Immunological Etiology Research Articles

O-3 Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648

NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis, including factors associated with the timing of the onset of treatment effect. Patients with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in patients with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized patients. Duration of response (DOR) per BICR and PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) per investigator were exploratory endpoints. Among all patients randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo at 13-month minimum follow-up. ORR (95% CI) was 47% (42–53) with NIVO + chemo, 28% (23–33) with NIVO + IPI, and 27% (22–32) with chemo. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 months; 39%, 48%, and 23%, respectively). Piecewise HRs of overall survival between treatment arms and factors associated with delayed onset of effect of NIVO + IPI relative to chemo-based regimens will be presented. The majority of treatment-related adverse events with potential immunologic etiology (select TRAEs) were grade 1 or 2, and grade 3/4 events occurred in ≤ 6% of patients with NIVO + chemo and NIVO + IPI. Select TRAEs of any grade occurred within a median of 5 to 31 weeks with NIVO + chemo and 4 to 12 weeks with NIVO + IPI across organ categories. Nonendocrine select TRAEs resolved in most patients in the NIVO + chemo (57% to 91%) and NIVO + IPI (63% to 95%) groups across organ categories with the use of established management algorithms (median time to resolution, 2 to 17 weeks and 3 to 12 weeks, respectively). NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of patients with prolonged DOR vs chemo, along with acceptable safety profiles. These results provide further support for each regimen as a new potential first-line standard therapy in advanced ESCC.

Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648.

4035 Background: NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients (pts) with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis with 13-month (mo) minimum follow-up. Methods: Pts with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in pts with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized pts. Duration of response (DOR) per BICR and PFS2 per investigator (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) were exploratory endpoints. Results: Among all pts randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo. ORR (95% CI) was 47% (42–53), 28% (23–33), and 27% (22–32), respectively. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 mo; 39%, 48%, and 23%, respectively). Efficacy data by tumor cell PD-L1 and PD-L1 combined positive score will be presented. Grade 3/4 treatment-related adverse events with potential immunologic etiology (select TRAEs) occurred in ≤ 6% of pts with NIVO + chemo and NIVO + IPI, and non-endocrine select TRAEs resolved in 57%–95% of pts across organ categories (Table). Conclusions: NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of pts with prolonged DOR vs chemo, as well as acceptable safety profiles. These results provide further support for each regimen as a new potential 1L standard of care in advanced ESCC. Clinical trial information: NCT03143153. [Table: see text]

Histopathologic Characterization and Neurodegenerative Markers in Patients With Limbic Encephalitis Undergoing Epilepsy Surgery.

PurposeLimbic encephalitis is an increasingly recognized cause of medial temporal lobe epilepsy (mTLE) and associated cognitive deficits, potentially resulting in hippocampal sclerosis (HS). For several reasons, these patients usually do not undergo epilepsy surgery. Thus, histopathologic examinations in surgical specimens of clearly diagnosed limbic encephalitis are scarce. The purpose of this study was a detailed histopathologic analysis of surgical tissue alterations, including neurodegenerative markers, in patients with limbic encephalitis undergoing epilepsy surgery.MethodsWe investigated the surgical specimens of six patients operated on with mTLE related to limbic encephalitis (among them four patients were with GAD65 and one with Ma1/2 antibodies), and compared the findings to a control group with six patients matched according to age at the time of surgery without limbic encephalitis and without early inciting events.ResultsHistopathologic analysis in the group with limbic encephalitis revealed HS in four patients, while three of them also displayed signs of an active inflammatory reaction with lymphocytes. In one of the patients with GAD65-encephalitis who was suffering from a late-onset mTLE and a long disease course, neurodegenerative protein markers (β-amyloid and hyperphosphorylated tau) were found coexisting with inflammatory reactions and HS. Investigations in the control group did not reveal any inflammatory reaction or neurodegenerative marker.ConclusionOur findings suggest a possible link between long-lasting immune reactions in the medial temporal lobe, HS, and further toward the development of neurodegenerative diseases. Presently, however, a causal relationship between these entities cannot yet be established. Furthermore, our results suggest that an immunological etiology should always be considered in late onset (> 18 years) mTLE, also in cases of long disease duration and the presence of HS.

