Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation.

BACKGROUND: Skeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling. METHODS: An exploratory longitudinal study was conducted to assess serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model. RESULTS: During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation. CONCLUSION: Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.

Evaluation of Antibody Responses in Patients with B-Cell Malignancies after Two and Three Doses of Anti-SARS-CoV-2 S Vaccination-A Retrospective Cohort Study.

Patients with B-cell malignancies are at a higher risk of severe SARS-CoV-2 infections. Nevertheless, extensive data on the immune responses of hematological patients and the efficacy of the third dose of the vaccine are scarce. The goal of this study was to determine standardized anti-SARS-CoV-2 S antibody levels and to evaluate differences between treatment modalities in response to the second and third vaccines among patients with B-cell malignancies treated at the University Hospital Krems and the University Hospital of Vienna. The antibody levels of a total of 80 patients were retrospectively analyzed. The results indicate a significant increase in antibody production in response to the third vaccination. The highest increases could be observed in patients in a "watchful-waiting" and "off-therapy" setting. Encouragingly, approximately one-third of patients who did not develop antibodies in response to two vaccinations achieved seroconversion after the third vaccination. "Watchful-waiting", "off-therapy" and treatment with BTK inhibitors were indicative for increased antibody response after the third dose compared to anti-CD19 CAR T-cell and anti-CD-20 antibody treatment. In summary, the results of this study underline the pre-eminent role of the need for complete vaccination with three doses for the development of protective immunity in patients with B-cell malignancies.

On the continuous (R)evolution of antibody-based and CAR T cell therapies in multiple myeloma: an early 2022 glance into the future.

INTRODUCTION: The pace at which the identification of novel therapeutic targets has led to the approval of multiple myeloma (MM) agents during the last two decades is nothing more than spectacular. Nevertheless, MM remains an incurable disease. Therefore, there is an urgent need for additional, innovative therapeutics. Immune dysfunction and the tumor-permissive immune bone marrow microenvironment represent hallmarks of MM pathophysiology. Naked monoclonal antibodies directed against SLAMF7 and CD38 already constitute backbones of today's MM therapy. Novel immunotherapeutic modalities including antibody-drug-conjugates (ADC), bispecific antibodies (BsAb), and chimeric-antigen-receptor T cells are on the way to once more revolutionize future MM therapy. AREAS COVERED: The present review article summarizes the most recent results on MM immunotherapies presented at the 2021 Annual Meeting of the American Society of Hematology; and throws a glance on ongoing preclinical and clinical efforts aiming at further increasing their efficacy, while reducing their toxicity. EXPERT OPINION: With the approvals of the first-in-class BCMA-targeting ADC (belantamab mafodotin) and two BCMA-targeting CAR T cell products (Ide-cel, Cilta-cel); and the approval of the first-in-class BCMAxCD3 BsAb immediately pending, the era of modern next-generation immunotherapies in MM is continuously evolving. Long-term disease-free survival and potential cure of MM are finally within reach.

Evaluation of diagnostic and treatment approaches to acute dyspnea in a palliative care setting among medical doctors with different educational levels.

BACKGROUND: Dyspnea is common in patients with advanced cancer. Diagnostic procedures in patients with dyspnea are mandatory but often time-consuming and hamper rapid treatment of the underlying refractory symptoms. Opioids are the first-line drugs for the treatment of refractory dyspnea in palliative care patients with advanced lung cancer. METHODS: To evaluate the knowledge levels of medical doctors with different educational levels on the diagnosis of and treatment options for dyspnea in patients with advanced lung cancer in a palliative care setting, a case report and survey were distributed to physicians at the University Hospital Krems, describing acute dyspnea in a 64-year-old stage IV lung cancer patient. A total of 18 diagnostic and 22 therapeutic options were included in the survey. The physicians were asked to suggest and rank in order of preference their diagnosis and treatment options. Statistical analyses of the data were performed, including comparison of the responses of the senior doctors and the physicians in training. RESULTS: A total of 106 surveys were completed. The respondents were 82 senior physicians and 24 physicians in training (response rates of 86% and 80%, respectively). Regarding diagnostic investigations, inspection and reading the patient's chart were the most important diagnostic tools chosen by the respondents. The choices of performing blood gas analysis (p = 0.01) and measurement of oxygen saturation (p = 0.048) revealed a significant difference between the groups, both investigations performed more frequently by the physicians in training. As for non-pharmacological treatment options, providing psychological support was one of the most relevant options selected. A significant difference was seen in choosing the option of improving a patient's position in relation to level of training (65.9% senior physicians vs. 30.4% physicians in training, p = 0.04). Regarding pharmacological treatment options, oxygen application was the most chosen approach. The second most frequent drug chosen was a ß-2 agonist. Only 9.8% of the senior physicians and 8.7% of the physicians in training suggested oral opioids as a treatment option, whereas intravenous opioids were suggested by 43.9% of the senior physicians and 21.7% of the physicians in training (p = 0.089). For subcutaneous application of opioids, the percentage of usage was significantly higher for the physicians in training than for the senior physicians (78.3% vs. 48.8%, p = 0.017, respectively). CONCLUSION: The gold standard treatment for treating refractory dyspnea in patients with advanced lung cancer is opioids. Nevertheless, this pharmacological treatment option was not ranked as the most important. Discussing hypothetical cases of patients with advanced lung cancer and refractory dyspnea with experienced doctors as well as doctors at the beginning of their training may help improve symptom control for these patients.

