Microbiota dynamics in a randomized trial of gut decontamination during allogeneic hematopoietic cell transplantation.

BACKGROUNDGut decontamination (GD) can decrease the incidence and severity of acute graft-versus-host disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). In this pilot study, we examined the impact of GD on gut microbiome composition and the incidence of aGVHD in HCT patients.METHODSWe randomized 20 patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).RESULTSThe 2 arms did not differ in the predefined primary outcome of Shannon diversity of the gut microbiome at 2 weeks post-HCT (genus, P = 0.8; species, P = 0.44) or aGVHD incidence (P = 0.58). Immune reconstitution of T cell and B cell subsets was similar between groups. Five patients in the no-GD arm had 8 BSI episodes versus 1 episode in the GD arm (P = 0.09). The BSI-causing pathogens were traceable to the gut in 7 of 8 BSI episodes in the no-GD arm, including Staphylococcus species.CONCLUSIONWhile GD did not differentially affect Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut pathogens.TRIAL REGISTRATIONClinicalTrials.gov NCT02641236.FUNDINGNIH, Damon Runyon Cancer Research Foundation, V Foundation, Sloan Foundation, Emerson Collective, and Stanford Maternal & Child Health Research Institute.

Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children.

Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4+CD25+CD127-Foxp3+ regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 × 106 and 0.67 × 106 IU/m2 per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 × 106 IU/m2 per day in children and 2 × 106 IU/m2 per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4+ T cells (Tcons) or CD8+ T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, P = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.

Timeliness of access to lung cancer diagnosis and treatment: A scoping literature review.

The Institute of Medicine recently called for increased understanding of and commitment to timely care. Lung cancer can be difficult to diagnose, resulting in delays that may adversely affect survival; rapid diagnosis and treatment therefore is critical for enabling improved patient outcomes. This scoping review provides an update on timeliness of lung cancer care over the past decade. We searched PubMed for English-language articles published from 2007 to 2016 that report wait time intervals related to diagnosis and treatment of lung cancer. Two authors independently reviewed titles and abstracts for inclusion. Abstracted data included sample size, patient population, study type, dates of study, wait times, and information on disparities, survival, costs, healthcare utilization, and interventions. The final review included 65 studies from 21 different countries. A total of 96 unique variations of wait intervals were reported (e.g., time to diagnosis from first pulmonologist visit, imaging, or initial evaluation), making comparisons across studies difficult. The most common interval was diagnosis to treatment initiation, with reported medians ranging from 6 to 45 days. Fourteen articles reported information on survival, 14 on healthcare utilization, 18 on disparities, and 14 on interventions; results varied by study. Significant variation exists in how access to care time delays are reported. Many patients across different facilities and countries appear to be facing substantial waits to receive lung cancer diagnosis and care. Further research, using common wait-interval metrics, is needed to evaluate and improve timeliness of lung cancer diagnosis and treatment.

Primary, systemic amyloidosis and the dermatologist: where classic skin lesions may provide the clue for early diagnosis.

Primary amyloidosis may present with skin lesions as a primary or sole expression of underlying plasma-cell dyscrasia. Classic skin lesions of primary, systemic amyloidosis are listed, and features suggestive of the diagnosis are discussed. Where this condition is considered in the dermatologist's differential, the investigations described may lead to an early diagnosis. When therapy can be initiated before the onset of organ failure, survival may be prolonged.