients with KS, 157 (58.4%) had Type I, 64 (23.8%) Type II and 18 (6.7%) Type III while 30 (11.2%) could not be classified. Their mean age was 54.1 years and 190 (70.6%) were male. The majority presented with a combination of cardiac and allergic symptoms [Panel A] and medication was the most commonly reported trigger [Panel B]. Electrocardiographically, 75.1% of cases had ST segment elevation with only 3.3% demonstrating no abnormalities. Coronary imaging was available in 228 (84.8%) patients showing occlusive lesions (32.5%), vascular spasm (16.2%), or normal coronary arteries (51.3%). Percutaneous coronary intervention or coronary artery bypass grafting was performed in 70 (29.4%) of the 238 patients with available information. Conclusions: Hypersensitivity induced ACS is most frequently triggered by medications, and the majority of patients have patent coronary arteries suggesting microvascular dysfunction. KS should be considered in the differential diagnosis of myocardial infarction with non-obstructive coronary arteries.

The epidemiologic correlation of melanoma and chronic lymphocytic leukemia (CLL) has been the subject of several population studies. In the present article, through the presentation of five illustrative cases of patients with melanoma and CLL, several aspects of this complex relationship are highlighted, with a focus on the increased incidence of melanoma in patients with CLL, its speculated etiology, and the impact of CLL stage and disease duration on the incidence and prognosis of melanoma. Furthermore, the rare entity of the synchronous diagnosis of melanoma and CLL in biopsied lymph nodes is discussed, along with its implications on the diagnostic and therapeutic procedures. In addition, the available data on the treatment choices in patients with melanoma and CLL are presented and the efficacy and safety of fludarabine, anti-CD20 monoclonal antibodies, new targeted therapies for CLL, and checkpoint inhibitors are further discussed. Finally, since no formal guidelines are available for the management of this group of patients, guidelines are proposed for skin-cancer screening in patients with CLL, for the correct interpretation of BRAF mutation analysis in lymph-node specimens with ‘collision of tumors,’ and for the optimal use of imaging studies in the diagnosis of metastatic disease in patients with CLL and melanoma, while a treatment approach for such patients is also suggested. The information and proposed guidelines provided in the present article comprise a useful guide for physicians managing such patients, focusing on diagnostic challenges and therapeutic dilemmas posed by the coexistence of the two disease entities.

Immune checkpoint inhibitors (ICI) have altered the prognosis of patients with melanoma over the past few years, with immune-related adverse effects (irAEs) being the only factor limiting their use. Neurologic and cardiac irAEs are rare, but usually severe. We reviewed the files of patients with melanoma treated with ICIs in one center to retrieve data from patients with neurologic irAEs. Patients with a combination of neurologic and cardiac manifestations were further analyzed. We also reviewed the literature for similar syndromes. Five out of 482 (1.01%) patients developed a neurologic syndrome and we present three patients with a constellation of neurologic and cardiac irAEs. A 66-year-old woman and a 68-year-old man presented with a constellation of findings after being treated with ipilimumab and nivolumab, respectively, for melanoma in the adjuvant setting and were eventually diagnosed with myasthenia gravis with cardiac involvement. An 80-year-old woman developed diffuse asymmetric muscle weakness, bilateral ptosis and asymptomatic high serum troponin levels after adjuvant treatment with nivolumab and ipilimumab for a stage IIIB melanoma. After excluding ischemic heart disease, she was diagnosed with axonal polyradiculoneuropathy and myocarditis. Neurologic or cardiac irAEs in patients treated with ICIs are uncommon (

Coronavirus disease 19 (COVID-19) has become a pandemic. Diabetic patients tend to have poorer outcomes and more severe disease (Kumar et al. in Diabetes Metab Syndr 14(4):535–545, 2020. https://doi.org/10.1016/j.dsx.2020.04.044 ). However, the vast majority of studies are representative of Asian and Caucasian population and fewer represent an African-American population. In this single-center, retrospective observational study, we included all adult patients (> 18 years old) admitted to Einstein Medical Center, Philadelphia, with a diagnosis of COVID-19. Patients were classified according to having a known diagnosis of diabetes mellitus. Demographic and clinical data, comorbidities, outcomes and laboratory findings were obtained. Our sample included a total of 355 patients. 70% were African-American, and 47% had diabetes. Patients with diabetes had higher peak inflammatory markers like CRP 184 (111–258) versus 142 (65–229) p = 0.012 and peak LDH 560 (384–758) versus 499 (324–655) p = 0.017. The need for RRT/HD was significantly higher in patients with diabetes (21% vs 11% p = 0.013) as well as the need for vasopressors (28% vs 18% p = 0.023). Only age was found to be an independent predictor of mortality. We found no significant differences in inpatient mortality p = 0.856, need for RRT/HD p = 0.429, need for intubation p = 1.000 and need for vasopressors p = 0.471 in African-Americans with diabetes when compared to non-African-Americans. Our study demonstrates that patients with COVID-19 and diabetes tend to have more severe disease and poorer clinical outcomes. African-American patients with diabetes did not differ in outcomes or disease severity when compared to non-African-American patients.