Gut microbiome in neuropsychiatric disorders.

Neuropsychiatric disorders are a significant cause of death and disability worldwide. The mechanisms underlying these disorders include a constellation of structural, infectious, immunological, metabolic, and genetic etiologies. Advances in next-generation sequencing techniques have demonstrated that the composition of the enteric microbiome is dynamic and plays a pivotal role in host homeostasis and several diseases. The enteric microbiome acts as a key mediator in neuronal signaling via metabolic, neuroimmune, and neuroendocrine pathways. In this review, we aim to present and discuss the most current knowledge regarding the putative influence of the gut microbiome in neuropsychiatric disorders. We examined some of the preclinical and clinical evidence and therapeutic strategies associated with the manipulation of the gut microbiome. targeted taxa were described and grouped from major studies to each disease. Understanding the complexity of these ecological interactions and their association with susceptibility and progression of acute and chronic disorders could lead to novel diagnostic biomarkers based on molecular targets. Moreover, research on the microbiome can also improve some emerging treatment choices, such as fecal transplantation, personalized probiotics, and dietary interventions, which could be used to reduce the impact of specific neuropsychiatric disorders. We expect that this knowledge will help physicians caring for patients with neuropsychiatric disorders.

Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): Expanded efficacy, safety, and subgroup analyses from CheckMate 649.

240 Background: CheckMate 649 is a randomized, global phase 3 study of 1L programmed death-1 (PD-1) inhibitor–based therapies in advanced non-HER2-positive GC/GEJC/EAC that demonstrated superior overall survival (OS) with NIVO + chemo vs chemo, leading to approvals in the US and other countries. Clinically meaningful long-term survival benefit with NIVO + chemo vs chemo was observed with 24 months (mo) of minimum follow-up in all randomized patients (pts) for both OS (HR 0.79 [95% CI 0.71–0.88]) and progression-free survival (PFS; HR 0.79 [95% CI 0.70–0.89]; Janjigian YY et al; ESMO 2021). We present expanded analyses of NIVO + chemo vs chemo with minimum follow-up of 24 mo. Methods: Adults with previously untreated, unresectable advanced or metastatic GC/GEJC/EAC were enrolled regardless of PD-ligand (L)1 expression. Pts with known HER2-positive status were excluded. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses, then NIVO 240 mg Q2W), or chemo. Dual primary endpoints were OS and PFS (per blinded independent central review) in pts with PD-L1 combined positive score (CPS) ≥ 5 for NIVO + chemo vs chemo. Hierarchically tested secondary endpoints included OS in NIVO + chemo vs chemo (PD-L1 CPS ≥ 1, then all randomized). Results: Of 2031 pts, 1581 were randomized to NIVO + chemo or chemo. In all randomized pts, 41% of pts (NIVO + chemo) and 44% of pts (chemo) received subsequent therapy. Median PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was 12.2 (95% CI 11.3–13.5) mo with NIVO + chemo and 10.4 (95% CI 9.7–11.2) mo with chemo (HR 0.75 [95% CI 0.67–0.84]). 51% of pts (NIVO + chemo) and 43% of pts (chemo) had > 50% reduction from baseline in tumor burden, while 24% and 17% had > 80% reduction, respectively. The HR (95% CI) for OS was 0.66 (0.56–0.77) among pts with a PD-L1 CPS ≥ 10 (median OS for NIVO + chemo vs chemo: 15.0 [95% CI 13.7–16.7] vs 10.9 [95% CI 9.8–11.9] mo). OS benefit was observed with NIVO + chemo vs chemo across multiple additional subgroups, and these data will be presented. No new safety signals were identified. The majority of the treatment-related adverse events with potential immunologic etiology were grade 1 or 2 and grade 3 or 4 events were reported in ≤ 5% of pts in both treatment arms. Conclusions: NIVO + chemo continued to demonstrate clinically meaningful efficacy and an acceptable safety profile with longer follow-up, further supporting the use of NIVO + chemo as a standard 1L therapy in previously untreated pts with advanced GC/GEJC/EAC. Clinical trial information: NCT02872116.

The abnormal level of HSP70 is related to Treg/Th17 imbalance in PCOS patients

BackgroundPolycystic ovary syndrome (PCOS) is a disease with chronic nonspecific low-grade inflammation. The imbalance of immune cells exists in PCOS. Several studies have found that heat shock protein 70 (HSP70) may be involved in the immunological pathogenesis of PCOS, but the relationship between HSP70 and Regulatory T cell (Treg)/T helper cell 17(Th17) ratio remains unclear. This study aims to explore the correlation between HSP70 and Treg/Th17 ratio and to provide evidence for the role of HSP70 in the immunological etiology of PCOS.ResultsThere was no significant difference in age and body mass index (BMI) between the two groups. The concentrations of basal estradiol (E2), basal follicle-stimulating hormone (FSH) did not show a significant difference between the two groups. The concentrations of basal luteinizing hormone (LH) (P < 0.01), testosterone (T) (P < 0.01), glucose (P < 0.001) and insulin (P < 0.001) in PCOS patients were significantly higher than those in the control group. The protein levels of HSP70 were significantly higher in serum in the PCOS group (P < 0.001). The percentage of Treg cells was significantly lower (P < 0.01), while the percentage of the Th17 cells of the PCOS group was significantly higher than that of the control group (P < 0.05). The ratio of Treg/Th17 in the PCOS group was significantly lower (P < 0.001). The concentrations of Interleukin (IL)-6, IL-17, and IL-23 were significantly higher, while the levels of IL-10 and Transforming growth factor-β (TGF-β) were significantly lower in the PCOS group (P < 0.001). Spearman rank correlation analysis showed a strong negative correlation of serum HSP70 levels with Treg/Th17 ratio, IL-10, and TGF-β levels. In contrast, HSP70 levels were significantly positively correlated with IL-6, IL-17, IL-23, LH, insulin, and glucose levels.ConclusionThe abnormal level of HSP70 is correlated with Treg/Th17 imbalance and corresponding cytokines, which indicates that HSP70 may play an important role in PCOS immunologic pathogenesis.

M036 DOBUTAMINE-INDUCED EOSINOPHILIA

Eosinophilia can occur in response to allergens, drugs, parasites, immunologic, neoplastic and idiopathic etiologies. We present an unusual scenario of eosinophilia in the wake of a routinely used inotrope, dobutamine.

Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067

BackgroundTreatment-free survival (TFS) characterizes disease control after discontinuation of immune checkpoint inhibitors (ICIs) until subsequent therapy or death. We previously evaluated TFS in a pooled analysis of the CheckMate 067...

Complicated encephalitis in pediatrics

Encephalitis is a potentially fatal inflammation of the brain parenchyma, of infectious or immunological etiology. This article is a case report of a 9-month-old child who evolved to death, demonstrating the difficulty in making the diagnosis, due to the symptoms of this disease being, in most cases, nonspecific and with several differential diagnoses.

Immunomodulatory Therapy Reduces the Severity of Placental Lesions in Chronic Histiocytic Intervillositis.

