Early blast clearance during sequential conditioning prior to allogeneic stem cell transplantation in patients with acute myeloid leukaemia.

For patients with relapsed or refractory AML, sequential conditioning prior to allogeneic stem cell transplantation (alloSCT) is an established and potentially curative treatment option. Early response to treatment during conditioning indicates chemotherapy-responsive disease and may have prognostic value. We retrospectively evaluated blast clearance on day 5 after melphalan, administered 11 days prior to alloSCT as part of a sequential conditioning in 176 patients with active AML. Overall survival (OS) was 52% (95% confidence interval [CI] 45%-60%), and relapse-free survival (RFS) was 47% (95% CI 40%-55%) at 3 years. Patients who achieved early blast clearance did not show a significant improvement in OS and RFS (OS, hazard ratio [HR] HR 0.75, p 0.19; RFS, HR 0.71, p 0.09, respectively), but had a significantly lower non-relapse mortality rate (HR 0.46, p 0.017). HLA-mismatched donor, older age, adverse genetic risk and higher comorbidity scores were associated with inferior survival outcomes. A high initial blast count was only associated with inferior prognosis in patients receiving chemotherapy-only compared to total body irradiation containing conditioning therapy. These results indicate that for patients transplanted with active AML, sensitivity to chemotherapy might be of less importance, compared to other disease- and transplant-related factors.

Comparable outcomes for TBI-based versus treosulfan based conditioning prior to allogeneic hematopoietic stem cell transplantation in AML and MDS patients.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a standard treatment for patients with AML and MDS. The combination of fractionated total body irradiation(8GyTBI/Flu) with fludarabine is an established conditioning regimen, but fludarabine/treosulfan(Flu/Treo) constitutes an alternative in older/comorbid patients. We conducted a retrospective analysis of 215 AML(in CR) and 96 MDS patients undergoing their first allo-HCT between 2011 and 2022, identifying 53 matched Flu/Treo and 8GyTBI/Flu patients through propensity score matching. Median follow-up of survivors was 3.3 years and 4.1 years. For the Flu/Treo group, 1-year non-relapse mortality (2% vs. 10%, p = 0.03) was lower, while 1-year relapse incidence (16% vs. 13%, p = 0.81) was similar. Three-year outcomes, including relapse-free survival and graft-versus-host disease incidence, were comparable (OS: 81% vs. 74%, p = 0.70; RFS: 78% vs. 66%, p = 0.28; chronic GvHD: 34% vs. 36%, p = 0.97; acute GvHD (100 days): 11% vs. 23%, p = 0.11). Multivariable analysis, considering age, ECOG, HCT-CI, and MRD status, revealed no associations with main outcomes. Dose-reduced conditioning with Flu/Treo or 8GyTBI/Flu demonstrated favorable and comparable survival rates exceeding 70% at 3 years with 1-year NRM rates below 10% and low relapse rates in the matched cohort. These data underline the need for further evaluation of TBI and Treo-based conditionings in prospective trials.

Inotuzumab Ozogamicin as Induction Therapy for Patients Older Than 55 Years With Philadelphia Chromosome-Negative B-Precursor ALL.