In the evolving immune-oncology landscape, numerous patients with cancer are constantly treated with immune checkpoint inhibitors (ICPIs) but among them, only sporadic cases with pre-existing hepatitis B virus (HBV) and hepatitis C virus (HCV) are recorded. Despite the global dissemination of HBV and HCV infections, viral hepatitis-infected patients with cancer were traditionally excluded from ICPIs containing trials and current evidence is particularly limited in case reports, retrospective cohort studies and in few clinical trials on advanced hepatocellular carcinoma. Thus, many concerns still remain about the overall oncological management of this special subpopulation, including questions about the efficacy, toxicity and reactivation risks induced by ICPIs. Here, we examine the natural course of both HBV and HCV in cancer environment, review the latest antiviral guidelines for patients undergoing systematic cancer therapies, estimating treatment-related immunosuppression and relocate immunotherapy in this therapeutic panel. Among the ICPIs-treated cases with prior viral hepatitis, we focus further on those experienced HBV or HCV reactivation and discuss their host, tumor and serological risk factors, their antiviral and immunological management as well as their hepatitis and tumor outcome. Based on a low level of evidence, immunotherapy in these specific cancer cases seems to be associated with no inferior efficacy and with a relevantly low reactivation rate. However, hepatitis reactivation and subsequent irreversible complications appeared to have poor response to deferred antiviral treatment. While, the prophylactic use of modern antiviral drugs could eliminate or diminish up front the viral load in most cases, leading to cure or long-term hepatitis control. Taking together the clinical significance of preventive therapy, the low but existing reactivation risk and the potential immune-related hepatotoxicity, a comprehensive baseline assessment of liver status, including viral hepatitis screening, before the onset of immunotherapy should be suggested as a reasonable and maybe cost-effective strategy but the decision to administer ICPIs and the necessity of prophylaxis should always be weighed at a multidisciplinary level and be individualized in each case, up to be established by future clinical trials.

Background Invasive mould infections (IMIs) are very rare in patients with lymphoid malignancies. However, IMIs, mostly due to Aspergillus species, have been increasingly reported in such patients receiving ibrutinib (IBR). There is paucity of information regarding non-Aspergillus invasive mould infections (NAIMIs) in this setting, OBJECTIVES: To review our recent experience and the published literature on the topic. Patients/methods We present a case of invasive sinusitis caused by Fusarium in a patient with refractory chronic lymphocytic leukaemia (CLL) who was treated with IBR and review the 12 published cases of NAIMIs during IBR. Results Nearly all cases of NAIMIs in the setting of IBR use were encountered in patients with CLL. Mixed fungal infections, brain involvement and late-onset infections were common. Conclusions Although rare, NAIMIs should be considered in patients who receive IBR.

We report a 44-year-old male, who was diagnosed with hypogonadotropic hypogonadism after complaining of erectile dysfunction, depression, and fatigue. He was started on testosterone replacement therapy. He persistently complained of fatigue despite increasing the dose of testosterone over two years and having therapeutic testosterone levels. He was found to have homozygous C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation. After treatment with folate and B12, his symptoms resolve completely. MTHFR is a key enzyme in the folate pathway, and it plays an essential role in homocysteine metabolism. Homozygous C677T individuals have decreased activity of MTHFR enzyme with increased homocysteine levels, which is associated with increased risk of thrombosis. An association has been reported between C677T variant and male infertility. Patients identified to have hyperhomocysteinemia should be treated with B-complex vitamin supplements. Our case emphasizes other possible etiologies for fatigue and erectile dysfunction in a male with hypogonadism on testosterone therapy. Also, it shows possible association between MTHFR gene mutation and male hypogonadism.

MicroRNAs are small non-coding RNA species with the ability to post-transcriptionally control the expression of multiple genes, that have gained substantial interest because of their expression alterations that accompanies aging and possible age-related pathologies. Given the constant rise in the number of patients suffering from age-related diseases –due to the increase of the aging population in the western world- the exploration of the role of specific microRNAs in the etiopathology of these diseases is expected to have great impact. Degenerative arthritis or osteoarthritis is of the most common age-related diseases and possible the one with the most limited therapeutic options. In this review therefore, we highlight recent advances considering the implication of microRNAs in processes known to contribute to the development of this disease. We also critically present the analytical approaches adopted so far, in an attempt to facilitate the acknowledgment of the necessary experimental tactic that will lead to the establishment of microRNAs as biomarkers and/or therapeutic agents for this age-related pathology.

The widespread use of immune checkpoint inhibitors has shed light to several unusual immune-related adverse effects of the drugs. Severe cutaneous adverse reactions are generally rare with anti-PD1 agents. We present in this paper the case of a 48-year-old patient with melanoma who developed bullous pemphigoid-like skin lesions along with fever, arthralgia and overt eosinophilia following adjuvant treatment with nivolumab. The condition was successfully treated with corticosteroids and a rechallenge with another anti-PD1 agent did not lead to recurrence of the skin lesions. We also reviewed the literature on the epidemiologic, clinical, and histopathologic characteristics of bullous pemphigoid as well as on the treatment and prognosis of this dermatologic condition in patients with melanoma or other malignancies under treatment with immune checkpoint inhibitors.

Background: Ectopic thyroid tissue is a rare entity with a prevalence of 1 per 300,000 persons. Malignancy in ectopic thyroid tissue is reported in Case: A 65-year old woman was incidentally found to have a 3.1 cm mass with coarse calcifications in the superior mediastinum on CT scan of chest. Ultrasound confirmed the presence of hypoechoic mass which was separate from thyroid. Additionally, a 0.5cm TI-Rad 4 left thyroid lobe nodule was found. FNA of the mediastinal mass was suspicious for follicular thyroid neoplasm. Thyramir testing was positive for BRAF V600E and TERT c-124C>T mutations. Thyroid function tests showed frank hyperthyroidism and elevated thyroid stimulating immunoglobulins. Thyroid uptake and scan showed diffuse uptake of 67% at 24 hours. The patient underwent simultaneous excision of mediastinal mass and total thyroidectomy. The pathology of mediastinal mass showed papillary thyroid cancer with tall and sclerosis features with one involved lymph node. The pathology of thyroid gland did not show any malignancy. She was treated with 100 mCi I-131. Post treatment Whole Body Nuclear Scan after treatment revealed metastatic disease in left lower lung area. Discussion: Ectopic thyroid gland is usually found anywhere between forman caecum and mediastinum. It is rare to find ectopic thyroid tissue in the presence of eutopic thyroid gland which can create a diagnostic dilemma. Only a very few case reports of thyroid cancer arising from ectopic thyroid tissue have been reported. Our case is unique as the eutopic thyroid gland had Graves’ disease with no malignancy but the ectopic thyroid tissue developed aggressive papillary thyroid cancer. There are no specific guidelines for the management of carcinoma in ectopic thyroid glands, possibly due to the rarity of the condition. Our case has a clear metastasis to the lungs. However, it is important to differentiate ectopic thyroid tissue with carcinoma from thyroid cancer metastasis which can be difficult at times. Without specific guidelines for the management of cancer in ectopic thyroids, an individualised approach can be taken using the same therapeutic principals used in the management of eutopic thyroid cancer. Additionally, a finding of a normal thyroid gland or a benign condition in the thyroid gland should not exclude the diagnosis of malignancy in ectopic thyroid tissues. 1) Vázquez, Oscar R., et al. “Ectopic papillary thyroid cancer with distant metastasis.” Case reports in endocrinology 2018 (2018).

Cholesterol homeostasis plays a significant role in skeletal development and the dysregulation of cholesterol-related mechanism has been shown to be involved in the development of cartilage diseases including osteoarthritis (OA). Epidemiological studies have shown an association between elevated serum cholesterol levels and OA. Furthermore, abnormal lipid accumulation in chondrocytes as a result of abnormal regulation of cholesterol homeostasis has been demonstrated to be involved in the development of OA. Although, many in vivo and in vitro studies support the connection between cholesterol and cartilage degradation, the mechanisms underlying the complex interactions between lipid metabolism, especially HDL cholesterol metabolism, and OA remain unclear. The current review aims to address this problem and focuses on key molecular players of the HDL metabolism pathway and their role in ΟΑ pathogenesis. Understanding the complexity of biological processes implicated in OA pathogenesis, such as cholesterol metabolism, may lead to new targets for drug therapy of OA patients.

Our study looked at the relationship between insulin use and clinical outcomes in COVID-19. A response to our article, written by Dr. Chia Sing Kow and Dr. Syed Shahzad Hasan raised a few questions. They mentioned our use of hemoglobin A1c may be inaccurate as the patients in our study had high rates of CKD or ESRD which could alter the hemoglobin A1c levels. However due to the limitations of our patient population and perhaps in a lot of other sample populations in the real-world setting, it was the most feasible way to represent glucose control.The writers also suggested that the use of metformin, a potential confounder, was also not adjusted for. This should be considered in future research but addition of too many variables in a regression model may lead to less reliability of results for our study.The letter writers also suggested that the results of our paper may lead to misinterpretation by readers and may influence providers to not use insulin therapy for their patients when necessary due to fear of worse outcomes in the setting of COVID-19. We reiterated that it is very important that the data not be misinterpreted, and that nowhere in our paper did we imply or suggest that patients who need insulin therapy to treat their diabetes should not receive proper therapy due to the association we delineated in our paper. Instead, more careful surveillance of patients with advanced diabetes is needed especially when admitted with COVID-19.

Immune-related adverse effects (AEs) of PD-1 inhibitors can affect almost every organ, but the skin, intestine, lung, eye, and liver are the most commonly affected organs. Here, we present the case of a 62-year-old female patient with stage IIIc melanoma treated with nivolumab in an adjuvant setting who sequentially developed hyperthyroidism, hypothyroidism, acute hepatitis, and pneumonitis. Six months before the emergence of pneumonitis, the patient had discontinued treatment with nivolumab because of acute hepatitis. Information on pneumonitis after nivolumab discontinuation in the literature is scarce, whereas most of the cases emerge during the first 2.5 months of treatment. Patients with multiple immune-related AEs comprise a group of special interest as the identification of factors affecting the susceptibility of patients to immune-related AEs of PD-1 inhibitors may lead to a more rational use of these drugs. Human leukocyte antigen haplotype and Fcγ receptor polymorphisms are possible targets of the relevant research.

Numerous studies have revealed a variety of pathways involved in the development of melanoma, however, the molecular and genetic divergence of underlying mechanisms remain vague. In a mouse model, we studied the expression pattern of insulin-like growth factor 2 mRNA-binding protein 1 (Igf2bp1) and target genes microphthalmia-associated transcription factor (Mitf), v-myc avian myelocytomatosis viral oncogene homolog (Myc), B-cell lymphoma 2 (Bcl2), prothymosin alpha (Ptma) and melan-A (Mlana) in relation to tumor-growth characteristics. The in vivo expression of the aforementioned genes was assessed by quantitative Real Time-Polymerase Chain Reaction (RT-PCR) in tumors established by B16-F1-derived clones. Gene expression was correlated with tumor growth characteristics. Simultaneous expression of elevated levels of Myc, Igf2bp1, Ptma and Mitf characterizes tumors with a more aggressive phenotype. Our findings introduce a tumor-specific molecular signature possibly associated with melanoma heterogeneity. The concomitant overexpression of key molecules such as IGF2BP1, PTMA, MYC and MITF could serve as prognostic or predictive marker.

Purpose The definition of two well-studied genetic generalized epilepsy syndromes (GGE) − juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic-clonic seizures alone (GTCS) − suggests the absence of structural cerebral abnormalities. Nevertheless, there are various reports of such abnormalities (especially in JME), where effects mainly occur within thalamus and mesial prefrontal regions. This raises the question of whether JME is particularly linked to midline structure abnormalities, which may also involve the corpus callosum. Method We studied callosal morphology in a well-matched sample of 22 JME patients, 15 GTCS patients, and 42 controls (CTL) for all of whom we obtained T1-weighted data on a 3 T MRI scanner. More specifically, we measured callosal thickness at 100 equidistant points across the callosal surface, and subsequently compared the three groups (JME, GTCS, and CTL) against each other. Results Significant differences between JME patients and controls were observed within the callosal genu, anterior midbody, and isthmus, with thinner regions in JME patients. There were no significant differences between GTCS patients and controls, and also not between JME patients and GTCS patients. Conclusion The present outcomes point to callosal abnormalities in JME patients suggesting an impairment of interhemisperic communication between prefrontal, motor, parietal and temporal cortices. These findings further support the notion that structural aberrations are present and differentiated across GGE syndromes, with significant callosal deviations from normality in JME.

Corticotropin Releasing Factor (CRF) neuropeptides coordinate the stress response via two distinct membrane receptors (CRF-Rs). We have previously shown expression of both CRF-Rs in human breast cancer tissues. In the present study, we examined in vitro using the MCF-7 cell line model, the regulation of CRF-Rs expression and their signaling in hormone-dependent breast cancer growth. Our findings show that similarly to breast cancer biopsies, the predominant receptor type expressed in the cell line is CRF-R2α. The transcription of CRF-R1 and CRF-R2 is up and down-regulated respectively by exposure to estradiol (E2); however this effect seems not to be exerted at the level of promoter gene methylation, although in human breast cancer specimens, CRF-R1 methylation was found to be positively associated with the presence of steroid hormone receptors. Finally, we showed that specific activation of CRF-R2 increased the migration of MCF-7 cells and potentiated an estrogen-inducing effect. Our data support an involvement of CRF-R signaling in breast cancer pathophysiology via a regulatory steroid-hormone interplay.

Background Seizures are common in children with acute lymphoblastic leukemia (ALL). As ALL survival rates are improving, the challenge to minimize treatment related side effects and late sequelae rises. Here, we studied the frequency, timing, etiology and risk factors of seizures in ALL patients. Methods The study included children aged 1–17.9 years at diagnosis of B-cell-precursor and T cell ALL who were treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2015. Detailed patient data were acquired from the NOPHO ALL2008 registry and by review of medical records. Results Seizures occurred in 81/1464 (5.5%) patients. The cumulative incidence of seizures at one months was 1.7% (95% CI: 1.2–2.5) and at one year 5.3% (95% CI 4.2–6.5%). Patients aged 10–17.9 years, those with T cell immunophenotype, CNS involvement, or high-risk induction with dexamethasone had higher risk for seizures in univariable analyses. Only age remained a risk factor in multivariable analyses (the cumulative incidence of seizures for patients 10–17.9 years old at one year was 9.0% (95% CI: 6.2–12.9)). Of the 81 patients with seizures, 43 had posterior reversible encephalopathy syndrome (PRES), 15 had isolated seizures, nine had sinus venous thrombosis (SVT), three had stroke-like syndrome, and 11 had other neurotoxicities. Epilepsy diagnosis was reported in totally 11 ALL survivors at last follow up. Conclusion Seizures are relatively common in ALL patients and occur most often in patients with PRES, SVT, or as an isolated symptom. Older children have higher risk of seizures.

Background Approximately one third of women who develop melanoma at childbearing age are diagnosed during gestation or the postpartum period, facing pregnancy-associated melanoma (PAM). However, only some retrospective studies with heterogeneous data have analyzed the impact of pregnancy on melanoma development, and no evidence exists about the behavior and the management of BRAF-mutated disease. Subjects, Materials, and Methods In order to better describe the evolution of BRAF V600E-mutated PAM, we present here all consecutive cases diagnosed in our site during the last 7 years, recording oncological, obstetrical, and perinatal parameters, as well as the therapeutic decisions for both melanoma and gestation. Based on our institutional experience, we weigh the current published evidence and discuss upcoming clinical considerations about the prognosis of PAM, the role of BRAF status, and the possible treatment options during pregnancy in localized or advanced/metastatic disease. Five women were diagnosed with newly metastatic or relapsed BRAF V600E-mutated PAM (four during gestation and one in the 1st year postpartum) between 2012 and 2019. All of them developed extensive metastatic disease with multiple organ involvement, and four developed brain metastases. All cases experienced melanoma progression in less than 6 months under targeted therapy and died soon independently of the followed sequence of treatments. All the neonates were delivered alive and healthy, but one developed melanoma earlier than the second year of life. Results Reviewing the literature to confirm our unfavorable outcomes, no specific data on BRAF-mutated PAM were retrieved and current evidence still supports that the prognosis of PAM should be guided by the established risk factors, whereas the management of advanced/metastatic PAM should be evaluated on a case-by-case basis. Conclusion More data are required to ascertain whether BRAF-mutated profile adversely affects PAM outcome, although the clinicians should be aware to detect any potential melanoma lesion during pregnancy as soon as possible, treating it locally, regardless of its BRAF status. Implications for Practice The prognosis and management of pregnancy-associated melanoma whether BRAF-mutated or wild type, is currently guided by the same parameters as in the nonpregnant condition. In this special nontrial subpopulation, BRAF-mutated status seems to have a detrimental effect on disease outcome, independently of the following treatments. In early stage melanoma, wide local excision with or without sentinel lymph node dissection may be curative at any trimester of gestation, while in advanced/metastatic setting, therapeutic strategy including immune-checkpoint or BRAF/MEK inhibitors, is more challenging, regardless of BRAF status, and should be based on an individualized decision in each case at a multidisciplinary level.

Immune checkpoint inhibitors (ICBs) have revolutionized cancer treatment producing remarkable and durable responses for a range of malignancies. However, the additional modulation of immune response by ICBs may rarely cause immune-related infectious complications, including re-activation of latent tuberculosis infection (LTBC) with detrimental effects on those patients’ outcome. Here, we present two “real-world” melanoma cases that were treated in our department with blockade of PD-1/PD-L1 and developed active Mycobacterium tuberculosis (MTB) during immunotherapy. In view of these cases, we review the literature for ICB-associated MTB reactivation and discuss our considerations about the possible interactions of immunotherapy and the underlying co-existent mycobacterial infection. Based on the current evidence from preclinical findings prior to this experience, we raise questions regarding cancer patients who are at higher risk for developing MTB infection, whether ICB-treated patients should be considered immunocompromised, and how they should be managed for latent and/or active tuberculosis. Aside from the well-established clinical benefit of immunotherapy, the blockade of PD-1/PD-L1 axis may concurrently disrupt the immune control of specific opportunistic infections such as tuberculosis that should be carefully and expectantly managed in order to avoid compromising the outcome of cancer treatment and the affected patient’s survival.