Chronic histiocytic intervillositis (CHI) is a rare, but highly recurrent inflammatory placental lesion wherein maternal macrophages infiltrate the intervillous space. Pregnancies with CHI are at high risk of fetal growth restriction, miscarriage or stillbirth. Presently, the diagnosis can only be made after histopathological examination of the placenta. Given its proposed immunological etiology, current treatments include aspirin, heparin, and immunomodulatory agents. However, the rationale for these medications is largely based upon small case series and reports as there is a lack of larger studies investigating treatment efficacy. Therefore, this study sought to determine whether inclusion of immunomodulatory medications was effective at reducing the severity of lesions and improving pregnancy outcomes in subsequent pregnancies. Thirty-three women with a history of CHI in at least one pregnancy (index case) were identified retrospectively through medical records. Twenty-eight participants presented with a first subsequent pregnancy and a further 11 with a second subsequent pregnancy at a specialist clinic for pregnancy after loss. Data on maternal demographics, medical history, medication, pregnancy outcome, and placental pathology was collected and compared between pregnancies. Twenty-seven (69%) subsequent pregnancies were treated with at least one or both of prednisolone and hydroxychloroquine. Inclusion of at least one immunomodulatory agent in treatment regimen resulted in an almost 25% increase in overall livebirth rate (61.5 vs. 86.2%). In women treated with immunomodulatory medication a greater proportion of placentas had reduced severity of lesions compared to those treated without (86.7 vs. 33.3%, respectively). A reduction in CHI severity was associated with a 62.3% improvement in livebirth rate compared to those where severity remained unchanged in relation to the index case. These data provide preliminary evidence that the use of immunomodulatory medication in the management of CHI improves histopathological lesions and the chance of livebirth in subsequent pregnancies. Due to CHI's rarity and ethical and feasibility issues, randomized controlled trials in affected women are challenging to conduct. As a result, collaboration between centers is required in future to increase study sample sizes and elucidate the mechanisms of hydroxychloroquine and prednisolone in reducing pathology.

Diagnostic and Management Strategies for Patients with Chronic Prostatitis and Chronic Pelvic Pain Syndrome.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common and often heterogenous condition that can have severe consequences on patient quality of life. In this review, we describe the pathophysiology, diagnostic work-up, and treatment of patients with CP/CPPS incorporating the most recent literature. Studies have demonstrated that CP/CPPS involves a complex pathophysiology, including infectious, immunologic, neurologic, endocrinologic, and psychologic etiologies, with frequent intersections between the different entities. Despite robust research assessing a variety of therapeutics targeting these etiologies, clinical trials have failed to identify an empiric treatment strategy applicable specifically to older adult male patients with CP/CPPS. As such, it can be challenging to manage older male patients with this condition. The advent of clinical phenotyping of patients with CP/CPPS has led to advances in tailored management strategies. Monomodal therapy has been largely unsuccessful because of the unclear and complex etiology of CPPS. As a result, CP/CPPS therapy has transitioned to a multimodal approach, including both pharmacologic and non-pharmacologic therapies. The best studied pharmacologic therapies include antibiotics, alpha-blockers, anti-inflammatory and immunomodulatory agents, phytotherapies, phosphodiesterase inhibitors, hormonal agents, neuromodulatory agents, and antidepressants. The best studied non-pharmacological therapies include pelvic floor physical therapy, myofascial trigger point release, acupuncture and electroacupuncture, psychological support and biofeedback, and electrocorporeal shockwave therapy and local thermotherapy.

Animal models of diabetic retinopathy.

The retina is the posterior neuro-integrated layer of the eye that conducts impulses induced by light to the optic nerve for human vision. Diseases of the retina often leads to diminished vision and in some cases blindness. Diabetes mellitus (DM) is a worldwide public health issue and globally, there is an estimated 463 million people that are affected by DM and its consequences. Diabetic retinopathy (DR) is a blinding complication of chronic uncontrolled DM and is the most common cause of blindness in the United States between the ages 24–75. It is estimated that the global prevalence of DR will increase to 191.0 million by 2030, of those 56.3 million possessing vision-threatening diabetic retinopathy (VTDR). For the most part, current treatment modalities control the complications of DR without addressing the underlying pathophysiology of the disease. Therefore, there is an unmet need for new therapeutics that not only repair the damaged retinal tissue, but also reverse the course of DR. The key element in developing these treatments is expanding our basic knowledge by studying DR pathogenesis in animal models of proliferative and non-proliferative DR (PDR and NPDR). There are numerous models available for the research of both PDR and NPDR with substantial overlap. Animal models available include those with genetic backgrounds prone to hyperglycemic states, immunologic etiologies, or environmentally induced disease. In this review we aimed to comprehensively summarize the available animal models for DR while also providing insight to each model’s ocular therapeutic potential for drug discovery.

Drug-induced Myopathies.

Differential diagnosis of muscle pain and weakness is extensive, including neurological, vertebral, arthrogenic, vascular, traumatic, immunological, endocrine, genetic and infectious aetiologies, as well as medication or toxin-related causes. Muscles are highly sensitive to a large number of drugs, especially with high doses. Although many drug classes can cause toxic myopathy, a significant number of cases are caused by lipid-lowering drugs, long-term use of corticosteroids, and, most often, alcohol misuse. Some drug interactions, e.g. those that are metabolised via the enzyme CYP3A4, can increase the serum levels of the drugs and drug-induced toxicity. A careful history of patient's drug and alcohol consumption is therefore vital. Clinical symptoms depend on the drug, dosage and patient's sensitivity. They can vary from asymptomatic increase in serum levels of creatine kinase, mild myalgia and cramps to muscle weakness, rhabdomyolysis, kidney failure and even death. The pathogenesis is often only partially known and multifactorial. Toxic myopathy is often reversible once the drug is discontinued, alternative drug therapy is started or a different dosage regimen is chosen. Complications such as acute kidney failure must be avoided, and analgesic therapy may be indicated.

Zinc transporter 8 (ZnT8) autoantibody prevalence in black South African participants with type 1 diabetes

BackgroundAutoantibodies to β-cell specific antigens are markers of type 1 diabetes. The most recently identified autoantibodies are targeted to the zinc transporter 8 (ZnT8) protein located in the membrane of β-cell insulin secretory granules. The prevalence of ZnT8 autoantibodies in newly diagnosed participants with type 1 diabetes has been found to range from 33 to 80 %. Due to the lack of data on the immunological aetiology of type 1 diabetes in African populations, this study aimed to determine the prevalence of ZnT8 autoantibodies in black South Africans with type 1 diabetes and whether ZnT8 autoantibody positivity was associated with age at diagnosis and disease duration.MethodsParticipants with type 1 diabetes and controls were recruited from the greater Johannesburg area, South Africa. Positivity for ZnT8, GAD65 and IA2 autoantibodies was determined by ELISA.ResultsParticipants with type 1 diabetes (n = 183) and controls (n = 49) were matched for age (29.1 ± 9.53 vs. 27.3 ± 7.29, respectively; p = 0.248). The mean age at diagnosis for participants with type 1 diabetes was 20.8 ± 8.46 years. The prevalence of ZnT8 autoantibody positivity was 17.5 % (32 of 183) in participants with type 1 diabetes with a median disease duration of 7.00 [2.00; 11.0] years. ZnT8 autoantibody prevalence in newly diagnosed participants (< 1 year duration) was 27.3 % (6 of 22). Logistic regression analysis found an association between ZnT8 autoantibody positivity and shorter disease duration (OR: 0.9 (0.81-1.00); p = 0.042). In addition, ZnT8 autoantibody positivity was significantly associated with an increased chance of being GAD65 (OR: 3.37 (1.10–10.3)) and IA2 (OR: 8.63 (2.82–26.4)) autoantibody positive. Multiple regression analysis found no association between ZnT8 autoantibody positivity and age at diagnosis. However, the presence of ≥ 2 autoantibodies was associated with a younger age at diagnosis of type 1 diabetes when compared to participants with ≤ 1 autoantibody (B = -5.270; p = 0.002).ConclusionsThe presence of ZnT8 autoantibodies was not related to a younger age at diagnosis in black South African patients with type 1 diabetes. However, the greater the numbers of autoantibodies present in an individual the earlier the age at diagnosis. ZnT8 autoantibodies decline with disease duration in the black South African population.

Immunity and Gilles de la Tourette syndrome: A systematic review and meta-analysis of evidence for immune implications in Tourette syndrome.