PURPOSE: Despite recent advances in adapting the intensity of treatment for older patients with ALL, current protocols are associated with high rates of early deaths, treatment-related toxicity, and dismal prognosis. We evaluated inotuzumab ozogamicin and dexamethasone (Dex) as induction therapy in older patients with ALL within the German Multicenter Study Group for Adult ALL (GMALL). PATIENTS AND METHODS: The open-label, multicenter, phase II, INITIAL-1 trial enrolled 45 patients older than 55 years with newly diagnosed, CD22-positive, BCR::ABL-negative B-precursor ALL (B-ALL). Patients received up to three cycles of inotuzumab ozogamicin/Dex and up to six cycles of age-adapted GMALL consolidation and maintenance therapy. RESULTS: Forty-three evaluable patients with common/pre-B (n = 38) and pro-B ALL (n = 5), with a median age of 64 years (range, 56-80), received at least two cycles of inotuzumab ozogamicin induction therapy. All patients achieved complete remission (CR/CR with incomplete hematologic recovery). Twenty-three (53%) and 30 (71%) patients had no evidence of molecularly assessed measurable residual disease (minimum 10e-4 threshold) after the second and third inductions, respectively. After a median follow-up of 2.7 years, event-free survival at one (primary end point) and 3 years was 88% (95% CI, 79 to 98) and 55% (95% CI, 40 to 71), while overall survival (OS) was 91% (95% CI, 82 to 99) and 73% (95% CI, 59 to 87), respectively. None of the patients died during 6 months after the start of induction. Most common adverse events having common toxicity criteria grade ≥3 during induction were leukocytopenia, neutropenia, thrombocytopenia, anemia, and elevated liver enzymes. One patient developed nonfatal veno-occlusive disease after induction II. CONCLUSION: Inotuzumab ozogamicin-based induction followed by age-adapted chemotherapy was well tolerated and resulted in high rates of remission and OS. These data provide a rationale for integrating inotuzumab ozogamicin into first-line regimens for older patients with B-ALL.

Pretransplant spleen volume and outcome after hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML).

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment modality for patients with acute myeloid leukemia (AML). Here, we investigated the predictive value of spleen volume on outcome parameters and engraftment kinetics after HSCT in a large cohort of AML patients. A total of 402 patients who received their first HSCT between January 2012 and March 2019 were included in this retrospective study. Spleen volume was correlated to clinical outcome and engraftment kinetics. Median follow-up was 33.7 months (95% confidence interval [CI], 28.9-37.4 months). Patients were subdivided based on median spleen volume of 238.0 cm3 (range 55.7-2693.5 cm3) into a small spleen volume (SSV) and a large spleen volume (LSV) group. LSV was associated with inferior overall survival (OS) after HSCT (55.7% vs. 66.6% at 2 years; P = 0.009) and higher cumulative incidence of NRM (28.8% vs. 20.2% at 2 years; P = 0.048). The adjusted hazard ratio for NRM in the LSV group was 1.55 (95% CI, 1.03-2.34). Time to neutrophil or platelet engraftment and the occurrence of acute or chronic graft-versus-host disease (GVHD) were not significantly different between both groups. Higher spleen volume at the time of HSCT was independently linked to adverse outcomes such as inferior OS and higher cumulative incidence of NRM in AML patients after HSCT. Engraftment kinetics and GVHD were not associated with spleen volume.

Hippocampal Subfield Volumes Predict Disengagement from Maintenance Treatment in First Episode Schizophrenia.

OBJECTIVES: Disengagement from treatment is common in first episode schizophrenia (FES) and is associated with poor outcomes. Our aim was to determine whether hippocampal subfield volumes predict disengagement during maintenance treatment of FES. METHODS: FES patients were recruited from sites in Boston, New York, Shanghai, and Changsha. After stabilization on antipsychotic medication, participants were randomized to add-on citalopram or placebo and followed for 12 months. Demographic, clinical and cognitive factors at baseline were compared between completers and disengagers in addition to volumes of hippocampal subfields. RESULTS: Baseline data were available for 95 randomized participants. Disengagers (n = 38, 40%) differed from completers (n = 57, 60%) by race (more likely Black; less likely Asian) and in more alcohol use, parkinsonism, negative symptoms and more impairment in visual learning and working memory. Bilateral dentate gyrus (DG), CA1, CA2/3 and whole hippocampal volumes were significantly smaller in disengagers compared to completers. When all the eight volumes were entered into the model simultaneously, only left DG volume significantly predicted disengagement status and remained significant after adjusting for age, sex, race, intracranial volume, antipsychotic dose, duration of untreated psychosis, citalopram status, alcohol status, and smoking status (P < .01). Left DG volume predicted disengagement with 57% sensitivity and 83% specificity. CONCLUSIONS: Smaller left DG was significantly associated with disengagement status over 12 months of maintenance treatment in patients with FES participating in a randomized clinical trial. If replicated, these findings may provide a biomarker to identify patients at risk for disengagement and a potential target for interventions.

