Endoplasmic reticulum stress produced by Thapsigargin affects the occurrence of spike-wave discharge by modulating unfolded protein response pathways and activating immune responses in a dose-dependent manner.

The Endoplasmic Reticulum (ER) is associated with many cellular functions, from post-transcriptional modifications to the proper folding of proteins, and disruption of these functions causes ER stress. Although the relationship between epileptic seizures and ER stress has been reported, the contribution of ER stress pathways to epileptogenesis is still unclear. This study aimed to investigate the possible effects of ER stress-related molecular pathways modulated by mild- and high-dose Thapsigargin (Tg) on absence epileptic activity, CACNA1H and immune responses in WAG/Rij rats. For this purpose, rats were divided into four groups; mild-dose (20 ng) Tg, high-dose (200 ng) Tg, saline, and DMSO and drugs administered intracerebroventriculary. EEG activity was recorded for 1 h and 24 h after drug administration following the baseline recording. In cortex and thalamus tissues, GRP78, ERp57, GAD153 protein changes (Western Blot), Eif2ak3, XBP-1, ATF6, CACNA1H mRNA expressions (RT-PCR), NF-κB and TNF-α levels (ELISA) were measured. Mild-dose-Tg administration resulted in increased spike-wave discharge (SWD) activity at the 24th hour compared to administration of saline, and high-dose-Tg and it also significantly increased the amount of GRP78 protein, the expression of Eif2ak3, XBP-1, and CACNA1H mRNA in the thalamus tissue. In contrast, high-dose-Tg administration suppressed SWD activity and significantly increased XBP-1 and ATF6 mRNA expression in the thalamus, and increased NF-κB and TNF-α levels. In conclusion, our findings indicate that Tg affects SWD occurrence by modulating the unfolded protein response pathway and activating inflammatory processes in a dose-dependent manner.

Etanercept Ameliorates Vascular, Endocrine, and Ovarian Changes in a Rat Model of DHEA-Induced Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disorder affecting women of reproductive age. This study examined the efficacy of etanercept (ETA), an anti-TNF-α drug, in alleviating endocrine, metabolic, and vascular dysfunction in a rat model of PCOS. Prepubertal female Wistar rats were divided into three groups: control, PCOS, and PCOS+ETA. The PCOS groups received dehydroepiandrosterone (DHEA) treatment, whereas the PCOS+ETA group received both DHEA and ETA. After 35 days, various biomarkers were evaluated, including systemic blood pressure, endothelial function, and eNOS and TNF-α expression levels in the thoracic aorta and ovaries. The PCOS group exhibited ovarian morphological changes, increased body weight, and hormonal imbalances, whereas the PCOS+ETA group showed restored levels of these parameters. Systemic blood pressure, urinary albumin levels, and protein excretion did not differ significantly differ among the groups. Endothelium-dependent relaxation, eNOS expression, TNF-α expression in the thoracic aorta, and TNF-α expression in the ovaries were restored to normal levels in the PCOS+ETA group. Furthermore, ovarian morphology was improved in the PCOS+ETA group. In conclusion, etanercept treatment shows promise in mitigating hormonal disturbances and vascular dysfunction in patients with PCOS, suggesting potential therapeutic advantages.

A comparison of the prognostic performance of the Lugano 2014 and RECIL 2017 response criteria in patients with NHL from the phase III GOYA and GALLIUM trials.

The Lugano 2014 criteria are the standard for response assessment in lymphoma. We compared the prognostic performance of Lugano 2014 and the more recently developed response evaluation criteria in lymphoma (RECIL 2017), which relies primarily on computed tomography and uses unidimensional measurements, in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) from the phase III GOYA and GALLIUM trials, respectively. Concordance between responses according to the Lugano 2014 and RECIL 2017 criteria was analyzed. Landmark analyses of progression-free survival (PFS) and overall survival (OS) by end of treatment (EOT) and end of induction (EOI) response status according to RECIL 2017 and Lugano 2014 criteria, and prognostic value of response at EOT/EOI were also compared. Overall, 1333 patients were included from GOYA and 502 from GALLIUM. Complete response (CR) status according to RECIL 2017 criteria showed high concordance with complete metabolic response (CMR) status by Lugano 2014 criteria in both GOYA (92.5%) and GALLIUM (92.4%). EOT and EOI CR/CMR status by both criteria was highly prognostic for PFS in GOYA (RECIL 2017 [CR]: hazard ratio [HR], 0.35 [95% confidence interval [CI] 0.26-0.46]; Lugano 2014 [CMR]: HR, 0.35 [95% CI 0.26-0.48]; both p < .0001) and GALLIUM (RECIL 2017 [CR]: HR, 0.35 [95% CI 0.23-0.53]; Lugano 2014 [CMR]: HR, 0.21 [95% CI 0.14-0.31]; both p < .0001). In conclusion, response categorization by RECIL 2017 is similar to that by Lugano 2014 criteria, with high concordance observed. Both were prognostic for PFS and OS.

Measuring Potentially Avoidable Acute Care Transfers From Long-Term Care Homes in Quebec: a Cross Sectional Study.

Background: Potentially avoidable emergency department transfers (PAEDTs) and hospitalizations (PAHs) from long-term care (LTC) homes are two key quality improvement metrics. We aimed to: 1) Measure proportions of PAEDTs and PAHs in a Quebec sample; and 2) Compare them with those reported for the rest of Canada. Methods: We conducted a repeated cross-sectional study of residents who were received at one tertiary hospital between April 2017 and March 2019 from seven LTC homes in Quebec, Canada. The MedUrge emergency department database was used to extract transfers and resident characteristics. Using published definitions, PAEDTs and PAHs were identified from principal emergency department and hospitalization diagnoses, respectively. PAEDT and PAH proportions were compared to those reported by the Canadian Institute for Health Information. Results: A total of 1,233 transfers by 692 residents were recorded, among which 36.3% were classified as being potentially avoidable: 22.8% 'PAEDT only', 11.6% 'both PAEDT & PAH', and 1.9% 'PAH only'. Shortness of breath was the most common reason for transfer. Pneumonia was the most common diagnosis from the 'both PAEDT & PAH' category. PAEDTs and PAHs accounted for 95% and 37% of potentially avoidable transfers, respectively. Among 533 hospitalizations, 31.3% were PAHs. These proportions were comparable to the rest of Canada, with some differences in proportions of transfers due to congestive heart failure, urinary tract infection, and implanted device management. Conclusions: PAEDTs far outweigh PAHs in terms of frequency, and their monitoring is important for quality assurance as they may inform LTC-level interventions aimed at their reduction.

Taxonomy of Interventions to Reduce Acute Care Transfers From Long-term Care Homes: A Systematic Scoping Review.

OBJECTIVE: To develop a taxonomy of interventions aimed at reducing emergency department (ED) transfers and/or hospitalizations from long-term care (LTC) homes. DESIGN: A systematic scoping review. SETTING AND PARTICIPANTS: Permanent LTC home residents. METHODS: Experimental and comparative observational studies were searched in MEDLINE, CINAHL, Embase Classic + Embase, the Cochrane Library, PsycINFO, Social Work Abstracts, AMED, Global Health, Health and Psychosocial Instruments, Joanna Briggs Institute EBP Database, Ovid Healthstar, and Web of Science Core Collection from inception until March 2020. Forward/backward citation tracking and gray literature searches strengthened comprehensiveness. The Mixed Methods Appraisal Tool was used to assess study quality. Intervention categories and components were identified using an inductive-deductive thematic analysis. Categories were informed by 3 intervention dimensions: (1) "when/at what point(s)" on the continuum of care they occur, (2) "for whom" (ie, intervention target resident populations), and (3) "how" these interventions effect change. Components were informed by the logistical elements of the interventions having the potential to influence outcomes. All interventions were mapped to the developed taxonomy based on their categories, components, and outcomes. Distributions of components by category and study year were graphically presented. RESULTS: Ninety studies (25 randomized, 23 high quality) were included. Six intervention categories were identified: advance care planning; palliative and end-of-life care; onsite care for acute, subacute, or uncontrolled chronic conditions; transitional care; enhanced usual care (most prevalent, 31% of 90 interventions); and comprehensive care. Four components were identified: increasing human resource capacity (most prevalent, 93%), training or reorganization of existing staff, technology, and standardized tools. The use of technology increased over time. Potentially avoidable ED transfers and/or hospitalizations were measured infrequently as primary outcomes. CONCLUSIONS AND IMPLICATIONS: This proposed taxonomy can guide future intervention designs. It can also facilitate systematic reviews and precise effect size estimations for homogenous interventions when outcomes are comparable.

A prognostic model integrating PET-derived metrics and image texture analyses with clinical risk factors from GOYA.

Image texture analysis (radiomics) uses radiographic images to quantify characteristics that may identify tumour heterogeneity and associated patient outcomes. Using fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT)-derived data, including quantitative metrics, image texture analysis and other clinical risk factors, we aimed to develop a prognostic model that predicts survival in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) from GOYA (NCT01287741). Image texture features and clinical risk factors were combined into a random forest model and compared with the international prognostic index (IPI) for DLBCL based on progression-free survival (PFS) and overall survival (OS) predictions. Baseline FDG-PET scans were available for 1263 patients, 832 patients of these were cell-of-origin (COO)-evaluable. Patients were stratified by IPI or radiomics features plus clinical risk factors into low-, intermediate- and high-risk groups. The random forest model with COO subgroups identified a clearer high-risk population (45% 2-year PFS [95% confidence interval (CI) 40%-52%]; 65% 2-year OS [95% CI 59%-71%]) than the IPI (58% 2-year PFS [95% CI 50%-67%]; 69% 2-year OS [95% CI 62%-77%]). This study confirms that standard clinical risk factors can be combined with PET-derived image texture features to provide an improved prognostic model predicting survival in untreated DLBCL.

Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study.

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.35- 2.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15-1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.

High Throughput Screening for Drug Discovery and Virus Detection.

BACKGROUND: High throughput screening systems are automated labs for the analysis of many biochemical substances in the drug discovery and virus detection process. This paper was motivated by the problem of automating testing for viruses and new drugs using high throughput screening systems. The emergence of severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) at the turn of 2019-2020 presented extraordinary challenges to public health. Existing approaches to test viruses and new drugs do not use optimal schedules and are not efficient. OBJECTIVES: The scheduling of activities performed by various resources in a high throughput screening system affects its efficiency, throughput, operations cost, and quality of screening. This study aims to minimize the total screening (flow) time and ensure the consistency and quality of screening. METHODS: This paper develops innovative mixed-integer models that efficiently compute optimal schedules for screening many microplates to identify new drugs and determine whether samples contain viruses. The methods integrate job-shop and cyclic scheduling. Experiments are conducted for a drug discovery process of screening an enzymatic assay and a general process of detecting SARS-CoV-2. RESULTS: The method developed in this article can reduce screening time by as much as 91.67%. CONCLUSION: The optimal schedules for high throughput screening systems greatly reduce the total flow time and can be computed efficiently to help discover new drugs and detect viruses.

Front-line emergency department nurses' and physicians' assessments of processes of elder-friendly care for quality improvement.

INTRODUCTION: Geriatric emergency department (ED) care has gained increasing importance and interest due to increasing visits in seniors. AIM: Among ED front-line nurses and physicians, to assess and compare ratings of elder-friendly care process indicators, variability in ratings, and concurrent validity of ratings. METHODS: Four Quebec EDs' full-time registered nurses and physicians rated their geriatric care using 9 subscales. Nurse and physician subscale scores were compared. Inter-rater variability within disciplines and variability between nurses and physicians were measured. Associations between the subscale scores and perceived overall quality of care were tested. RESULTS: 38 nurses and 36 physicians completed the survey (83% of 89 eligible). Scores differed by discipline for 3 of 9 subscales computed; nurses had higher mean scores on Protocols, Family-Centered Discharge, and Staff Education. Very high variation for Staff Education was found within disciplines. Variations for Family-Centered Discharge differed significantly between nurses and physicians. Almost all subscale scores were significantly positively associated with perceived overall quality of care. CONCLUSIONS: ED nurses and physicians rate geriatric care components similarly except for protocols, discharge processes, and continuing education. The subscales have concurrent validity. Results suggest a need for improvement in continuing educational strategies with a particular attention to discharge processes.

Age dependent effects of Retigabine on absence seizure in WAG/Rij rats; an experimental study.

Retigabine (RTG, Ezogabine, DC23129) is the first neuronal potassium channel opener in the treatment of epilepsy and exerts its effects through the activation of neuronal KCNQ2/3 potassium channels; in higher doses, it acts also on sodium and voltage-gated calcium channels. The aim of this study was to investigate possible age-dependent therapeutic effects of RTG on spike-and-wave discharges (SWD) in an animal model of absence epilepsy using WAG/Rij rats. In this study, 6- and 12-month-old WAG/Rij rats were used. For both age categories, three sub-groups that consisted of one control group (n=7) by the administration of 20% DMSO (control) and two study groups by the administration of 5 mg/kg (n=7) and 15 mg/kg RTG (n=7) were designed. EEG electrodes were placed onto the skull of anaesthetized animals; and baseline EEG was recorded for one hour after a recovery period from surgery. Then, the pre-determined two distinct doses of RTG and 20% DMSO were administered as a solvent via intraperitoneal injections, and EEG was recorded for 3 hours. After injection, both doses of RTG increased the total SWD number and duration of SWD in the first and second hours in 12-month-old rats. These parameters were elevated compared to 6-month-old rats. Age-dependent effects of RTG were observed in SWD activity. Pro-epileptic effects in middle-aged WAG/Rij rats were demonstrated in both RTG doses. Differences in the distribution of KCNQ2/3 channels and switch of GABAergic system from inhibitory to excitatory with age might contribute to increased SWD activity in middle-aged rats.

Clinical characteristics and therapeutic outcomes of paroxysmal nocturnal hemoglobinuria patients in Turkey: a multicenter experience.

The aim of this study is to collect paroxysmal nocturnal hemoglobinuria (PNH) patient data from hematology centers all over Turkey in order to identify clinical features and management of PNH patients. Patients with PNH were evaluated by a retrospective review of medical records from 19 different institutions around Turkey. Patient demographics, medical history, laboratory findings, and PNH-specific information, including symptoms at the diagnosis, complications, erythrocyte, and granulocyte clone size, treatment, and causes of death were recorded. Sixty patients (28 males, 32 females) were identified. The median age was 33 (range; 17-77) years. Forty-six patients were diagnosed as classic PNH and 14 as secondary PNH. Fatigue and abdominal pain were the most frequent presenting symptoms. After eculizumab became available in Turkey, most of the patients (n = 31/46, 67.4%) were switched to eculizumab. Three patients with classic PNH underwent stem cell transplantation. The median survival time was 42 (range; 7-183 months) months. This study is the first and most comprehensive review of PNH cases in Turkey. It provided us useful information to find out the differences between our patients and literature, which may help us understand the disease.

End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA.

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)-based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose-PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee-assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.

Effects of leptin, ghrelin and neuropeptide y on spike-wave discharge activity and certain biochemical parameters in WAG/Rij rats with genetic absence epilepsy.

This study aimed to evaluate the effects of leptin, ghrelin and neuropeptide-Y on the development of nonconvulsive seizure activity and their role on combating oxidative stress and cytokines produced by the systemic immune response in the WAG/Rij rat model for genetic absence epilepsy. Current study showed that all three peptides aggravated spike wave discharges activity and affected the oxidative stress in WAG/Rij rats without any significant changes in the levels of IL-1ß, IL-6 and TNF-α except leptin that only induced an increment in the concentration of IL-1ß. Our results support the modulatory role of these endogenous peptides on absence epilepsy.

Use of rotational thromboelastometry for a global screening of coagulation profile in patients of myeloproliferative neoplasms.

Chronic myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem/progenitor cell characterized by thrombohemorrhagic complications and a tendency to transform into acute leukemia. The pathogenesis of thrombosis in MPN is complex and results from a multifaceted interplay of clinical and disease-related factors. Rotational thromboelastometry (ROTEM) provides the complete and rapid information about all stages of the coagulation process. Here, we assess ROTEM parameters as a screening of coagulation profile in patients with MPNs. In particular, higher mean maximum clot firmness values were found in Essential thrombocythemia and Polycythemia vera patients when compared to healthy controls. Rotational thromboelastometry may be able to detect MPN patients who are susceptible to thrombotic and/or hemorrhagic complications. The predictive value of ROTEM for thrombosis remains to be established to classify subsets of patients at prominent risk who may benefit from prophylaxis with antithrombotic drugs.

Comparison of Cilostazol and Naftidrofuryl in an Experimental Acute Ischemia-Reperfusion Model.

