In relapsed or refractory (RR) metastatic germ cell cancer (GCC), high-dose (HD) chemotherapy (CTX) plus autologous stem cell transplantation is considered the standard of care. Limited data exist ...regarding the efficacy of HD-CTX following conventionally dosed salvage regimens (CDRs). This analysis explores and contrasts the efficacy of HD-CTX as the first or subsequent salvage regimen.
Data were retrospectively collected to explore the efficacy of HD-CTX administered as the first (group A) or subsequent salvage CTX (group B) after a CDR. The primary endpoint was OS from the time of HD-CTX. Associations of survival, overall response rate (ORR), and toxicity with clinical characteristics were explored using stratified Kaplan–Meier and Cox regression models.
Overall, 283 patients with GCC were included from 11 international centers, with 159 patients (56%) in group A and 124 patients (44%) in group B. The first salvage treatment was administered between 1998 and 2022, with a median follow-up of 27.0 standard deviation (SD) 46.2 months for group A and 17.0 (SD 48.5) months for group B. The median OS from HD-CTX treatment initiation was not reached in group A, compared with 25 months in group B (P = 0.00027), associated with 2- and 5-year OS rates of 74% and 63% (group A) versus 53% and 37% (group B), respectively. When administered as the first salvage treatment, HD-CTX was associated with a higher ORR (79% versus 60%; P = 0.013) and lower nonhematologic grade ≥3 toxicity rate (78% versus 97%; P < 0.001). Concerning risk factor analysis for the total cohort, the International Prognostic Factors Study Group score was the only independent predictor of OS in multivariable analysis (P = 0.006).
When administered as the initial salvage treatment or after CDR, HD-CTX exhibits curative potential for patients with RR GCC. The efficacy and safety outcomes were more favorable when HD-CTX was conducted as the first salvage treatment line.
•HD-CTX demonstrates curative potential, whether administered as the first or subsequent salvage regimen.•When used as the first salvage therapy, OS was superior with a 2-year OS rate of 74%.•HD-CTX yielded a higher 79% ORR when administered as the initial salvage treatment.•HD-CTX was linked to lower grade ≥3 toxicities as the initial salvage regimen.•Whether administered as the first or subsequent salvage regimen, HD-CTX should always be considered.
Chemomodulation of cytarabine by fludarabine has been attributed with a higher antileukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, ...randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, of which 281 were evaluable) were randomly assigned to SHAI (cytarabine, 1 g/m(2) bid, days 1-2 and 8-9 (3 g/m(2) for patients ≤ 60 years with refractory AML or ≥ 2nd relapse); idarubicin 10 mg/m(2) daily, days 3-4 and 10-11) or F-SHAI (SHAI with fludarabine, 15 mg/m(2), 4 h before cytarabine). Although complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time to treatment failure from 2.04 to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic stem cell transplantation, with a significantly higher number of patients in CR or incomplete remission in the F-SHAI group (22 vs 10%, P<0.01). In conclusion, fludarabine has a beneficial, although moderate, impact on the antileukemic efficacy of high-dose cytarabine-based salvage therapy for relapsed and refractory AML.
Cancer patients frequently suffer from gastrointestinal complications. However, a comprehensive, practical and evidence-based guideline on this issue is not yet available.
An expert group was put ...together by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) to develop a guideline on gastrointestinal complications in cancer patients. For each subtopic, a literature search was carried out in PubMed, Medline and Cochrane databases and the strength of recommendation and the quality of the published evidence for major therapeutic strategies were categorized using a modification of the ‘Infectious Diseases Society of America’ criteria. Consensus discussions were held on each of the topics.
Recommendations were made with respect to non-infectious and infectious gastrointestinal complications. For all recommendations, the strength of the recommendation and the level of evidence are presented.
This guideline is an evidence-based approach to the diagnosis and management of gastrointestinal complications in cancer patients.
Objectives
The incidence of HIV‐related non‐Hodgkin lymphoma (NHL) but not that of Hodgkin lymphoma (HL) has been declining. The aim of the study was to compare HIV‐infected patients with NHL and HL ...with respect to antiretroviral therapy (ART) exposure at the time of lymphoma diagnosis.