Association of Aripiprazole With Reduced Hippocampal Atrophy During Maintenance Treatment of First-Episode Schizophrenia.

PURPOSE/BACKGROUND: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. METHODS/PROCEDURES: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). FINDINGS/RESULTS: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. IMPLICATIONS/CONCLUSIONS: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.

Effect of citalopram on hippocampal volume in first-episode schizophrenia: Structural MRI results from the DECIFER trial.

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.

Cavernoma-related epilepsy in cavernous malformations located within the temporal lobe: surgical management and seizure outcome.

OBJECTIVE: Cavernoma-related epilepsy (CRE) is a frequent symptom in patients with cerebral cavernous malformations (CCMs). Reports on surgical management and seizure outcome of epileptogenic CCM often focus on intracranial cavernoma in general. Therefore, data on CCMs within the temporal lobe are scarce. The authors therefore analyzed their institutional data. METHODS: From 2003 to 2018, 52 patients suffering from CCMs located within the temporal lobe underwent surgery for CRE at University Hospital Bonn. Information on patient characteristics, preoperative seizure history, preoperative evaluation, surgical strategies, postoperative complications, and seizure outcome was assessed and further analyzed. Seizure outcome was assessed 12 months after surgery according to the International League Against Epilepsy (ILAE) classification and stratified into favorable (ILAE class I) versus unfavorable (ILAE classes II-VI). RESULTS: Overall, 47 (90%) of 52 patients with CCMs located in the temporal lobe and CRE achieved favorable seizure outcome. Pure lesionectomy was performed in 5 patients, extended lesionectomy with resection of the hemosiderin rim in 38 patients, and anterior temporal lobectomy in 9 patients with temporal lobe CCM. Specifically, 36 patients (69%) suffered from drug-resistant epilepsy (DRE), 3 patients (6%) from chronic CRE, and 13 patients (25%) sustained sporadic CRE. In patients with DRE, favorable seizure outcome was achieved in 32 (89%) of 36 patients. Patients with DRE were significantly older than patients with CCM-associated chronic or sporadic seizures (p = 0.02). Furthermore, patients with DRE more often underwent additional amygdalohippocampectomy following the recommendation of presurgical epileptological evaluation. CONCLUSIONS: Favorable seizure outcome is achievable in a substantial number of patients with epileptogenic CCM located in the temporal lobe, even if patients suffered from drug-resistant CRE. For adequate counseling and monitoring, patients with CRE should undergo a thorough pre- and postsurgical evaluation in dedicated epilepsy surgery programs.

Mesh fistula after ventral hernia repair: What is the optimal management?

BACKGROUND: A mesh-related intestinal fistula is an uncommon and challenging complication of ventral hernia repair. Optimal management is unclear owing to lack of prospective or long-term data. METHODS: We reviewed our prospective data for mesh-related intestinal fistulas from 2004 to 2017and compared suture repair versus ventral hernia repair with mesh at the time of mesh-related intestinal fistula takedown. RESULTS: Eighty-two mesh-related intestinal fistulas were treated; none of the fistulas had closed spontaneously, and all fistula persisted at the time of our treatment. Mean age was 61 ± 12 years with 33-month follow-up. Comorbidities were similar between groups. Defects were 2.5-times larger in ventral hernia repair with mesh (324 ± 392 cm2 vs 1301 ± 133 cm2; P = .044). Components separation (64% vs 21%; P = .0003) and panniculectomy (35% vs 7%; P = .0074) were more common in ventral hernia repair with mesh. Mortality occurred in 4 patients. Complications were similar. In patients undergoing ventral hernia repair with non-bridged, acellular, porcine dermal matrix, hernia recurrence was less than in patients without mesh (26% vs 66%; P = .0030). Only partial excision of the mesh involved with the fistula resulted in a substantial increase in developing another fistula (29% vs 6%; P < .05). CONCLUSION: Patients undergoing preperitoneal ventral hernia repair with mesh for mesh-related intestinal fistula had a lesser rate of hernia recurrence and similar complications compared to suture repair despite larger hernias. Complete mesh excision decreases the risk of fistula recurrence. We maintain that ventral hernia repair with mesh during mesh-related intestinal fistula takedown represents the best opportunity for a durable herniorrhaphy.