Evaluation of Ki-67 as a Prognostic Marker in Diffuse Large B-Cell Lymphoma-A Single-Center Retrospective Cohort Study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and prognostic information is essential in finding the right treatment. This study evaluated the prognostic significance of Ki-67 in patients with DLBCL. METHODS: Patients with DLBCL, treated with first-line R-CHOP, were retrospectively analyzed in groups of high (>70%) and low (≤70%) Ki-67. Parameters of interest were the international prognostic index (IPI), treatment response, progression-free survival (PFS) and overall survival (OS). A chi-squared test or Fisher's exact test was conducted to analyze categorical variables. Kaplan-Meier and log-rank tests were applied for survival analyses. Finally, a multivariate linear regression analysis was performed, including gender, Ki-67 ≤ 70% or >70%, IPI and presence of B symptoms. RESULTS: Overall, 58 patients were included. No significant association was found between Ki-67 status and IPI (p = 0.148) or treatment response (p = 0.373). Survival in patients with high Ki-67 was significantly inferior with respect to OS (p = 0.047) but not PFS (p = 0.138). Multivariate linear regression, however, yielded only IPI as a risk factor for OS. CONCLUSION: Future studies with larger patient cohorts are needed in order to elucidate the prognostic role of Ki-67 in patients with DLBCL treated with R-CHOP.

Management of Adverse Events and Supportive Therapy in Relapsed/Refractory Multiple Myeloma.

Relapsed/refractory (RR) multiple myeloma (MM) patients are a fragile population because of prolonged drug exposure and advanced age. Preserving a good quality of life is of high priority for these patients and the treatment of disease- and treatment-related complications plays a key role in their management. By preventing and limiting MM-induced complications, supportive care improves patients' outcome. Erythropoietin-stimulating agents and bisphosphonates are well-established supportive strategies, yet novel agents are under investigation, such as anabolic bone agents and activin receptor-like kinase (ALK) inhibitors. The recent dramatic changes in the treatment landscape of MM pose an additional challenge for the routine care of RRMM patients. Multidrug combinations in first and later lines increase the risk for long-lasting toxicities, including adverse cardiovascular and neurological events. Moreover, recently approved first-in-class drugs have unique side-effect profiles, such as ocular toxicity of belantamab mafodotin or gastrointestinal toxicity of selinexor. This review discusses current standards in supportive treatment of RRMM patients, including recommendations in light of the recent SARS-CoV-19 pandemic, and critically looks at the incidence and management of side effects of standard as well as next generation anti-MM agents.

Evaluation of Antibody Responses to COVID-19 Vaccines among Solid Tumor and Hematologic Patients.

Vaccination is the primary public health strategy to cope with the COVID-19 pandemic. Although solid tumor and hematologic patients are at higher risk of serious COVID-19-related complications, data on immune responses to COVID-19 vaccines in this patient cohort are particularly scarce. The present study, therefore, aimed at the standardized determination of anti-SARS-CoV-2 spike protein antibody titers among non-vaccinated versus vaccinated solid tumor and hematologic patients who are under clinical observation or under treatment at the University Hospital Krems. Standardized anti-SARS-CoV-2 S antibody titers of a total of 441 patients were retrospectively analyzed. Our results show that antibody titers against the SARS-CoV-2 spike protein are significantly higher in solid tumor versus hematologic patients. While SARS-CoV-2 antibody titers were equal among sexes, an age-dependent decrease was observed. Of note, our studies additionally show that complete vaccination represents a valuable predictor for high anti-SARS-CoV-2 antibody responses in solid tumor and hematologic patients. In summary, to date, this is one of the largest studies to comprehensively evaluate the impact of various COVID-19 vaccines on anti-SARS-CoV-2 S antibody production in solid tumor and hematologic patients. Our findings aim to support future vaccination strategies in these highly vulnerable patients, including vaccination booster programs and alternative protective approaches.

