Investigator and independent review committee exploratory assessment and verification of tumor response in a non-Hodgkin lymphoma study

Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accurate and reliable measurement and identification of tumors. Regulatory agencies recommend blinded reviews of imaging data by independent review committees (IRCs). Differences in response outcomes that arise between IRCs and site investigators raise regulatory/sponsor concerns. Here, we evaluate discrepant tumor response assessments by the IRC and unblinded investigators (complete versus partial response, respectively) occurring in 52 (13% of 393 IRC-assessed responders) of 447 enrolled patients with treatment-naïve non-Hodgkin lymphoma from a randomized study. The IRC and investigators were \u27likely correct\u27 in 73% and 25% of cases, respectively (p \u3c .001). Investigators were more likely to make errors by misinterpreting lymph node data and not utilizing PET results. This post hoc finding suggests a possible role for post-training site evaluation/audit, with retraining as needed, and a specialized consensus committee for concurrent blinded review of site/central data

Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor

BackgroundSeveral chemicals in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis.ObjectivesThe objective of this study was to provide a detailed characterization of molecular and biochemical responses of female fathead minnows to a model aromatase inhibitor, fadrozole (FAD).MethodsFish were exposed via water to 0, 3, or 30 microg FAD/L for 8 days and then held in clean water for 8 days, with samples collected at four time points during each 8-day period. We quantified ex vivo steroid production, plasma steroids, and plasma vitellogenin (Vtg) concentrations and analyzed relative transcript abundance of 10 key regulatory genes in ovaries and 3 in pituitary tissue by real-time polymerase chain reaction.ResultsEx vivo 17beta-estradiol (E2) production and plasma E2 and Vtg concentrations were significantly reduced after a single day of exposure to 3 microg or 30 microg FAD/L. However, plasma E2 concentrations recovered by the eighth day of exposure in the 3-microg/L group and within 1 day of cessation of exposure in the 30-microg/L group, indicating concentration- and time-dependent physiologic compensation and recovery. Concentration-dependent increases in transcripts coding for aromatase (A isoform), cytochrome P450 side-chain cleavage, steroidogenic acute regulatory protein, and follicle-stimulating hormone receptor all coincided with increased E2 production and recovery of plasma E2 concentrations.ConclusionsResults of this research highlight the need to consider compensation/adaptation and recovery when developing and interpreting short-term bioassays or biomarkers or when trying to predict the effects of chemical exposures based on mode of action

Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704

Double hit lymphoma (DHL) and double protein-expressing (MYC and BCL2) lymphomas (DPL) fare poorly with R-CHOP; consolidative autologous stem cell transplant (ASCT) may improve outcomes. S9704, a phase III randomized study of CHOP +/−R with or without ASCT allows evaluation of intensive consolidation. Immunohistochemical analysis identified 27 of 198 patients (13.6%) with MYC IHC overexpression and 20 (74%) harboring concurrent BCL2 overexpression. Four had DHL and 16 had DPL only. With median follow-up 127 months, there is a trend favoring outcomes after consolidative ASCT in DPL and MYC protein overexpressing patients, whereas all DHL patients have died irrespective of ASCT

Is local review of positron emission tomography scans sufficient in diffuse large B-cell lymphoma clinical trials? A CALGB 50303 analysis

BACKGROUND: Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5-point scale (5-PS). METHODS: In CALGB 50303, patients with DLBCL received frontline R-CHOP or DA-EPOCH-R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5-PS with progression-free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. RESULTS: Agreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (\u3c66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p = 0.03) and OS (p = 0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable. CONCLUSIONS: These data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials

Use of chemical mixtures to differentiate mechanisms of endocrine action in a small fish model