INTRODUCTION: Naftidrofuryl and cilostazol are drugs with proven efficacy in the treatment of claudication in peripheral vascular disease. In this experimental study, we evaluated the effects of naftidrofuryl and cilostazol in ischemia-reperfusion (IR) injury on various tissues. MATERIALS AND METHODS: 40 male albino Wistar rats (8-12 weeks old, 250-350 g.) are randomly divided into 4 groups: Control (Group 1), sham (group 2), cilostazol pre-treatment (group 3), naftidrofuryl pre-treatment (group 4). During 21 days placebo is given to group 2, 12 mg/kg/day cilostazol is given to group 3, 50 mg/kg/day naftidrofuryl is given to group 4 orally. Ischemia and reperfusion are induced at the lower hind limb in Groups 2, 3 and 4. Ischemic muscle, kidney, liver, heart, brain and blood samples are obtained. The total antioxidant capacity, oxidant levels and oxidative stress index are studied for each group. RESULTS: Both drugs have protective effects of remote organ injury following IR. Systemic effects are similar to each other, both have protective effects of IR injury. It showed no statistical significance in the total antioxidant capacity. Total oxidant levels are significantly affected by cilostazol in the heart (p < 0.01) and by naftidrofuryl in the liver (p < 0.01). The effect on oxidative stress was only significant with cilostazol on the heart (p < 0.01). CONCLUSION: Cilostazol and naftidrofuryl had beneficial effects in all tissues against tissue damage caused by IR injury. In ischemic muscle, kidney and heart cilostazol had improved outcomes comparing to naftidrofuryl. Naftidrofuryl had benefits over cilostazol in liver tissue.

Effect of Oil Extract from Microalgae (Schizochytrium sp.) on the Viability and Apoptosis of Human Osteosarcoma Cells.

BACKGROUND: Osteosarcoma is a malignant tumor type that starts in bone and occurs most frequently in adolescents. Traditional techniques are insufficient, especially for metastatic ones. As alternative treatment techniques, natural products are worthy of examining due to being safe and innovative. Essential polyunsaturated fatty acids, mainly omega-3 and omega-6 fatty acids, have various positive effects on human health and growth. In addition, some PUFAs show anti-cancer activity by inducing apoptosis, specifically in cancer cells. OBJECTIVE: Here, the study aims to investigate the time and dose-dependent effects of oil extract from Schizochytrium sp. against the osteosarcoma cell line. MATERIALS AND METHODS: Human Fetal Osteoblast Cells (hFOB) and osteosarcoma cells (SAOS-2) were treated with different concentrations of fatty acid samples. GC-FID was performed for fatty acid composition analysis of Schizochytrium sp. MTT-cell viability and Annexin V-apoptosis assays were performed to investigate the time and dose-dependent effects of the samples on cell lines. RESULTS: The oil extract sample has a specific activity against the SAOS-2 cancer line and decreases cell proliferation, especially at high dose treatments. Apoptosis assay results indicate that the oil extract sample causes a significant increase in the number of apoptotic cells in the SAOS-2 cell line (71.7% of SAOS-2 cells), which shows its selective activity against bone cancer cell line as a natural anti-cancer molecule. CONCLUSION: It was observed that Schizochytrium sp. extract has a time and dose-dependent ability to induce apoptosis, specifically in SAOS-2 cells.

Experiences of an Emergency Department Visit Among Older Adults and Their Families: Qualitative Findings From a Mixed-Methods Study.

BACKGROUND: Emergency department (ED) visits are critical events for older adults, but little is known regarding their experiences, particularly about their physical needs, the involvement of accompanying family members, and the transition back to the community. OBJECTIVE: To explore experiences of an ED visit among patients aged 75 and older. METHODS: In a mixed-methods study, a cohort of patients aged 75 and older (or a family member) discharged from the ED back to the community was recruited from 4 urban EDs. A week following discharge, structured telephone interviews supplemented with open-ended questions were conducted. A subsample (76 patients, 32 family members) was purposefully selected. Verbatim transcripts of responses to the open-ended questions were thematically analyzed. RESULTS: Experiences related to physical needs included comfort, equipment supporting mobility and autonomy, help when needed, and access to drink and food. Family members required opportunities to provide patient support and greater involvement in their care. At discharge, patients/families required adequate discharge education, resolution of their health problem, information on medications, and greater certainty about planned follow-up medical and home care services. CONCLUSIONS: Our findings suggest several areas that could be targeted to improve patient and family perceptions of the care at an ED visit.

A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA.

