Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

Validation of the test for finding word retrieval deficits (WoFi) in detecting Alzheimer's disease in a naturalistic clinical setting

Background Detecting impaired naming capacity contributes to the detection of mild (MildND) and major (MajorND) neurocognitive disorder due to Alzheimer’s disease (AD). The Test for Finding Word retrieval deficits (WoFi) is a new, 50-item, auditory stimuli-based instrument. Objective The study aimed to adapt WoFi to the Greek language, to develop a short version of WoFi (WoFi-brief), to compare the item frequency and the utility of both instruments with the naming subtest of the widely used Addenbrooke’s cognitive examination III (ACEIIINaming) in detecting MildND and MajorND due to AD. Methods This cross-sectional, validation study included 99 individuals without neurocognitive disorder, as well as 114 and 49 patients with MildND and MajorND due to AD, respectively. The analyses included categorical principal components analysis using Cramer’s V, assessment of the frequency of test items based on corpora of television subtitles, comparison analyses, Kernel Fisher discriminant analysis models, proportional odds logistic regression (POLR) models and stratified repeated random subsampling used to recursive partitioning to training and validation set (70/30 ratio). Results WoFi and WoFi-brief, which consists of 16 items, have comparable item frequency and utility and outperform ACEIIINaming. According to the results of the discriminant analysis, the misclassification error was 30.9%, 33.6% and 42.4% for WoFi, WoFi-brief and ACEIIINaming, respectively. In the validation regression model including WoFi the mean misclassification error was 33%, while in those including WoFi-brief and ACEIIINaming it was 31% and 34%, respectively. Conclusions WoFi and WoFi-brief are more effective in detecting MildND and MajorND due to AD than ACEIIINaming

The Effect of Low-Level Laser Therapy on Bone Healing after Rapid Maxillary Expansion: A Systematic Review

Objective: The study aimed to systematically appraise the evidence on the effects of low level laser therapy (LLLT) on bone healing following rapid maxillary expansion (RME). Methods: Electronic search was performed in MEDLINE, Scopus, and Embase databases using appropriate Medical Subject Heading terms, with no time restriction. ClinicalTrials.gov (www.clinicaltrials.gov) was also searched using the terms "low level laser therapy" and "maxillary expansion." Selection criteria: Original research articles on human clinical trials that involved both RME and LLLT were included. Animal studies were also assessed on an exploratory basis. Results: The search strategy resulted in 12 publications (4 randomized controlled trials, 8 animal studies). In human studies, bone density was assessed radiographically (either two-dimensional or three-dimensional imaging). Regardless of the discrepancies in the intervention protocols, the total of the trials revealed that LLLT had stimulatory effects on bone regeneration after RME. The studies in animal models measured the formation and maturation of new bone qualitatively or quantitatively. Conclusions: Despite the limited evidence, LLLT seems to be a promising intervention for stimulating immediate bone regeneration and healing after midpalatal suture expansion. Long-term, randomized clinical trials are needed to formulate safe results and establish a reliable clinical protocol, rendering the method clinically applicable. © Copyright 2018, Mary Ann Liebert, Inc. 2018

Are Thyroid Hormone and Tumor Cell Proliferation in Human Breast Cancers Positive for HER2 Associated?

Objective. This study investigated whether thyroid hormone (TH) levels are correlated to cell proliferation (Ki67), in euthyroid breast cancer patients. Design and Methods. 86 newly diagnosed breast cancer patients with estrogen receptor (ER) positive tumors, who referred for surgery, were included in the study. Results. FT3, FT4, and TSH were within normal range. No correlation was seen between Ki67 and FT3 (r=-0.17, P=0.15), FT4 (r=-0.13, P=0.25), or TSH (r=-0.10, P=0.39) in all patients studied. However, subgroup analysis showed that, in HER2(+) patients, a negative correlation existed between FT3 levels and Ki67 (r=-0.60 and P=0.004) but not between Ki67 and FT4 (r=0.04 and P=0.85) or TSH (r=-0.23 and P=0.30). In HER2(-) patients, there was no significant correlation between Ki67 and FT3 (r=-0.06, P=0.67), FT4 (r=-0.15, P=0.26), or TSH (r=-0.09, P=0.49). Phospho-p44/total p44 ERK levels were found to be increased by 2-fold in HER2(+) versus HER2(-) tumors. No difference was detected in phospho-p42/total p42 ERK levels. Conclusions. TH profile is not altered in patients with newly diagnosed breast cancer. However, FT3 levels, even within normal range, are negatively correlated with cell proliferation in HER2(+) breast cancer tumors. This response may be due to the interaction between ERK and TH signaling. © 2015 Iordanis Mourouzis et al

Efficacy and safety of first-line everolimus therapy alone or in combination with octreotide in gastroenteropancreatic neuroendocrine tumors. A hellenic cooperative oncology group (HeCOG) study