The neurobiology of Gilles de la Tourette syndrome (GTS) is known to involve corticostriatal loops possibly under genetic control. Less is known about possible environmental triggers of GTS. Specifically, immune-related events following possible environmental inducers have been evoked, but important controversies still exist. In this systematic review and meta-analysis, we looked for evidence in favor of such possibilities. We performed a systematic review and meta-analysis of all immunological data in PubMed. We found large discrepancies concerning immune dysfunctions in GTS, and meta-analyzing cytokines data did not allow us to conclude there is an involvement of specific cytokines in GTS neurobiology. When looking specifically at pediatric autoimmune neuropsychiatric disorder associated with streptococcus/pediatric acute onset neuropsychiatric syndrome, we found some important evidence of a possible infectious involvement but in a limited number of studies. Our meta-analysis found an increased level of anti-streptolysin O antibodies in GTS patients, but the level of anti-DNase B antibodies was not increased. Too many questions still exist to allow us to definitively reach the conclusion that there is an infectious and immunological etiology in GTS. Much work is still needed to elucidate the possible role of immunology in GTS neurobiology and to favor immunological treatment rather than classical treatment.

Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): Expanded efficacy and safety analyses from CheckMate 577.

4003 Background: In CheckMate 577 (NCT02743494), NIVO demonstrated a significant and clinically meaningful improvement in disease-free survival (DFS; primary endpoint) vs placebo (PBO) and was well tolerated in patients (pts) with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease. Median DFS doubled with NIVO vs PBO (22.4 vs 11.0 months; HR 0.69; 96.4% CI 0.56–0.86; P = 0.0003). Serious treatment-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported for &lt; 10% of pts with NIVO and 3% with PBO. Methods: Pts were randomized 2:1 to NIVO 240 mg or PBO Q2W for 16 weeks, followed by NIVO 480 mg or PBO Q4W. Here, we present additional efficacy, safety, and quality-of-life (QoL) data from CheckMate 577. Results: 794 pts were randomized (NIVO, 532; PBO, 262). Distant recurrence was reported for 29% vs 39% and locoregional recurrence for 12% vs 17% of pts in the NIVO vs PBO groups, respectively. Median distant metastasis-free survival was 28.3 vs 17.6 months with NIVO vs PBO (HR 0.74; 95% CI 0.60–0.92). Median progression-free survival 2 (PFS2; time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was not reached with NIVO vs 32.1 months with PBO (HR 0.77; 95% CI 0.60–0.99). TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) reported for NIVO are presented in the table. Results for the FACT-ECS and FACT-G7 showed similar trends for QoL improvement from baseline for NIVO and PBO during treatment and maintained benefit post-treatment. Conclusions: Adjuvant NIVO demonstrated clinically meaningful efficacy, an acceptable safety profile, and maintained QoL, providing further support for its use as a new standard of care for pts with resected EC/GEJC who received neoadjuvant CRT with residual pathologic disease. Clinical trial information: NCT02743494. [Table: see text]

First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): Expanded efficacy and safety data from CheckMate 649.