BACKGROUND: Rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard therapy for diffuse large B cell lymphoma (DLBCL). Obinutuzumab (G), a glycoengineered, type II anti-CD20 monoclonal antibody, has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in patients with advanced DLBCL. We present the final analysis results of the Phase III GOYA study (NCT01287741), which compared the efficacy and safety of G-CHOP versus R-CHOP in patients with previously untreated DLBCL. METHODS: Patients aged ≥ 18 years with previously untreated advanced DLBCL were randomly assigned to receive eight 21-day cycles of R or G, plus six or eight cycles of CHOP. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival, other time-to-event endpoints, and safety; investigator-assessed PFS by cell of origin subgroup was an exploratory endpoint. RESULTS: A total of 1418 patients were randomized, with 1414 included in this final analysis (G-CHOP, N = 704; R-CHOP, N = 710). Five-year PFS rates were 63.8% and 62.6% for G-CHOP and R-CHOP, respectively (stratified hazard ratio 0.94, 95% CI 0.78-1.12; p = 0.48). The results of the secondary efficacy endpoints did not show a benefit of G-CHOP over R-CHOP. In the exploratory analysis, a trend towards benefit with G-CHOP over R-CHOP was apparent in the patients with germinal center B cell DLBCL. The safety profile of G-CHOP was as expected, and no new safety signals were observed. More grade 3-5 (75.1% vs 65.8%), serious (44.4% vs 38.4%), and fatal (6.1% vs 4.4%) adverse events (AEs) were observed in the G-CHOP arm compared with the R-CHOP arm, respectively, with the most common fatal AEs being infections. A higher incidence of late-onset neutropenia occurred in the G-CHOP arm (8.7%) versus the R-CHOP arm (4.9%). CONCLUSIONS: The final analysis, similar to the primary analysis, did not show a PFS benefit of G-CHOP over R-CHOP in previously untreated patients with DLBCL. The results of the secondary endpoints were consistent with the primary endpoint. Further exploratory analyses and investigation of biomarkers are ongoing.

Impact of bone marrow biopsy on response assessment in immunochemotherapy-treated lymphoma patients in GALLIUM and GOYA.

The utility of posttreatment bone marrow biopsy (BMB) histology to confirm complete response (CR) in lymphoma clinical trials is in question. We retrospectively evaluated the impact of BMB on response assessment in immunochemotherapy-treated patients with previously untreated follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the phase 3 Study of Obinutuzumab (RO5072759) Plus Chemotherapy in Comparison With Rituximab Plus Chemotherapy Followed by Obinutuzumab or Rituximab Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin's Lymphoma (GALLIUM; NCT01332968) and A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA; NCT01287741) trials, respectively. Baseline BMB was performed in all patients, with repeat BMBs in patients with a CR by computed tomography (CT) at end of induction (EOI) and a positive BMB at baseline, to confirm response. Positron emission tomography imaging was also used in some patients to assess EOI response (Lugano 2014 criteria). Among patients with an EOI CR by CT in GALLIUM and GOYA, 2.8% and 4.1%, respectively, had a BMB-altered response. These results suggest that postinduction BMB histology has minimal impact on radiographically (CT)-defined responses in both FL and DLBCL patients. In GALLIUM and GOYA, respectively, 4.7% of FL patients and 7.1% of DLBCL patients had a repeat BMB result that altered response assessment when applying Lugano 2014 criteria, indicating that bone marrow evaluation appears to add little value to response assessment in FL; however, its evaluation may still have merit in DLBCL.

Baseline SUVmax did not predict histological transformation in follicular lymphoma in the phase 3 GALLIUM study.

A minority of patients with follicular lymphoma (FL) undergo histological transformation (HT). This retrospective analysis of 549 patients from the phase 3 GALLIUM study (NCT01332968) assessed the relationship between maximum standardized uptake value (SUVmax) at baseline on positron emission tomography (PET) and HT risk. Previously untreated patients with high tumor burden grade 1-3a FL received obinutuzumab- or rituximab-based chemotherapy induction. The relationship between baseline SUVmax (bSUVmax) and HT risk was assessed using cutoff values for SUVmax >10 and >20. Overall, 15 of 549 (2.7%) patients with baseline PET scans experienced biopsy-confirmed HT (median follow-up, 59 months). More than 65% of patients had bSUVmax > 10, with 3.3% of these experiencing HT. Only 1 of 74 (1.4%) patients with bSUVmax > 20 underwent HT. Median bSUVmax in patients with HT vs without HT was 12.4 (range, 8.1-28.0) vs 11.8 (range, 3.1-64.4), respectively; median bSUVrange (the difference between bSUVmax of the most and least 18F-fluorodeoxyglucose-avid lymphoma sites) was 8.0 (range, 1.1-23.9) vs 7.1 (range, 0.0-59.8), respectively. There was no temporal relationship between bSUVmax and HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting that there may be little benefit in rebiopsy of lesions to exclude HT based on SUVmax alone before initiating therapy in patients with high tumor burden FL.