Methods
HIV‐infected patients with NHL and HL included in a prospective multicentre cohort study since January 2005 were compared with respect to ART exposure and viral load at the time of lymphoma diagnosis.
Results
As of 31 December 2012, data for 329 patients with NHL and 86 patients with HL from 31 participating centres were available. Patients with HL were more likely to be on ART (73.5% vs. 39.1%, respectively; P < 0.001) and more frequently had a viral load below the detection limit (57.3% vs. 27.9%, respectively; P < 0.001) than patients with NHL. The proportion of patients with HL was 8.0% in ART‐naïve patients, 34.8% in patients with current HIV RNA < 50 HIV‐1 RNA copies/mL, and 50.0% in patients with both HIV RNA < 50 copies/mL for > 12 months and a CD4 cell count of > 200 cells/μL. Of note, 45.8% of all patients with NHL were not currently on ART and had a CD4 count of < 350 cells/μL.
Conclusions
This prospective cohort study shows that HL was as common as NHL in patients with sustained viral suppression and limited immune deficiency. In contrast to NHL, the majority of patients with HL were on effective ART, suggesting that ART provides insufficient protection from developing HL. The high proportion of untreated patients with NHL suggests missed opportunities for earlier initiation of ART.
Synucleinopathies like Parkinson's disease and dementia with Lewy bodies originate from a complex and still largely enigmatic interplay of genetic predisposition, age, and environmental factors. ...While progressively declining motor functions hallmark late-life symptoms, first signs of the disease often surface already decades earlier during midlife. To better understand early disease stages with respect to the genetic, temporal, and environmental dimension, we interrogated hippocampal transcriptome data obtained during midlife for a mouse model overexpressing human
, a pivotal gene in synucleinopathies, under different environments. To relate differentially expressed genes to human, we integrated expression signatures for aging and Parkinson's disease. We identified two distinctive modes of age-dependent disturbances: First, cellular processes seemingly activated too early that reflected advanced stages of age and, second, typical longitudinal adaptations of the system that no longer occurred during midlife. Environmental enrichment prevented both disturbances modes despite persistent
overload. Together, our results caution the view that expression changes characterising early stages of
-related pathology reflect accelerated aging alone. Instead, we provide evidence that failure to undergo healthy adaptions during midlife represents a second origin of disturbances. This bimodal disturbance principle could inform therapeutic efforts to distinguish between preventive and restorative attempts to target the disease.
Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the
Ataxin-3
gene resulting in a polyglutamine (polyQ)-expansion in ...the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine
Ataxin-3
locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.
In contrast to younger patients, the prognosis of elderly patients with advanced Hodgkin's disease (HD) has not improved substantially over the last 20 years. We thus carried out a prospectively ...randomized study (HD9elderly) to compare the BEACOPP regimen in this setting against standard COPP-ABVD. Between February 1993 and 1998, 75 patients aged 66–75 years with newly diagnosed HD in advanced stages were recruited into the HD9 trial as a separate stratum (HD9elderly). Patients were assigned to eight alternating cycles of COPP and ABVD or eight cycles of BEACOPP in baseline doses. Radiotherapy was given to initial bulky or residual disease. In total, 68 of 75 registered patients were assessable: 26 were treated with COPP-ABVD and 42 with BEACOPP baseline. There were no significant differences between COPP-ABVD and BEACOPP in terms of complete remission (76%), overall survival (50%) and freedom from treatment failure (FFTF) (46%) at 5 years. At a median follow-up of 80 months, a total of 37 patients died: 14/26 patients (54%) treated with COPP-ABVD and 23/42 patients (55%) with BEACOPP. Two patients (8%) treated with COPP-ABVD and nine patients (21%) treated with BEACOPP died of acute toxicity. Hodgkin-specific FFTF at 5 years was 55% after COPP-ABVD and 74% after BEACOPP (P=0.13). Thus, there are no differences in survival between these regimens in elderly patients.
Oxaliplatin plus fluorouracil/folinic acid (5-FU/FA) every 2 weeks has shown promising activity in advanced gastric cancer. This study assessed the efficacy and safety of weekly oxaliplatin plus ...5-FU/FA (FUFOX regimen) in the metastatic setting. Patients with previously untreated metastatic gastric cancer received oxaliplatin (50 mg m(-2)) plus FA (500 mg m(-2), 2-h infusion) followed by 5-FU (2000 mg m(-2), 24-h infusion) given on days 1, 8, 15 and 22 of a 5-week cycle. The primary end point of this multicentre phase II study was the response rate according to RECIST criteria. A total of 48 patients were enrolled. Median age was 62 years and all patients had metastatic disease, with a median number of three involved organs. The most common treatment-related grade 3/4 adverse events were diarrhoea (17%), deep vein thrombosis (15%), neutropenia (8%), nausea (6%), febrile neutropenia (4%), fatigue (4%), anaemia (4%), tumour bleeding (4%), emesis (2%), cardiac ischaemia (2%) and pneumonia (2%). Grade 1/2 sensory neuropathy occurred in 67% of patients but there were no episodes of grade 3 neuropathy. Intent-to-treat analysis showed a response rate of 54% (95% CI, 39-69%), including two complete responses. At a median follow-up of 18.1 months (range 11.2-26.2 months), median survival is 11.4 months (95% CI, 8.0-14.9 months) and the median time to progression is 6.5 months (95% CI, 3.9-9.2 months). The weekly FUFOX regimen is well tolerated and shows notable activity as first-line treatment in metastatic gastric cancer.
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene which results in progressive neurodegeneration in the striatum, cortex, ...and eventually most brain areas. Despite being a monogenic disorder, environmental factors influence HD characteristics. Both human and mouse studies suggest that mutant HTT (mHTT) leads to gene expression changes that harbor potential to be modulated by the environment. Yet, the underlying mechanisms integrating environmental cues into the gene regulatory program have remained largely unclear. To better understand gene-environment interactions in the context of mHTT, we employed RNA-seq to examine effects of maternal separation (MS) and environmental enrichment (EE) on striatal gene expression during development of BACHD rats. We integrated our results with striatal consensus modules defined on HTT-CAG length and age-dependent co-expression gene networks to relate the environmental factors with disease progression. While mHTT was the main determinant of expression changes, both MS and EE were capable of modulating these disturbances, resulting in distinctive and in several cases opposing effects of MS and EE on consensus modules. This bivalent response to maternal separation and environmental enrichment may aid in explaining their distinct effects observed on disease phenotypes in animal models of HD and related neurodegenerative disorders.
The goal of this analysis was to define the role of the moderate-intensity fludarabin Ara-C amsacrin (FLAMSA)-reduced intensity conditioning (RIC) regimen for patients with high-risk AML undergoing ...allogeneic SCT (alloSCT) in first CR1. High-risk was defined by (1) AML secondary to MDS or radio/chemotherapy, (2) unfavorable cytogenetics or (3) delayed response to induction chemotherapy. A total of 23 of 44 AML patients referred to the University of Munich for alloSCT in CR1 between 1999 and 2006 fulfilled these criteria and received FLAMSA chemotherapy, followed by RIC (4 Gy TBI/cyclophosphamide/ATG) for alloSCT. Twenty-two patients engrafted, one died in aplasia. Two-year cumulative incidences for relapse and nonrelapse mortality (NRM) were 4.6 and 22.5%, respectively. Four-year overall and leukemia-free survival was 72.7% (median follow-up among survivors: 35 months). The results of this high-risk cohort were compared to the outcome of 21 consecutive standard-risk patients <55 years, who had received standard, myeloablative sibling SCT in CR1 AML within the same center and time period. Survival and cumulative incidences of relapse and NRM were identical in both groups. In conclusion, the FLAMSA-RIC regimen produces long-term remission in a high proportion of patients with high-risk AML transplanted in CR1. In this cohort, FLAMSA-RIC showed equivalent antileukemic activity as compared to the standard protocols.
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