One More Time: Redo Paraesophageal Hernia Repair Results in Safe, Durable Outcomes Compared with Primary Repairs.

The incidence and causes of failed paraesophageal hernia repairs (PEHR) remain poorly understood. Our study aimed to evaluate long-term clinical outcomes after reoperative fundoplication as compared with initial PEHR. A prospectively maintained institutional hernia-specific database was queried for PEHR between 2008 and 2017. Patients with prior history of PEHR were categorized as "redo" paraesophageal hernia (RPEH). Primary outcomes included postoperative morbidity, mortality, symptom resolution, and hernia recurrence. A total of 402 patients underwent minimally invasive PEHR (Initial PEH = 305, RPEH = 97). Redo PEHR had more prevalent preoperative nausea/vomiting (50.6% vs 34.1%, P < 0.007) and weight loss (24.1% vs 13.5%, P < 0.02). RPEH had had longer mean operative time (256.4 ± 91.2 vs 190.3 ± 59.9 minutes, P < 0.0001) and higher rate of conversion to open (10.3% vs 0.67%, P < 0.0001); however, no difference was noted in postoperative complications, hernia recurrence, or mortality between cohorts. Laparoscopic revision of prior PEHR in symptomatic patients can be safely performed with favorable outcomes compared with initial PEHR. Despite redo procedures seeming to be more technically demanding (as noted by longer operative time and higher conversion rates), outcomes are similar and overall resolution of symptoms is achieved in most patients.

Jak-TGFß cross-talk links transient adipose tissue inflammation to beige adipogenesis.

The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as ß3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFß signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFß signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by ß3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.

Ciprofloxacin versus colistin prophylaxis during neutropenia in acute myeloid leukemia: two parallel patient cohorts treated in a single center.

Patients undergoing intensive chemotherapy for acute myeloid leukemia are at high risk for bacterial infections during therapy-related neutropenia. However, the use of specific antibiotic regimens for prophylaxis in afebrile neutropenic acute myeloid leukemia patients is controversial. We report a retrospective evaluation of 172 acute myeloid leukemia patients who received 322 courses of myelosuppressive chemotherapy and had an expected duration of neutropenia of more than seven days. The patients were allocated to antibiotic prophylaxis groups and treated with colistin or ciprofloxacin through 2 different hematologic services at our hospital, as available. The infection rate was reduced from 88.6% to 74.2% through antibiotic prophylaxis (vs without prophylaxis; P=0.04). A comparison of both antibiotic drugs revealed a trend towards fewer infections associated with ciprofloxacin prophylaxis (69.2% vs 79.5% in the colistin group; P=0.07), as determined by univariate analysis. This result was confirmed through multivariate analysis (OR: 0.475, 95%CI: 0.236-0.958; P=0.041). The prophylactic agents did not differ with regard to the microbiological findings (P=0.6, not significant). Of note, the use of ciprofloxacin was significantly associated with an increased rate of infections with pathogens that are resistant to the antibiotic used for prophylaxis (79.5% vs 9.5% in the colistin group; P<0.0001). The risk factors for higher infection rates were the presence of a central venous catheter (P<0.0001), mucositis grade III/IV (P=0.0039), and induction/relapse courses (vs consolidation; P<0.0001). In conclusion, ciprofloxacin prophylaxis appears to be of particular benefit during induction and relapse chemotherapy for acute myeloid leukemia. To prevent and control drug resistance, it may be safely replaced by colistin during consolidation cycles of acute myeloid leukemia therapy.