Autologous stem cell transplantation is safe and effective for fit,older myeloma patients: exploratory results from the Myeloma XI trial

Autologous stem cell transplant (ASCT) remains the standard of care for consolidation after induction therapy for eligible patients with newly diagnosed myeloma. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on a patient’s fitness rather than a strict age cut-off. Data from the UK NCRI Myeloma XI trial, a large phase III randomized controlled trial with pathways for transplant-eligible and -ineligible patients, were used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including an analysis using an age-matched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the transplant-eligible pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in progression-free survival associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged <65, 65-69 and 70-75 years. In an age-matched population of patients including those in both the transplant- eligible and -ineligible pathways there was a significant advantage associated with undergoing ASCT with increases in progression-free survival (hazard ratio 0.41, P<0.0001) and overall survival (hazard ratio 0.51, P<0.0001), which persisted even after adjustment for baseline covariates including those related to frailty and response to induction. These findings support the use of ASCT for selected fit, older myeloma patients. EudraCT number, 2009-010956-93     

Gleich syndrome: a systematic review

Characterized chiefly by hypereosinophilia and angioedema, Gleich syndrome is a rare disorder with unclear clinical and therapeutic findings. Other symptoms include increased IgM levels, weight gain, fever, and urticaria. Herein we review Gleich syndrome and assess clinical features, epidemiology, and treatment options. Thirty-two articles including case reports or case series of eosinophilic angioedema and Gleich syndrome were included. Data regarding patient age, gender, and history, clinical and biological manifestations, and treatment protocols were recorded. The most common clinical findings include recurrent or non-recurrent angioedema, fever, urticaria, weight gain, blood eosinophilia, and elevated immunoglobulin levels. Corticosteroid therapy is the mainstay of treatment. Gleich syndrome is a distinctive hypereosinophilic entity with a benign course and good response to systemic corticosteroids. More studies are needed to evaluate the pathophysiology of this syndrome and lead to better therapeutic options.     

Adiposity and estrogen receptor-positive,postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case–cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case–control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m² compared to women with BMI 18.5–25 kg/m², the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05–2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43–2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11–2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68–1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity–breast cancer relationship but does not explain all of the association.     

Interval breast cancer risk associations with breast density,family history and breast tissue aging

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case–control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first-degree family history by questionnaire, measured body mass index (BMI) and calculated age-adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age-adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69–0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts—an increased risk of developing an interval breast cancer.     

Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy

Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3–5 sessions, 20–26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.     

Epileptic Activity Intrinsically Generated in the Human Cerebellum

Neoplastic or dysplastic neuronal tissue in the brain stem and cerebellum can become epileptogenic in pediatric patients. However, it is unknown whether such tissue may transform intrinsic properties of the human cerebellum, making it capable of generating epileptic population activity. We noninvasively detected epileptiform signals unaveraged in a pediatric patient with epilepsy due to a tumor in the middle cerebellar peduncle. Analysis of generators of the signals revealed that the cerebellum ipsilateral and contralateral to the tumor was the dominant interictal spike generator and could initiate ictal activity, suggesting that human cerebellum may become capable of intrinsically generating epileptic activity. ANN NEUROL 2020;88:418–422.