Combined Lanreotide Autogel and Temozolomide Treatment of Progressive Pancreatic and Intestinal Neuroendocrine Tumors: The Phase II SONNET Study.

BACKGROUND: In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. MATERIALS AND METHODS: SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. RESULTS: Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. CONCLUSIONS: LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile.

CXCR4 PET/MRI for follow-up of gastric mucosa-associated lymphoid tissue lymphoma after first-line Helicobacter pylori eradication.

Posttreatment evaluation of gastric mucosa-associated lymphoid tissue (MALT) lymphoma currently relies on esophagogastroduodenoscopy with histological assessment of biopsies. Overexpression of the G protein-coupled C-X-C chemokine receptor type 4 (CXCR4) has been previously observed in MALT lymphoma. The aim of this prospective study was to evaluate positron emission tomography (PET) with the novel CXCR4 tracer [68Ga]Pentixafor as a potential alternative to follow up biopsies for assessment of residual disease (noncomplete remission [CR]) after first-line Helicobacter pylori eradication. Forty-six post-H pylori eradication [68Ga]Pentixafor-PET/magnetic resonance imaging (MRI) examinations of 26 gastric MALT lymphoma patients, and 20 [68Ga]Pentixafor-PET/MRI examinations of 20 control group patients without lymphoma, were analyzed. In the MALT lymphoma group, time-matched gastric biopsies were used as reference standard and showed CR in 6 cases. Pooled examination-based accuracy, sensitivity, specificity, and positive and negative predictive values of [68Ga]Pentixafor-PET for detection of residual gastric MALT lymphoma at follow-up were 97.0%, 95.0%, 100.0%, 100.0%, and 92.9%, respectively. Maximum and mean PET standardized uptake values showed moderate correlation with immunohistochemistry-based CXCR4+ cell counts, with correlation coefficients of r = 0.51 and r = 0.52 (P = .008 and P = .006). In summary, CXCR4 imaging with [68Ga]Pentixafor-PET may represent a promising test for assessment of residual gastric MALT lymphomas after H pylori eradication.

Chemokine receptor-targeted PET/CT provides superior diagnostic performance in newly diagnosed marginal zone lymphoma patients: a head-to-head comparison with [18F]FDG.

BACKGROUND: In patients with marginal zone lymphoma (MZL), [18F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [68Ga]Ga-PentixaFor when compared to [18F]FDG PET/CT in MZL. METHODS: Thirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [68Ga]Ga-PentixaFor and [18F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUVmax/peak), and calculating target-to-background ratios (TBR, defined as lesion-based SUVpeak divided by SUVmean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted. RESULTS: On a patient-based level, [68Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [18F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [18F]FDG but missed by [68Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [68Ga]Ga-PentixaFor consistently provided increased metrics when compared to [18F]FDG: SUVmax, 10.3 (range, 2.53-37.2) vs. 5.72 (2.32-37.0); SUVpeak, 6.23 (1.58-25.7) vs. 3.87 (1.54-27.7); P < 0.01, respectively. Concordant TL TBR on [68Ga]Ga-PentixaFor (median, 3.85; range, 1.05-16.0) was also approximately 1.8-fold higher relative to [18F]FDG (median, 2.08; range, 0.81-28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06). CONCLUSIONS: In newly diagnosed MZL patients, [68Ga]Ga-PentixaFor identified more sites of disease when compared to [18F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [68Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging.

Risk as a pattern over time: Delineation of time-dependent risk factors in biological, psychological, and social variables in cancer patients.

BACKGROUND: Survival in cancer patients is associated with a multitude of biological, social, and psychological factors. Although it is well established that all these factors add to overall mortality, it is not well understood how the predictive power of these parameters changes in a comprehensive model and over time. METHODS: Patients who attended the authors' outpatient clinic were invited to participate. The authors followed 5180 mixed cancer patients (51.1% female; mean age, 59.1 years [SD = 13.8]) for up to 16 years and analyzed biological (age, sex, cancer site, anemia), psychological (anxiety, depression), and social variables (marital status, education, employment status) potentially predicting overall survival in a Cox proportional hazards model. RESULTS: The median survival time for the entire sample was 4.3 years (95% confidence interval, 4.0-4.7). The overall survival probabilities for 1 and 10 years were 76.8% and 38.0%, respectively. Following an empirical approach, the authors split the time interval into five periods: acute, subacute, short-term, medium-term, and long-term. A complex pattern of variables predicted overall survival differently in the five periods. Biological parameters were important throughout most of the time, social parameters were either time-independent predictors or tended to be more important in the longer term. Of the psychological parameters, only depression was a significant predictor and lost its predictive power in the long-term. CONCLUSIONS: The findings of this study allow the development of comprehensive patient-specific models of risk and resilience factors addressing biopsychosocial needs of cancer patients, paving the way for a personalized treatment plan that goes beyond biomedical cancer care.