The purpose of this study was to explore the efficacy and safety of everolimus administered as a first-line treatment in newly diagnosed patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP NETs). This phase II, multicenter, single-arm study included patients with well-differentiated GEP NETs and a Ki67 < 20%. Everolimus, at 10 mg/day, was administered until disease progression; 18 patients (72%) concomitantly received octreotide long-acting release (LAR), at 30 mg/month. The primary endpoint was the 15-month progression-free survival (PFS) rate. Twenty-five patients (grade 1: 11 patients, grade 2: 14 patients) were enrolled between August 2012 and October 2015. At a median follow-up of 58.1 months, the median PFS was 14.6 months, while the 15-month PFS rate was 48%; median overall survival had not been reached yet. Normal baseline chromogranin A (<4 nmol/l) confirmed a longer PFS (HR = 0.25, 95% CI 0.08–0.77, p = 0.016). Seven patients (28%) achieved an objective response (one complete response and six partial responses) in a median of 2.6 months. Twenty-three grade 3–4 events were recorded (14 patients). No fatal reactions occurred. This prospective phase II study unravels the notable activity of everolimus as a first-line treatment in patients with GEP NETS and contributes valuable information about the high activity of the combination of everolimus and octreotide LAR in this setting. Clinical trial information: NCT01648465. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Testicular function in poor-risk nonseminomatous germ cell tumors treated with methotrexate, paclitaxel, ifosfamide, and cisplatin combination chemotherapy

Our objective was to investigate the impact of methotrexate, paclitaxel, ifosfamide, and cisplatin (M-TIP) on long-term fertility in poor-risk nonseminomatous germ cell tumors (NSGCT). Thirty patients with poor-risk NSGCT (median age, 29 years; range, 17-62 years) were treated with methotrexate 250 mg/m2 with folinic acid rescue (day 1) and paclitaxel 175 mg/m2 (day 1), followed by ifosfamide 1.2 g/m2 and cisplatin 20 mg/m2 (days 2-6). Treatment consisted of 4 cycles of M-TIP administered every 3 weeks. Twenty-one patients were continuously disease-free at a median follow-up of 5.3 years (range, 0.9-8.4 years). Sperm count and hormonal analyses were examined prechemotherapy (30 patients) and postchemotherapy (21 patients). Counts were classified as follows: lower than 1 × 106/mL, azoospermia; 1-20 × 106/mL, oligospermia (OS); higher than 20 × 106/mL, normospermia (NS). Patients were followed for a median of 2.3 years (range, 0.9-3.8 years) postchemotherapy. The prechemotherapy median luteinizing hormone (LH) serum levels were slightly above the upper normal limit, whereas the serum levels of follicle-stimulating hormone (FSH) and testosterone (T) were within the reference interval. Eleven (52.3%) patients had NS prechemotherapy. Among the patients with NS, 72.7% still had NS following chemotherapy. Overall, 17 of 21 (80.9%; 33.3% OS and 47.6% NS) patients had recovery of spermatogenesis after treatment. The median FSH serum levels were significantly elevated at least 1 year postchemotherapy when compared with the pretreatment levels. Eighteen months after the completion of chemotherapy the median FSH levels had returned to the reference limits. Serum LH and T levels were unaffected by chemotherapy. Prior to chemotherapy 4 of 30 patients had fathered 5 children. Since completion of chemotherapy, 5 patients have fathered 5 children. The majority of men with poor-risk germ cell tumors who were treated with the M-TIP regimen demonstrated recovery spermatogenesis after treatment, and Leydig cell function was unaffected. Copyright © American Society of Andrology

Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe

Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1–7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide-excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p < 0.001). In multivariate analysis models for progression-free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC. © 2017 UIC

Cyclin D1 differential activation and its prognostic impact in patients with advanced breast cancer treated with trastuzumab

Introduction We sought to determine the level of activation of the critical components of the cyclin D1-mediated pathway and to evaluate their prognostic significance across the different molecular subtypes of advanced breast cancer. Patients and methods The study population comprised 219 female patients with advanced breast cancer who had been found to have human epidermal growth factor receptor 2 (HER2)-positive disease by local testing and were all treated with trastuzumab-based regimens. For all tumours, central testing for HER2 was performed, and cyclin D1 gene (CCND1) amplification, mRNA and protein expression were assessed by FISH, quantitative real-time-PCR and immunohistochemistry, respectively. Prognostic impact on clinical endpoints was evaluated with Cox regression analyses. Results After central testing, only 134 (61.2%) of 219 patients were confirmed to have HER2 gene amplification by FISH and/or 3+ HER2 protein expression by immunohistochemistry. After a median follow-up time of 136.0 months (95% CI 123.3 to 148.9), 105 (78.4%) HER2-positive patients and 76 (89.4%) HER2-negative patients had died, while 80% of the former and 87.1% of the latter had experienced a disease relapse. Patients with positive oestrogen receptor/progesterone receptor status presented with higher cyclin D1 mRNA expression. In the HER2-negative subgroup, patients with negative cyclin D1 protein expression were at higher risk of progression (HR= 1.66, 95%CI 1.01 to 2.72, Wald's p=0.045). Among de novo metastatic patients, the risk of progression was higher for patients with non-amplified CCND1 tumours (HR= 2.00, 95% CI 1.03 to 3.90, p=0.041). Conclusion Aberrant activation of the cyclin D1-mediated pathway appears to reduce the risk of progression in HER2-negative tumours, but not in HER2-positive ones. © Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy