CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer ...(NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB).
Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point.
Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1
2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients.
Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.
The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the ...level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known.
We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger.
The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval CI, 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%).
Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).
Acute Graft vs host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo HSCT), a potent form of cellular therapy that has the ...potential to cure malignant and benign hematological conditions. Gastrointestinal (GI) GVHD is the principal cause of nonrelapse mortality after allo HSCT. Allo HSCT alters the intestinal microbiota and recent research uncovered a microbiome-metabolome axis that can affect intestinal homeostasis and mitigate the severity of experimental GI GVHD. This axis can potentially be manipulated via dietary intervention or through probiotics or postbiotics or antibiotics in humans. In this review we summarize major findings of how microbial metabolites and particularly short chain fatty acids (SCFAs) could impact acute GI GVHD.
In this letter, we present in detail the system-level modeling of reconfigurable intelligent surface (RIS)-assisted cellular systems by considering a 3-dimensional channel model between base station, ...RIS, and user. We prove that the optimal placement of RIS to achieve wider coverage is exactly opposite to the base station, under the constraint of single RIS in each sector. We propose a novel beamforming design for RIS-assisted cellular systems and derive the achievable sum rate in the presence of ideal, discrete, and random phase shifters at RIS. Through extensive system-level evaluations, we then show that the proposed beamforming design achieves significant improvements as compared to the state-of-the-art algorithms.
Summary
Allogeneic haematopoietic stem cell transplantation (HCT) is a potent immunotherapy with curative potential for several haematological disorders. Overcoming the immunological barrier of acute ...graft‐versus‐host disease (GVHD) remains a fundamental impediment to expanding the efficacy of HCT. GVHD reflects a complex pathological interaction between the innate and adaptive immune systems of the host and donor. Over the past decade there has been a tremendous advancement in our understanding of the cellular and molecular underpinnings of this devastating disease. In this review, we cover several recently appreciated facets of GVHD pathogenesis including novel extracellular mediators of inflammation, immune subsets, intracellular signal transduction, post‐translation modifications and epigenetic regulation. We begin to develop general themes regarding the immunological pathways in GVHD pathogenesis, discuss critical outstanding questions, and explore new avenues for GVHD treatment and prevention.
Target tissue damage occurs as a consequence of pathological immune responses following allogeneic stem cell transplantation resulting in acute graft-versus-host disease (GVHD). Among those who study ...infections in plants, it is well recognized that tissues play a distinct role from the immune system in mediating disease severity. Recently, this has also been appreciated in mammals. However, the severity of immunopathology in the context of alloimmune diseases such as acute GVHD has been mainly understood and managed by direct targeting of immune cells to generate immune tolerance. The role of tissue-intrinsic factors that might contribute to regulation of acute GVHD severity has been largely overlooked. Here, we introduce the concept of “tissue tolerance” to discuss the tissue-specific programs that contribute to target tissue resilience, repair, and regeneration, and mitigate severity of acute GVHD without altering the load or function of alloreactive immune cells.
Methamphetamine-associated cardiomyopathy (MACM) is an increasingly recognized disease entity in the context of a rapidly spreading methamphetamine epidemic. MACM may afflict individuals with a wide ...range of ages and socioeconomic backgrounds. Presentations can vary greatly and may involve several complications unique to the disease. Given the public health significance of this disease, there is a relative dearth of consensus material to guide clinicians in understanding, diagnosing, and managing MACM. This review therefore aims to: (1) describe pathologic mechanisms of methamphetamine as they pertain to the development, progression, and prognosis of MACM, and the potential to recover cardiac function; (2) summarize existing data from epidemiologic studies and case series in an effort to improve recognition and diagnosis of the disease; (3) guide short- and long-term management of MACM with special attention to expected or potential sequelae of the disease; and (4) highlight pivotal unanswered questions in need of urgent investigation from a public health perspective.
Thirty percent to 90% of cancer survivors report impaired sleep quality post-treatment, which can be severe enough to increase morbidity and mortality. Lifestyle interventions, such as exercise, are ...recommended in conjunction with drugs and cognitive behavioral therapy for the treatment of impaired sleep. Preliminary evidence indicates that yoga-a mind-body practice and form of exercise-may improve sleep among cancer survivors. The primary aim of this randomized, controlled clinical trial was to determine the efficacy of a standardized yoga intervention compared with standard care for improving global sleep quality (primary outcome) among post-treatment cancer survivors.
In all, 410 survivors suffering from moderate or greater sleep disruption between 2 and 24 months after surgery, chemotherapy, and/or radiation therapy were randomly assigned to standard care or standard care plus the 4-week yoga intervention. The yoga intervention used the Yoga for Cancer Survivors (YOCAS) program consisting of pranayama (breathing exercises), 16 Gentle Hatha and Restorative yoga asanas (postures), and meditation. Participants attended two 75-minute sessions per week. Sleep quality was assessed by using the Pittsburgh Sleep Quality Index and actigraphy pre- and postintervention.
In all, 410 survivors were accrued (96% female; mean age, 54 years; 75% had breast cancer). Yoga participants demonstrated greater improvements in global sleep quality and, secondarily, subjective sleep quality, daytime dysfunction, wake after sleep onset, sleep efficiency, and medication use at postintervention (all P ≤ .05) compared with standard care participants.
Yoga, specifically the YOCAS program, is a useful treatment for improving sleep quality and reducing sleep medication use among cancer survivors.
The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is ...uncertainty about the benefit of chemotherapy for most patients, who have a midrange score.
We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death).
Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death endocrine vs. chemoendocrine therapy, 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25.
Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).
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