Eribulin in Patients with Liposarcoma and Leiomyosarcoma: A Retrospective Single-Center Experience.

INTRODUCTION: Soft tissue sarcomas are rare and heterogenous malignancies with a poor prognosis in advanced disease stages. Eribulin is used in metastatic liposarcoma (LPS) patients, who have failed first-line chemotherapy and has been approved for use in patients with LPS in the USA and Europe due to its efficacy in this histological subtype in a phase 3 trial. We have evaluated efficacy and tolerability of eribulin in LPS and leiomyosarcoma (LMS) patients in the routine clinical setting at our department. METHODS: In this retrospective single-center analysis, efficacy and safety of eribulin were retrospectively evaluated in advanced LPS and LMS patients at the Division of Oncology, Medical University of Vienna. RESULTS: A total of 32 adult patients treated with eribulin were identified and included in this analysis. Overall response rate was 9.4% for all patients, with one patient with LPS and two patients with LMS showing a partial response. Disease control rate (partial response plus stable disease) for all patients was 50% (LPS: 47.1%; LMS 53.3%). No statistically significant difference in median progression-free survival and overall survival was detected between patients with LPS and LMS (p = 0.807 and p = 0.519, respectively). Patients with LMS (n = 2) had received fewer previous therapy lines than patients with LPS (n = 14) (≤ previous treatment lines, p < 0.001). Toxicity was generally manageable, and grade 3 + 4 events were rare. CONCLUSION: The activity and tolerability of eribulin in LPS as in well in LMS patients in the routine clinical setting is comparable to outcomes reported in published phase 3 trials.

Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).

Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) accounts for 7% to 8% of newly diagnosed lymphomas. Because of its association with infectious causes, such as Helicobacter pylori (HP) or Chlamydophila psittaci (CP), and autoimmune diseases, it has become the paradigm of an antigen-driven malignancy. MALT lymphoma usually displays an indolent course, and watch-and-wait strategies are justified initially in a certain percentage of patients. In patients with gastric MALT lymphoma or ocular adnexal MALT lymphoma, antibiotic therapy against HP or CP, respectively, is the first-line management of choice, resulting in lymphoma response rates from 75% to 80% after HP eradication and from 33% to 65% after antibiotic therapy for CP. In patients who have localized disease that is refractory to antibiotics, radiation is widely applied in various centers with excellent local control, whereas systemic therapies are increasingly being applied, at least in Europe, because of the potentially systemic nature of the disease. Therefore, the objective of this review is to briefly summarize the clinicopathologic characteristics of this distinct type of lymphoma along with current data on management strategies.

The impact of COVID-19 on cancer care of outpatients with low socioeconomic status.

Patients with low socioeconomic status (SES) are among the most underserved groups of people regarding cancer care. Analyzing the impact of the coronavirus-induced disease 2019 (COVID-19) pandemic on health care disparities and calling attention to inequalities in cancer care is crucial to justify and initiate adequate countermeasures. We aimed to determine whether the COVID-19 pandemic aggravated health care disparities of cancer outpatients related to their SES and analyzed patient data of the largest university center providing services for patients with hematologic and oncologic disorders in Austria from 2018 to 2021. SES was assessed using three indicators: monthly net household income, level of education and occupational prestige. In total, 1217 cancer outpatients (51.1% female) with a mean age of 59.4 years (SD = 14.2) participated. In the first year of the pandemic, the relative proportion of individuals with low income, low education level and low occupational prestige seeking cancer care at our outpatient center decreased significantly (P ≤ .015). The strongest indicator was income, with a consistent effect throughout the first pandemic year. Countermeasures and specific interventions to support cancer patients with low SES in their access to health care should be initiated and prioritized.