Background: Hepatitis C (Hep C) infection is one of the leading causes of end stage liver disease and hepatocellular carcinoma. Several advances have been made in the treatment of Hep C infection. Harvoni (ledipasvir and sofosbuvir) is one of the treatment options. There have been no case reports of hypocalcemia or hypoparathyroidism associated with Harvoni therapy. We report a case of hypocalcemia and permanent hypoparathyroidism that began after Harvoni therapy. Case Presentation: A 64-year old African American man presented with weight loss and was diagnosed to have Hep C. He was treated with 12 weeks course of Harvoni. He was first noted to have low calcium level at 8.4 (8.4 – 10.3 mg/dl), during the last week of Harvoni treatment. Several previous calcium levels were normal. Four months later, he presented to Emergency Department with numbness, palpitations, and muscle cramping. His calcium was then 6.6 mg/dl, albumin 4.3 (3.4 - 4.8 mg/dl), PTH 18 (15 - 65 pg/ml), 25-hydroxy vitamin D 11 (30 - 50 ng/ml), magnesium 2.2 (1.6 – 2.6 mg/dl), phosphorus 3.8 (2.3 - 4.7 mg/dl) and 24-hour urine calcium was less than 2. Oral calcitriol, ergocalciferol and calcium carbonate were initiated and his calcium normalized. His calcium remained normal on calcitriol and calcium carbonate, but twice he had to be treated in emergency department for symptomatic hypocalcemia after missing his medications. Recently, he began PTH (1-84) (NATPARA). He has been tolerating parathyroid hormone injections well. Discussion: Harvoni is a combination medication of Ledipasvir and Sofosbuvir. Ledipasvir is a NS5A inhibitor. NS5A is an RNA binding protein required for the activity of RNA polymerase of hepatitis C virus. Sofosbuvir is a viral RNA polymerase inhibitor. There have been no case reports of hypoparathyroidism occurring with Harvoni therapy in the literature. Hypoparathyroidism most commonly results after anterior neck surgery like thyroidectomy, parathyroidectomy, or anterior neck dissection. Other causes include neck irradiation, infections like HIV, infiltration of the glands by heavy metals such as iron or copper; genetic disorders of parathyroid gland development, parathyroid hormone synthesis and calcium sensing receptor mutations, and finally autoimmune etiologies. Our patient had none of the risk factors for developing hypoparathyroidism. Nevertheless, he developed permanent, symptomatic hypoparathyroidism towards the end of Harvoni treatment, making Harvoni as the most likely cause of his hypoparathyroidism. More long-term data on this drug is needed to assess the risk of hypoparathyroidism after Harvoni therapy. Conclusion: Hypoparathyroidism leading to hypocalcemia could be a potential complication of Harvoni treatment. Monitoring calcium and parathyroid hormone levels prior to initiation and periodically after completion of Harvoni treatment should be recommended for all patients.

This retrospective cohort study assessed the prognostic significance of distant metastasis-free interval (DMFI) in patients with relapsed BRAF-mutant melanoma treated with BRAF with or without MEK inhibitors (BRAFi ± MEKi). Patients with a DMFI of up to 24 months were compared with those with DMFI of more than 24 months, with regard to their postrelapse progression-free survival (PR-PFS) and overall survival (PR-OS). In total, 109 patients were included in the study. Median DMFI was 25.3 (range: 3.4-188.2) months. Median PR-PFS in patients with DMFI of more than 24 months was 7.9 months [95% confidence interval (CI): 6.2-9.7] compared with 5.4 (95% CI: 4.2-6.7) months of those with shorter DMFI (P = 0.016). Median PR-OS was 15.6 months (95% CI: 13.6-17.6) in patients with DMFI of more than 24 months and 12.0 months (95% CI: 9.0-15.0) with DMFI of up to 24 months (P = 0.289). Multivariate Cox regression analysis showed that DMFI was independently and strongly associated with improved PR-PFS (adjusted hazard ratio = 3.21, 95% CI: 1.78-5.77, ≤ 24 vs. > 24 months) and longer PR-OS (adjusted hazard ratio: 2.09, 95% CI: 1.15-3.80, ≤ 24 vs. > 24 months). The present cohort study is one of the first to confirm the association of DMFI of more than 24 months with an indolent disease course, as shown by longer PR-PFS and PR-OS, in patients with relapsed stage IV melanoma treated by BRAF inhibitor/MEK inhibitor.

Unleashing adaptive immunity via immune checkpoint inhibitors (ICPIs) in many cancer types led to durable antitumor responses and prolonged survivals and also added some new immune-related adverse events (irAEs) to the ‘old-fashioned’ safety profile of chemotherapy. Among bowel and endocrine irAEs, immune-mediated hepatotoxicity/hepatitis is a less common and far less well-studied toxicity, which, however, could develop into a serious complication, especially when it becomes persistent or refractory to steroids. Its incidence, onset and severity vary widely, depending on the type of underlying treated cancer, the class, the dosage and the duration of immunotherapy as well as the way of its administration (as a single agent or in combination with other ICPI or chemotherapy). In this study, we present a patient with metastatic melanoma who developed severe steroid-resistant ir-hepatitis after treatment with ipilimumab and required triple concurrent immunosuppression with prednisolone, mycofenolate mofetil and tacrolimus in order for his liver toxicity to be resolved. Intrigued by this case, we focused further on melanoma, as the disease-paradigm of immunotherapy in cancer, reviewed the reported incidence of hepatotoxicity among phase III ICPIs-containing trials on melanoma and discussed the main clinical considerations regarding the diagnosis and the management of persistent/steroid-refractory ir-hepatitis. As more clinical experience is gradually gained on this challenging topic, better answers are provided to questions about the appropriate diagnostic workup, the necessity of liver biopsy, the available immunosuppressive options beyond corticosteroids (their combinations and/or their sequence) as well as the correct decision on withdrawing or resuming immunotherapy. Nonetheless, a thorough multidisciplinary discussion is still required to individualize the overall approach in each case after failure of steroids.

Sarcoidosis and sarcoid-like reactions (SLR) have been repeatedly reported in patients with melanoma treated with BRAF and MEK inhibitors. In the current study we present three patients that developed SLR under treatment with BRAF and mitogen-activated protein kinase (MEK) inhibitors for melanoma. Two patients developed mediastinal lymphadenitis with histological features of an SLR while on targeted therapy in the adjuvant setting, whereas one patient with metastatic melanoma developed granulomatous nephritis while receiving combination treatment with BRAF/MEK inhibitors and atezolizumab. In addition, we review the published literature on the pathogenesis, clinical characteristics, histologic features, imaging findings, and other potential useful diagnostic tools. We also address the need for a common terminology for these cases and propose an algorithm for the accurate diagnosis of BRAF/MEK inhibitor-induced SLR. We also review the currently available data on the treatment of these patients and suggest a treatment approach for SLR in patients with melanoma, as well as for the management of melanoma when SLR emerges.

Background AE37 is the Ii-Key hybrid of the MHC class II peptide, AE36 (HER2 aa:776–790). Phase I studies showed AE37 administered with granulocyte macrophage colony-stimulating factor (GM-CSF) to be safe and highly immunogenic. A prospective, randomized, multicenter phase II adjuvant trial was conducted to evaluate the vaccine's efficacy. Methods Clinically disease-free node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 [immunohistochemistry (IHC) 1–3+] were enrolled. Patients were randomized to AE37 + GM-CSF versus GM-CSF alone. Toxicity was monitored. Clinical recurrences were documented and disease-free survival (DFS) analyzed. Results The trial enrolled 298 patients; 153 received AE37 + GM-CSF and 145 received GM-CSF alone. The groups were well matched for clinicopathologic characteristics. Toxicities have been minimal. At the time of the primary analysis, the recurrence rate in the vaccinated group was 12.4% versus 13.8% in the control group [relative risk reduction 12%, HR 0.885, 95% confidence interval (CI) 0.472–1.659, P = 0.70]. The Kaplan–Meier estimated 5-year DFS rate was 80.8% in vaccinated versus 79.5% in control patients. In planned subset analyses of patients with IHC 1+/2+ HER2-expressing tumors, 5-year DFS was 77.2% in vaccinated patients (n = 76) versus 65.7% in control patients (n = 78) (P = 0.21). In patients with triple-negative breast cancer (HER2 IHC 1+/2+ and hormone receptor negative) DFS was 77.7% in vaccinated patients (n = 25) versus 49.0% in control patients (n = 25) (P = 0.12). Conclusion The overall intention-to-treat analysis demonstrates no benefit to vaccination. However, the results confirm that the vaccine is safe and suggest that vaccination may have clinical benefit in patients with low HER2-expressing tumors, specifically TNBC. Further evaluation in a randomized trial enrolling TNBC patients is warranted.

Introduction: Immune checkpoint inhibitors (ICIs) represent an important advance in the treatment of melanoma. ICIs may induce autoimmune phenomena caused by concurrent activation of the immune system against normal cells. During the last years, cases of musculoskeletal side effects, especially immune-mediated arthritis (IA), have been increasingly reported. Patient concerns: We present a 59-year-old woman, who was treated with pembrolizumab for a relapsed BRAF V600E mutated cutaneous malignant melanoma. The patient presented with right knee arthritis on week 30. Diagnosis: The erythrocyte sedimentation rate and serum C-reactive protein levels were elevated, while rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative. Imaging confirmed the presence of fluid mainly in the suprapatellar bursa. Synovial fluid analysis revealed an inflammatory effusion, while other etiologies of inflammatory arthritis were excluded. Interventions: Arthritis improved with an intra-articular injection of 8 mg dexamethasone. Twelve days later the arthritis relapsed in both knees, and although it was resistant to nonsteroidal anti-inflammatory treatment, it improved with systemic steroids. Tapering of methylprednisolone dose was feasible with the coadministration of leflunomide and subsequently hydroxychloroquine. Outcomes: Arthritis resolved and the patient is free of complications and disease activity 20 months after the initiation of the second line systemic treatment. Conclusions: We present an unusual case of IA associated with pembrolizumab treatment. The originality of the current report is based on the late occurrence, the monoarticular initial distribution, and uncommon location of IA at the knee.

Sickle cell disease (SCD), a hereditary form of chronic hemolytic anemia, is characterized by acute vascular occlusion and chronic complications as pulmonary hypertension (PH), a hallmark of higher mortality. This study aimed to determine peripheral blood expression of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme in SCD patients on the mRNA level and compared it with SOD2 expression in healthy individuals. It also aimed to detect possible differences in SOD2 expression among patients with/without specific SCD complications and to detect possible correlations with patient laboratory parameters. SOD2 mRNA levels were significantly lower in SCD patients in comparison with controls and correlated with red blood cell count, reticulocyte count, platelet count, C-reactive protein, ferritin, and brain natriuretic peptide values. SCD patients with echocardiographic indications of PH featured significantly reduced SOD2 expression in comparison with patients without such indications. Consequently, SOD2 expression emerges as a potential biomarker of PH in SCD being a link among hemolysis, inflammation, iron overload, oxidative stress, and SCD cardiopathy.

Ophthalmological complications constitute a class effect of treatment with BRAF inhibitors. Encorafenib is a new BRAF inhibitor currently being tested in phase 3 clinical trials for advanced or metastatic melanoma as monotherapy or in combination with the MEK-inhibitor binimetinib. In this study, we present a case of severe bilateral panuveitis and neurosensory hearing loss in an elderly patient treated with encorafenib and binimetinib for metastatic BRAF-mutant melanoma. This constellation of findings is compatible with incomplete Vogt-Koyanagi-Harada (VKH) disease. VKH disease is a rare multisystem disease characterized by granulomatous panuveitis, serous retinal detachments, and neurologic and dermatologic manifestations. In patients with melanoma, its emergence has been correlated to a favorable prognosis of the underlying melanoma by several authors. The patient reported here had a severe panuveitis and bilateral retinal detachments causing permanent visual impairment. She was treated with a long course of systemic corticosteroids, but at the same time, she achieved complete remission of the melanoma lasting for 26 months after permanent encorafenib and binimetinib discontinuation, without further antineoplastic treatment. VKH disease is a rare entity and the need for interdisciplinary cooperation for its diagnosis in patients with melanoma and uveitis is emphasized.