4002 Background: CheckMate 649 is the largest randomized, global phase 3 study of 1L programmed death (PD)-1 inhibitor–based therapy in GC/GEJC/EAC. 1L NIVO + chemo demonstrated superior overall survival (OS) vs chemo, with progression-free survival (PFS) benefit and an acceptable safety profile in pts whose tumors expressed PD-ligand (L)1 at combined positive score (CPS) ≥ 5 and ≥ 1, and in all randomized pts (Moehler et al. Ann Oncol 2020). We report additional data for all randomized pts. Methods: Eligible pts had previously untreated, unresectable advanced or metastatic GC/GEJC/EAC. Known HER2-positive pts were excluded. Pts were randomized to receive NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded central review in PD-L1 CPS ≥ 5 pts. Hierarchically tested secondary endpoints were OS in PD-L1 CPS ≥ 1 and all randomized pts. Results: At 12-month minimum follow-up for 1581 randomized pts, NIVO + chemo had a statistically significant OS benefit vs chemo (HR 0.80 [99.3% CI 0.68–0.94; P = 0.0002]) in all randomized pts; PFS benefit was also seen (HR 0.77 [95% CI 0.68–0.87]). OS benefit was observed in multiple prespecified subgroups, consistent with the primary population. Grade 3–4 treatment-related adverse events (TRAEs) were reported in 59% (NIVO + chemo) and 44% (chemo) of pts. TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) are shown in the table. Pts in the NIVO + chemo arm had decreased risk of symptom deterioration on treatment vs those in the chemo arm (HR 0.77 [95% CI 0.63–0.95; P = 0.0129]). Tolerability as measured by the FACT-Ga GP5 item was similar in both treatment groups. Conclusions: The addition of NIVO to chemo demonstrated improved OS and PFS benefit in all randomized pts, along with an acceptable safety profile and maintained tolerability as well as QoL, providing further support for NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116. [Table: see text]

Epidemiological Profile of Skin Diseases in a Tertiary Hospital of Kathmandu: An Annual Census

Introduction: Skin diseases are eighth most common reasons for outpatient in Nepal, and fourth cause of disability globally. Skin diseases varies with the reason, season and socioeconomic status. As the socioeconomic conditions are changing, so are the disease patterns. We planned to report the current trend of skin diseases in Kathmandu and compare with similar studies in past.&#x0D; Materials and methods: Outpatient department records of Civil Service Hospital from the year 2075 Bikram Sambat were reviewed after ethical clearance from institution review committee and were analyzed after tabulation.&#x0D; Results: Total number of cases were 9886 (4.51% of total hospital attendance). In total 8097 cases were new, males were 4218 (52.1%) and females 3879 (47.9%). Most common diagnosis was eczemas (18.47%), followed by dermatophytosis (15.29%). Eczemas, chronic urticaria, psoriasis and lichen planus were more common in the adult population of more than 30 years. While infections and acne were more common in young adults, 15-30 years, in both the sexes. Tinea was common during summer and so was scabies in males, while in females, melasma peaked in summer and chronic urticaria during spring and winter.&#x0D; Conclusion: The pattern of skin diseases is changing with the time. Diseases of possible allergic and immunologic etiology are increasing and diseases with infective etiology are still a huge burden on society.

Is Metformin a Possible Beneficial Treatment for Psoriasis? A Scoping Review.

Psoriasis is a chronic inflammatory condition with genetic, immunological, and metabolic etiology. The link between psoriasis and diabetes mellitus has been shown in genetic predisposition, environmental influences, inflammatory pathways, and insulin resistance, resulting in end-organ damage in both conditions. Because comorbidities often accompany psoriasis, the therapeutic management of the disease must also take into consideration the comorbidities. Given that metformin’s therapeutic role in psoriasis is not yet fully elucidated, we raised the question of whether metformin is a viable alternative for the treatment of psoriasis. We conducted this scoping review by searching for evidence in PubMed, Cochrane, and Scopus databases, and we used an extension for scoping reviews (PRISMA-ScR). Current evidence suggests that metformin is safe to use in psoriasis. Studies have shown an excellent therapeutic response to metformin in patients with psoriasis and comorbidities such as diabetes, metabolic syndrome, and obesity. There is no clear evidence supporting metformin monotherapy in patients with psoriasis without comorbidities. There is a need to further evaluate metformin in larger clinical trials, as a therapy in psoriasis.

Rare neurological presentations of Dengue Fever

In presence of abnormal neurological features infective, immunological and metabolic etiologies are also needed to be kept as possibility. Dengue fever may present with variety of neurological manifestations. This case series includes rare neurological presentation of dengue fever including first ever reported case of dengue fever induced bilateral abducens nerve palsy with another case of dengue cerebellitis. This case series along with previous studies suggest that imaging may be normal in these cases. This case series also highlighted the possible immunological etio-pathogenesis and role of steroids as treatment modality.