Impact of COVID-19 lockdown on routine oncology versus emergency care at a high volume cancer centre.

BACKGROUND: We investigated the influence of population-wide COVID-19 lockdown measures implemented on 16, March 2020 on routine and emergency care of cancer outpatients at a tertiary care cancer centre in Vienna, Austria. METHODS: We compared the number/visits of cancer outpatients receiving oncological therapies at the oncologic day clinic (DC) and admissions at the emergency department (ED) of our institution in time periods before (pre-lockdown period: 1 January - 15 March 2020) and after (post-lockdown period: 16 March- 31 May 2020) lockdown implementation with the respective reference periods of 2018 and 2019. Additionally, we analysed Emergency Severity Index (ESI) score of unplanned cancer patient presentations to the ED in the same post-lockdown time periods. Patient outcome was described as 3-month mortality rate (3-MM). RESULTS: In total, 16 703 visits at the DC and 2664 patient visits for the respective time periods were recorded at the ED. No decrease in patient visits was observed at the DC after lockdown implementation (P = .351), whereas a substantial decrease in patient visits at the ED was seen (P < .001). This translates into a 26%-31% reduction of cancer-related patient visits per half month after the lockdown at the ED (P < .001 vs. 2018 + 2019). There was no difference in the distribution of ESI scores at ED presentation (P = .805), admission rates or 3-MM in association with lockdown implementation (P = .086). CONCLUSION: We demonstrate the feasibility of maintaining antineoplastic therapy administration during the COVID-19 pandemic. However, our data underline the need for adapted management strategies for emergency presentations of cancer patients.

A phase II study of the PI3K inhibitor copanlisib in combination with the anti-CD20 monoclonal antibody rituximab for patients with marginal zone lymphoma: treatment rationale and protocol design of the COUP-1 trial.

BACKGROUND: Advanced stage marginal zone lymphoma (MZL) is an incurable indolent B-cell lymphoma, for which a wide variety of treatments ranging from single agent rituximab to more dose intense immunochemotherapy exists. One of the major goals in this palliative setting is to develop chemotherapy-free treatments, which approach the efficacy of immunochemotherapies, but avoid chemotherapy associated toxicity in this often elderly patient population. The PI3K inhibitor copanlisib has recently shown remarkable clinical activity in refractory or relapsed indolent B-cell lymphomas, among them MZL. Based on these data, copanlisib monotherapy was granted breakthrough designation by the FDA for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies. However, data are still limited in particular for MZL. Based on this, the COUP-1 trial aims at testing the toxicity and efficacy of copanlisib in combination with rituximab in treatment naive and relapsed MZL. METHODS: COUP-1 is a prospective, multicenter, single-arm, open-label, non-randomized phase II trial of 6 cycles (28 days cycle) of copanlisib (60 mg intravenous day 1, 8, 15) and rituximab (375 mg/m2 intravenous day 1) in the induction phase followed by a maintenance phase of copanlisib (d1, d15 every 4 weeks for a maximum of 12 cycles) and rituximab (d1 every 8 weeks for a maximum of 12 cycles) in patients aged ≥18 years with previously untreated or relapsed MZL in need of treatment. A total of 56 patients are to be enrolled. Primary endpoint is the complete response (CR) rate determined 12 months after start of induction therapy. Secondary endpoints include the overall response (OR) rate, progression free survival (PFS), overall survival (OS), safety and patient related outcome with quality of life. The study includes a translational bio-sampling program with the prospect to measure minimal residual disease. The study was initiated in November 2019. DISCUSSION: The COUP-1 trial evaluates the efficacy and toxicity of the treatment of copanlisib in combination with rituximab in patients with MZL and additionally offers the chance for translational research in this heterogenous type of lymphoma. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03474744 . Registration date: 03/23/2018.

Long-term Therapeutic Success of Intravenous Rituximab in 26 Patients with Indolent Primary Cutaneous B-cell Lymphoma.