Various assays with adult fish have been developed to identify potential endocrine-disrupting chemicals (EDCs) which may cause toxicity via alterations in the hypothalamic-pituitary-gonadal (HPG) axis. These assays can be sensitive and highly diagnostic for key mechanisms such as agonism of the estrogen and androgen receptors (ERs, ARs) and inhibition of steroid synthesis. However, most of the tests do not unambiguously identify AR antagonists. The purpose of this work was to explore the utility of a mixture test design with the fathead minnow (Pimephales promelas) for detecting different classes of EDCs including AR antagonists. Adults of both sexes were exposed via the water to EDCs with diverse mechanisms of action in the absence or presence of 17beta-trenbolone (TB), a potent AR agonist which masculinizes female fathead minnows. Similar to previous studies with the model AR antagonists flutamide and vinclozolin, exposure of females to the AR antagonist cyproterone acetate in the presence of TB decreased expression of an easily-observed masculinization response, nuptial tubercle formation. Mixture studies with TB and the model ER agonists, 17alpha-ethinylestradiol and bisphenol A, also showed inhibition of tubercle formation in the females, but unlike the AR antagonists, the estrogens markedly induced synthesis of vitellogenin (VTG: egg yolk protein), particularly in males. The ER agonists also offset TB-induced depressions in plasma VTG concentrations in female fish. Additional mixture experiments were conducted with TB and triclocarban, an anti-microbial reported to enhance AR-mediated responses, or ammonia, a "negative control" with no known direct effects on HPG function. Neither chemical affected VTG status in males or females in the absence or presence of TB; however, both slightly enhanced TB-induced tubercle formation in females. Based on studies described herein and elsewhere with the fathead minnow, a TB co-exposure assay appears to be an effective approach for clearly identifying AR antagonists as well as potential EDCs with other relevant mechanisms of action

Multicentric assessment of safety and efficacy of combinatorial adjuvant brain metastasis treatment by intraoperative radiotherapy and immunotherapy

Purpose Following surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy (EBRT) by enabling superior organ at risk preservation, reduction of in-hospital times and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). Methods In a multicentric approach incorporating individual patient data from six international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis (RN), leptomeningeal spread (LMS), local control (LC), distant brain progression (DBP) and estimated overall survival (OS). Results A total of 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow up was 13.2 (1.2-102.4) months and the median IORT dose was 25 (18-30) Gy prescribed to the applicator surface. There was one grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative RN rate was observed. The 1-year LCR was 98.0% and the 1-year DBP-free rate 60.0%. Median time to DBP was 5.5 (1.0-18.5) months in the subgroup of patients experiencing DBP and the cumulative LMS rate was 4.9%. The median estimated OS was 26 (1.2-not reached) months with a 1-year survival rate of 74.0%. Early initiation of IT/TT was associated with a non-significant trend towards improved DBP rate and OS. Conclusion The combination of ICIs/TT with IORT for resected BMs does not seem to increase toxicity, while yielding encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial

RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136294/1/bjh14480_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136294/2/bjh14480.pd

RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106

Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto-HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwesterm Oncology Group S1106 trial was designed to assess rituximab plushyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre-transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto-HCT. Fifty-three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2-year progression-free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi-centre transplant trials in MCL. RB achieved a 2-year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Chronic depression: development and evaluation of the luebeck questionnaire for recording preoperational thinking (LQPT)

<p>Abstract</p> <p>Background</p> <p>A standardized instrument for recording the specific cognitive psychopathology of chronically depressed patients has not yet been developed. Up until now, preoperational thinking of chronically depressed patients has only been described in case studies, or through the external observations of therapists. The aim of this study was to develop and evaluate a standardized self-assessment instrument for measuring preoperational thinking that sufficiently conforms to the quality criteria for test theory.</p> <p>Methods</p> <p>The "Luebeck Questionnaire for Recording Preoperational Thinking (LQPT)" was developed and evaluated using a german sample consisting of 30 episodically depressed, 30 chronically depressed and 30 healthy volunteers. As an initial step the questionnaire was subjected to an item analysis and a final test form was compiled. In a second step, reliability and validity tests were performed.</p> <p>Results</p> <p>Overall, the results of this study showed that the LQPT is a useful, reliable and valid instrument. The reliability (split-half reliability 0.885; internal consistency 0.901) and the correlations with other instruments for measuring related constructs (control beliefs, interpersonal problems, stress management) proved to be satisfactory. Chronically depressed patients, episodically depressed patients and healthy volunteers could be distinguished from one another in a statistically significant manner (p < 0.001).</p> <p>Conclusion</p> <p>The questionnaire fulfilled the classical test quality criteria. With the LQPT there is an opportunity to test the theory underlying the CBASP model.</p