Despite the recent introduction of mold-active agents (posaconazole and isavuconazole), in addition to amphotericin B products, to our armamentarium against mucormycosis, many uncertainties remain for the management of this uncommon opportunistic infection, as there are no data from prospective randomized clinical trials to guide therapy. In this mini-review, we present the current status of treatment options. In view of the heterogeneity of the disease (different types of affected hosts, sites of infection, and infecting Mucorales), mucormycosis management requires an individualized management plan that takes into account the net state of immunosuppression of the host, including comorbidities, certainty of diagnosis, site of infection, and antifungal pharmacological properties.

Recently, several types of immunotherapies have been shown to induce encouraging clinical results, though in a restricted number of patients. Consequently, there is a need to identify immune biomarkers to select patients who will benefit from such therapies. Such predictive biomarkers may be also used as surrogates for overall survival (OS). We have recently found correlations between immunologic parameters and clinical outcome in prostate cancer patients who had been vaccinated with a HER-2/neu hybrid polypeptide vaccine (AE37) and received one booster 6 months post-primary vaccinations. Herein, we aimed to expand these retrospective analyses by studying the predictive impact of HLA-A*24 and HLA-DRB1*11 alleles, which are expressed at high frequencies among responders in our vaccinated patients, for clinical and immunological responses to AE37 vaccination. Our data show an increased OS of patients expressing the HLA-DRB1*11 or HLA-A*24 alleles, or both. Vaccine-induced immunological responses, measured as interferon γ (IFN-γ) responses in vitro or delayed-type hypersensitivity reactions in vivo, were also higher in these patients and inversely correlated with suppressor elements. Preexisting (i.e., before vaccinations with AE37) levels of vaccine-specific IFN-γ immunity and plasma TGF-β, among the HLA-A*24 and/or HLA-DRB1*11 positive patients, were strong indicators for immunological responses to AE37 treatment. These data suggest that HLA-DRB1*11 and HLA-A*24 are likely to be predictive factors for immunological and clinical responses to vaccination with AE37, though prospective validation in larger cohorts is needed.

Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.

Melanoma, like most solid tumors, is highly heterogeneous in terms of invasive, proliferative, and tumor-initiating potential. This heterogeneity is the outcome of differential gene expression resulting from conditions in the tumor microenvironment and the selective pressure of the immune system. To investigate possible signatures combining immune-related gene expression and lymphocyte infiltration, we established a preclinical model using B16.F1-derived clones, in the context of melanoma aggressiveness. Combinatorial analyses revealed that tumors concomitantly expressing low levels of Tnf-a, Pd-1, Il-10, Il-1ra, Ccl5, Ido, high Il-9, and with low infiltration by CD45+, CD3+, CD4+ and CD8+ cells and a high CD4+:CD8+ T cell ratio exhibited the most aggressive growth characteristics. Overall, these results support the notion that the intratumoral immunologic network molds aggressive melanoma phenotypes.

In order to be optimally efficacious, therapeutic cancer vaccines must induce robust tumor-specific CD8(+) cytotoxic T cells, which are responsible for tumor cell lysis. Unlike cytotoxic drugs, which act directly on the tumor, cancer vaccines demonstrate new kinetics involving the generation of specific cellular immune responses, which need to be translated into antitumor responses to delay tumor progression and improve survival. These delayed kinetics of action establish a new concept of benefit in the long term, which implies a slow down in tumor growth rates, than a marked reduction in tumor size. Therefore, there is a significant need to identify intermediate biomarkers so that clinical responses can be evaluated in a timely manner. Therapeutic vaccination as a modality for cancer treatment has received significant attention with multiple clinical trials demonstrating improvements in overall survival. Significant challenges to this modality remain, including increasing vaccine potency and minimizing treatment-related toxicities and identifying prognostic and predictive biomarkers of clinical benefit that may guide to select and optimize the therapeutic strategies for patients most likely to gain benefit.

Background Aortic valve (AV) calcification is the major characteristic of AV sclerosis. Several forms of calcium salts accumulate including hydroxyapatite in late phases. Purpose We sought to examine whether a modified cholesterol – Vitamin D2 diet can produce AV calcification and stenosis in a rabbit model. Methods AV calcification was introduced in New Zealand male rabbits using the modified diet: normal chaw+ 0.5%w/w cholesterol+ 3.500IU Vitamin D2/kg/d (ergocalciferol). Thirty six rabbits were equally randomized into control (normal chaw) and experimental group (modified diet) for 12 weeks. Echocardiography was performed at baseline and the day before the sacrifice. AV Vmax, Transaortic pressure gradient and AV area (AVA) were measured (Vivid 7, GE). AV cusps (collected every 2 weeks, 3 per group) were processed for Fourier-Transformed Infrared Spectroscopy (FT-IR) to detect and characterize calcium salt deposition longitudinally (Nicolet 6700 spectrometer, OMNIC 7.3 software). AVs from surgical patients with severe AV stenosis were used for qualitative comparisons. Results None of the echocardiographic parameters was significantly altered with modified diet; baseline AVA: 0.32 ± 0.06 cm2 vs. 12 weeks: 0.37 ± 0.07, P = 0.18. FT-IR vibrations in the region of 1800-800 cm-1 demonstrated the peroxidation of lipids, advanced glycation end products (AGEs), deposition of CaCO3 and non-hydroxyapatite Ca3 (PO4)2. Further, the 840 cm-1 (HCO3-) band is in accordance to those obtained from human AVs. Conclusion Overall, our rabbit Vitamin D2 model did not produce any AV hemodynamic changes. Interestingly, FT-IR spectroscopy showed that Vitamin D2 stimulated formation of AGEs, deposition of carbonic and phosphate calcium salts in the rabbit AV, both present in human AVs. This study demonstrates that acidosis is an important pathway of AV calcification. Further analysis is needed to elucidate molecular mechanisms in this particular animal model.

In our recent phase I trial, we demonstrated that the AE37 vaccine is safe and induces HER-2/neu-specific immunity in a heterogeneous population of HER-2/neu + prostate cancer patients. Herein, we tested whether one AE37 boost can induce long-lasting immunological memory in these patients. Twenty-three patients from the phase I study received one AE37 boost 6-month post-primary vaccinations. Local/systemic toxicities were evaluated following the booster injection. Immunological responses were monitored 1-month (long-term booster; LTB) and 3-year (long-term immunity; LTI) post-booster by delayed-type hypersensitivity, IFN-γ ELISPOT and proliferation assays. Regulatory T cell (Treg) frequencies, plasma transforming growth factor-β (TGF-β) and indoleamine 2,3-deoxygenase (IDO) activity levels were also determined at the same time points. The AE37 booster was safe and well tolerated. Immunological monitoring revealed vaccine-specific long-term immunity in most of the evaluated patients during both LTB and LTI, although individual levels of immunity during LTI were decreased compared with those measured 3 years earlier during LTB. This was paralleled with increased Tregs, TGF-β levels and IDO activity. One AE37 booster generated long-term immunological memory in HER-2/neu + prostate cancer patients, which was detectable 3 years later, albeit with a tendency to decline. Boosted patients had favorable clinical outcome in terms of overall and/or metastasis-free survival compared with historical groups with similar clinical characteristics at diagnosis. We suggest that more boosters and/or concomitant disarming of suppressor circuits may be necessary to sustain immunological memory, and therefore, further studies to optimize the AE37 booster schedule are warranted.

Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of bound to antibody antigens. The effectiveness of this function varies for its several haplotypes, and it participates in the pathogenesis of viral infections, according to recent studies. The genetic locus of Fc-γ RIIA consists of two allelic genes: 131-Arg (R131) and 131-His (H131). Our aim was to correlate Fc-γ RIIA polymorphisms, by studying the prevalence of each allele using PCR-RFLPs (polymerase chain reaction-restriction fragment length polymorphisms), with latent Epstein-Barr virus (EBV) infection and the expression of latent membrane protein 1 (LMP1) in 40 patients with leukemic low grade B-cell lymphomas. R131 was found in 84.2% of EBV-positive patients, but only in 28.5% of EBV-negative patients (p = 0.001). A similar correlation was found for R131 and LMP1 expression (84.6% vs. 28.5%) (p = 0.002). Our results support the hypothesis that Fc-γ RIIA polymorphisms are a genetic risk factor for latent EBV infection and the expression of its oncogenic latency proteins.

Background Tumor immune cell infiltrates are essential in hindering cancer progression and may complement the TNM classification. CD8+ and CD163+ cells have prognostic impact in breast cancer but their spatial heterogeneity has not been extensively explored in this type of cancer. Here, their potential as prognostic biomarkers was evaluated, depending on their combined densities in the tumor center (TC) and the tumor invasive margin (IM). Methods CD8+ and CD163+ cells were quantified by immunohistochemistry of formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples from a cohort totaling 162 patients with histologically-confirmed primary invasive non-metastatic ductal breast cancer diagnosed between 2000 and 2015. Clinical follow-up (median 6.9 years) was available for 97 of these patients. Results Differential densities of CD8+ and CD163+ cells in the combined TC and IM compartments (i.e., high(H)/low(L), respectively for CD8+ cells and the reverse L/H combination for CD163+ cells) were found to have significant prognostic value for survival, and allowed better patient stratification than TNM stage, tumor size, lymph node invasion and histological grade. The combined evaluation of CD8+ and CD163+ cell densities jointly in TC and IM further improves prediction of clinical outcomes based on disease-free and overall survival. Patients having the favorable immune signatures had favorable clinical outcomes despite poor clinicopathological parameters. Conclusions Given the important roles of CD8+ and CD163+ cells in regulating opposing immune circuits, adding an assessment of their differential densities to the prognostic biomarker armamentarium in breast cancer would be valuable. Larger validation studies are necessary to confirm these findings. Trial registrations Study code: IRB-ID 6079/448/10-6-13 Date of approval: 10/06/2013 Retrospective study (2000–2010) First patient prospectively enrolled 14/2/2014 Electronic supplementary material The online version of this article (doi:10.1186/s40425-017-0240-7) contains supplementary material, which is available to authorized users.

Endothelial Nitric Oxide Synthase (eNOS) is crucial for vascular homeostasis. Polymorphisms T786C and G894T affect eNOS regulation and have been related to various diseases. Sickle Cell Disease (SCD), a clinically diverse chronic hemolytic anemia, implies impaired nitric oxide bioavailability. Our aim was to determine eNOS genotype for T786C and G894T polymorphisms in Greek patients with SCD and to elucidate its consequences and effects if any on clinical phenotype. Seventy nine steady state cases, mostly compound heterozygous for Sickle Cell anemia/beta thalassemia and 48 controls were measured. Peripheral blood DNA was extracted and genotyped with PCR-RFLPs and Sanger sequencing. Total RNA was extracted from 18 patients and 9 controls and eNOS mRNA levels were determined by real-time PCR. Genotypes, allele distribution and eNOS mRNA levels did not differ between patients and controls, or among patients with different beta globin gene mutations. The 786CC genotype was more common in S/S and β0/S patients with retinopathy. Moreover, 894TT S/S and β0/S patients tended to have a higher hematocrit than 894GG and GT ones. However, the T786C eNOS genotype does not seem to affect peripheral blood cell-derived eNOS mRNA levels, at least in steady state conditions. This work is the first one describing the effects of eNOS polymorphisms on different forms of SCD, the first enrolling SCD patients of Caucasian origin and the first determining eNOS mRNA levels in peripheral blood from steady-state SCD patients.