Systemic monotherapy with rituximab is a well-known treatment approach for primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone lymphoma. Both have excellent prognosis despite high relapse rates. To investigate the long-term effectiveness and clinical outcome of intravenous rituximab at a dose of 375 mg/m2 once weekly, data for 26 patients (17 primary cutaneous follicle centre lymphoma and 9 primary cutaneous marginal zone lymphoma) were analysed retrospectively. Complete remissions occurred in 20 (77%) and partial remissions in 6 patients (23%), demonstrating an overall response rate of 100%. The relapse rate was 52.9% in primary cutaneous follicle centre lymphoma and 88.9% in primary cutaneous marginal zone lymphoma. Ongoing complete remissions after therapy with rituximab were observed in 9 patients (34.6%) with a median progression-free survival of 161 months (13.4 years). These results confirm that intravenous rituximab is an effective and well-tolerated treatment with durable responses in a relevant percentage of patients at a median follow-up of 148 months (12.3 years).

Early progression of disease predicts shorter survival in MALT lymphoma patients receiving systemic treatment.

Early progression of disease (POD) within two years from diagnosis is linked with poor overall survival (OS) in follicular lymphoma but its prognostic role is less clear in extranodal marginal zone B-cell lymphoma (EMZL). We sought to identify prognostic factors associated with early POD and to determine whether is associated with inferior OS. We analyzed the impact of early POD in the IELSG19 clinical trial dataset (training set of 401 patients randomly assigned to chlorambucil or rituximab or chlorambucil plus rituximab). Reproducibility was examined in a validation set of 287 patients who received systemic treatment. In both sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without prior progression. OS was calculated from progression in patients with early POD and from 24 months after start of treatment in those without (reference group). Early POD was observed in 69 of the 384 (18%) evaluable patients of the IELSG19 study. Patients with high-risk MALT-IPI were more likely to have early POD (p=0.006). The 10-year OS rate was 64% in the early POD group and 85% in the reference group (HR= 2.42, 95%CI, 1.35-4.34; log-rank P=0.002). This prognostic impact was confirmed in the validation set, in which early POD was observed in 64 out of 224 (29%) evaluable patients with 10-year OS rate of 48% in the early POD group and 71% in the reference group (HR= 2.15, 95%CI, 1.19-3.90; log-rank P=0.009). In patients with EMZL who received front-line systemic treatment, early POD is associated with poorer survival and may represent a useful endpoint in future prospective clinical trials.

PET/MRI versus PET/CT in oncology: a prospective single-center study of 330 examinations focusing on implications for patient management and cost considerations.

PURPOSE: PET/MRI has recently been introduced into clinical practice. We prospectively investigated the clinical impact of PET/MRI compared with PET/CT, in a mixed population of cancer patients, and performed an economic evaluation of PET/MRI. METHODS: Cancer patients referred for routine staging or follow-up by PET/CT underwent consecutive PET/CT and PET/MRI, using single applications of [18F]FDG, [68Ga]Ga-DOTANOC, or [18F]FDOPA, depending on tumor histology. PET/MRI and PET/CT were rated separately, and lesions were assessed per anatomic region; based on regions, per-examination and per-patient accuracies were determined. A simulated, multidisciplinary team meeting served as reference standard and determined whether differences between PET/CT and PET/MRI affected patient management. The McNemar tests were used to compare accuracies, and incremental cost-effectiveness ratios (ICERs) for PET/MRI were calculated. RESULTS: Two hundred sixty-three patients (330 same-day PET/CT and PET/MRI examinations) were included. PET/MRI was accurate in 319/330 examinations and PET/CT in 277/330 examinations; the respective accuracies of 97.3% and 83.9% differed significantly (P < 0.001). The additional findings on PET/MRI-mainly liver and brain metastases-had implications for patient management in 21/263 patients (8.0%). The per-examination cost was 596.97 EUR for PET/MRI and 405.95 EUR for PET/CT. ICERs for PET/MRI were 14.26 EUR per percent of diagnostic accuracy and 23.88 EUR per percent of correctly managed patients. CONCLUSIONS: PET/MRI enables more appropriate management than PET/CT in a nonnegligible fraction of cancer patients. Since the per-examination cost is about 50% higher for PET/MRI than for PET/CT, a histology-based triage of patients to either PET/MRI or PET/CT may be meaningful.

Immunomodulatory treatment for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma).

The pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma has been characterized as a dynamic process driven by lymphoma cell dependency on T-cell signaling, chronic antigenic stimulation of marginal zone B-cells and activation of the nuclear factor-kappa B signaling pathway. This concept is underlined by the strong causal connection of chronic Helicobacter pylori associated gastritis and MALT lymphoma development based on perpetual auto-antigenic stimulation of Helicobacter pylori-specific T-cells, but also its association with further potential infectious triggers and autoimmune disorders for extragastric lymphoma sites. Thus, given the dependency of MALT lymphoma cells on the tumor microenvironment, this specific entity appears highly suitable for immunomodulatory treatment strategies. Several approaches have been assessed in the last years including promising data on immunomodulatory agents "IMiDs" thalidomide and lenalidomide, macrolide antibiotics and antibodies. The aim of the present review is to discuss rationales for immunomodulatory therapies in MALT lymphoma and to present the statu quo on immunomodulatory and therefore chemotherapy-free treatment strategies for these patients.

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors.

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

Transformed mucosa-associated lymphoid tissue lymphomas: A single institution retrospective study including polymerase chain reaction-based clonality analysis.

Given the lack of consistent data regarding the clinico-pathological features and clonal lymphomagenesis of patients with mucosa-associated lymphoid tissue (MALT) lymphoma and histological transformation (HT), we have systematically analysed 379 patients (32% gastric, 68% extra-gastric; median follow-up 52 months) diagnosed with HT at the Medical University Vienna 1999-2017, and reassessed tissues of identified patients by polymerase chain reaction (PCR)-based clonality analysis. HT was documented in 12/379 patients (3·2%) and occurred at a median time of 22 months (range; 6-202 months) after diagnosis of MALT lymphoma. By PCR-based clonality analysis, we detected a clear-cut clonal relationship of MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) in 8 of 11 analysed cases proving that the large majority of DLBCL following MALT lymphoma are clonally-related and constitute a real transformation. Interestingly, HT occurred within the first 2·5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally-unrelated (most likely secondary) lymphoma (82-202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1·5-33 months after HT, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.

Oral Ondansetron Offers Effective Antidiarrheal Activity for Carcinoid Syndrome Refractory to Somatostatin Analogs.

OBJECTIVES: Somatostatin analogs (SSAs) are standard for symptomatic patients with neuroendocrine tumors (NETs). However, most patients experience tachyphylaxis, and limited options exist for this so-called "refractory carcinoid syndrome." Recently, 5-HT3 antagonist ondansetron has been associated with reduction of bowel movement in a small series. The aim of this analysis was to assess effectiveness of ondansetron for symptomatic treatment of carcinoid syndrome. DESIGN AND PATIENTS: We have analyzed patients given ondansetron as bridging therapy for refractory carcinoid syndrome. The dose was 2 × 8 mg for 5 days, followed by reduction to 1 × 8 mg in case of benefit. RESULTS: A total of 14 patients with small bowel NETs metastatic to the liver were identified. All patients had been treated with SSAs for a median time of 18 months before aggravation of diarrhea. One patient had to be excluded because of an underlying infectious cause of diarrhea. The median number of daily bowel movements was 7 (range, 5-13) before initiation of therapy. At this time, seven patients had stable disease, whereas six patients showed radiological progression with symptomatic breakthrough. All 13 patients were scheduled for salvage therapy. Remarkably, in 85% (11/13) ondansetron resulted in a clinically relevant decrease of bowel movements to a median of 3 (1-4). The median time of ondansetron intake was 29 days (7 days to 29 months). In four patients, diarrhea recurred after initial improvement at an interval of 22-43 days, whereas the remaining seven had an ongoing benefit, including two long-term responders who refused further therapy because of pronounced decrease of symptoms (ondansetron for 14+ and 29+ months). CONCLUSION: Ondansetron offers symptomatic relief in the majority of patients. Although there was no influence on 5-HIAA levels, evidence from two patients suggests prolonged benefit. IMPLICATIONS FOR PRACTICE: Somatostatin analogs are standard treatment in patients with carcinoid syndrome and have an overall response rate of up to 50%. This symptomatic benefit, however, is lost in many patients because of the development of tachyphylaxis or tumor progression. Patients with this "refractory carcinoid syndrome" pose a therapeutic challenge and are sometimes faced with a detrimental effect on quality of life. In this article, the authors suggest the 5-HT3 receptor antagonist ondansetron as potential symptomatic therapy for patients with refractory diarrhea due to carcinoid syndrome. Although the number of patients in this retrospective series is limited, treatment was easily applicable, feasible, and safe and resulted in an ongoing symptomatic benefit in 85% of patients, including two long-term responders.

A MALT lymphoma prognostic index.

There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). This study aimed to develop and validate a specific prognostic tool to personalize and optimize treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging 3 independent cohorts of MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age ≥70 years (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.26-2.33), Ann Arbor stage III or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or ≥2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated between patients with different progression-free, overall, and cause-specific survival. The prognostic utility was retained in gastric and nongastric lymphomas, in each treatment arm (chlorambucil, rituximab, and rituximab plus chlorambucil), and was confirmed in the validation set. The new index, MALT-IPI, is a simple, accessible, and effective tool to identify MALT lymphoma patients at risk of poor outcomes. It may help define appropriate treatment approaches for individual patients.

GDF-15 in solid vs non-solid treatment-naïve malignancies.

AIM: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients. METHODS: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint. RESULTS: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease. CONCLUSIONS: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

Prolonged follow-up on lenalidomide-based treatment for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma)-Real-world data from the Medical University of Vienna.

Based on results of two pilot trials, lenalidomide (LEN) was found to be active and safe as monotherapy and showed an increased response rate of 80% in combination with rituximab (R) for patients with mucosa-associated lymphoid tissue (MALT) lymphoma. While initial results were promising, there are currently no data on long-term outcome, and larger international phase II/III trials on LEN for indolent lymphoma lack specific subgroup analyses. Thus, we have systematically analyzed 50 patients treated with LEN-based therapy (LEN-monotherapy n = 16, R-LEN n = 34) at the Medical University of Vienna 2009 to 2019 and investigated long-term outcome and relapse patterns. At a follow-up of more than 5 years (median 68 months), 54% of patients are free of relapse, and estimated median progression-free survival (PFS) was 72 months (95%CI 49-96). There was no difference in PFS according to stage of disease, i.e. localized versus disseminated disease (P = .67) and previous systemic treatment (P = .16). Interestingly, but with the caveat of the limited number of patients included in this series, primary extragastric disease had a superior PFS compared with gastric lymphoma (P = .04) and also depth of response, i.e. complete or partial response versus stable disease was associated with significantly prolonged PFS (P = .01). We documented four patients (8%) with pronounced improvement of response during follow-up including three patients initially rated as partial remission and finally achieving complete remission at 12 to 32 months. This highlights the potential of delayed responses to LEN treatment. Estimated overall survival at 5 years was excellent at 92%. These "real-world" data confirm long-term activity of LEN in MALT lymphoma.

Treatment of mucosa associated lymphoid tissue lymphoma with a long-term once-weekly regimen of oral azithromycin: Results from the phase II MALT-A trial.

The macrolide clarithromycin has been reported as active for therapy of mucosa associated lymphoid tissue (MALT) lymphoma. Pharmacokinetic properties, however, require continuous daily intake over a prolonged period of time. As the macrolide azithromycin is characterized by a long half-life as well as potential antineoplastic activity in vitro, we have performed a phase II trial of long-term once-weekly oral azithromycin for treatment of MALT lymphoma. In a 2-stage-design, 16 patients (10 f/6 m) with histologically verified and measurable MALT lymphoma were included in the first phase of the trial, which could be expanded to a maximum of 46 patients depending on remissions in the first phase. Patients were given oral azithromycin 1500 mg once-weekly 4 times a month, and restaging was performed after 3 and 6 months. Two patients had gastric and 14 extragastric MALT lymphoma; 12/16 patients were treatment-naive and received azithromycin as first line treatment. Tolerance of this regimen was excellent, and 14/16 patients received 6 months of treatment as scheduled, while 1 patient each discontinued after 4 (progressive disease) and 1 cycle (personal reasons), respectively. The most commonly observed side effects were mild nausea (n = 8) and diarrhea (n = 4). Efficacy, however, was low as only 4/16 patients (25%) responded, with 2 complete and 2 partial remissions, 9 patients (56%) had stable disease, and 3 patients 19%) were rated as progressive disease. As the predefined activity of more than 7/16 patients responding was not reached, the study was stopped after 16 patients. Although long-term once-weekly oral azithromycin showed some antilymphoma activity, the response rate was below the predefined threshold of interest. However, based on our data, one cannot rule out suboptimal dosing in our study; attempts to study azithromycin at a different mode of application might be warranted in the future.