Effect of cachexia on bone turnover in cancer patients: a case-control study.

BACKGROUND: Increased bone turnover is frequently observed in advanced cancer and predominantly related to bone metastases or therapy. Cachexia represents an important cause of morbidity and mortality in cancer patients. Key features are weight loss, muscle wasting and chronic inflammation, which induce profound metabolic changes in several organs, including the bone. However, whether cachexia contributes to abnormal bone metabolism in cancer patients is unknown. Aim of the present study was to determine the potential correlation of bone turnover markers with body composition and laboratory parameters in treatment-naïve cancer patients. METHODS: In this cross-sectional study we measured the levels of carboxy terminal telopeptide of collagen (CTX), an indicator of bone resorption, as well as osteocalcin (Ocn) and procollagen type I N-terminal propeptide (PINP), indicators of bone formation, in 52 cancer patients and correlated with body composition and laboratory parameters. Univariate and multivariate logistic analysis were performed to identify determinants of negative bone remodeling balance, estimated by CTX/Ocn and CTX/PINP ratio. RESULTS: Based on weight loss, body mass index and muscle mass, patients were divided into a cachectic (59.6%) and a control (40.4%) group. After correcting for the presence of bone metastases, our results showed a significant upregulation of CTX in cachectic patients compared to non-cachectic cancer patients (median 0.38 vs 0.27 ng/mL, p < 0.05), with no difference in Ocn and PINP levels (mean 14 vs. 16 ng/ml, p = 0.2 and median 32 vs. 26 µg/L, p = 0.5, respectively). In addition, the CTX/Ocn and the CTX/PINP ratio were indicative of bone resorption in 68% and 60% of cachexia patients, respectively (vs. 20% and 31% in the control group, p = 0.002 and p = 0.06). The main determinants of the unbalanced bone turnover were hypoalbuminemia for the CTX/Ocn ratio (OR 19.8, p < 0.01) and high CRP for the CTX/PINP ratio (OR 5.3, p < 0.01) in the multivariate regression analysis. CONCLUSIONS: CTX is substantially higher in cachectic patients compared to non-cachectic oncological patients and hypoalbuminemia as well as elevated CRP concentrations are independent predictors of a negative bone remodeling balance in cancer patients. These results strongly indicate that cachexia correlates with exacerbated bone turnover in cancer.

JunB is a key regulator of multiple myeloma bone marrow angiogenesis.

Bone marrow (BM) angiogenesis significantly influences disease progression in multiple myeloma (MM) patients and correlates with adverse prognosis. The present study shows a statistically significant correlation of the AP-1 family member JunB with VEGF, VEGFB, and IGF1 expression levels in MM. In contrast to the angiogenic master regulator Hif-1α, JunB protein levels were independent of hypoxia. Results in tumor-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs). Consequently, conditioned media derived from MM cells after JunB knockdown or JunB activation either inhibited or stimulated in vitro angiogenesis. The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections. In summary, in continuation of our previous study (Fan et al., 2017), the present report reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of AF transcription and consequently of MM BM angiogenesis. Our results thereby underscore worldwide efforts to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy.

Docetaxel, cisplatin and 5-FU compared with docetaxel, cisplatin and cetuximab as induction chemotherapy in advanced squamous cell carcinoma of the head and neck: Results of a randomised phase II AGMT trial.

PURPOSE: Induction chemotherapy (ICT) with cisplatin (P), 5-FU (F) and taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial, and toxicity and/or delay of radiotherapy (RT) may reduce the potential benefit of this treatment regimen. Here, we report the results of a randomised phase II trial comparing TPF with TP + cetuximab (C). PATIENTS AND METHODS: In this trial, 100 patients with locally advanced stage III or IV SCCHN were included in the analysis. Patients were randomly assigned to either TPF-ICT (N = 49) or TPC-ICT (N = 51), both followed by RT + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished. RESULTS: On an intention-to-treat basis, the ORR (complete remission + partial remission) was 74.5% in the TPC arm compared with 63.3% in the TPF arm (p = 0.109). OS was similar in both arms 400 days after treatment was initiated (86.1% [95% confidence interval {CI}, 73.0-93.1%] in the TPC arm and 78.5% [95% CI, 63.7-87.8%] in the TPF arm). TPC resulted in slightly less serious adverse events and in less haematological, but more skin toxicities. Two patients randomised in the TPC arm died during ICT and RT. Four patients in the TPF arm died after completion of RT. No delay from the end of ICT to RT + C was observed. A total of 83.1% of patients (80% in the TPC arm; 86% in the TPF arm) received RT without dose reduction and/or modification. CONCLUSION: TPC-containing ICT for patients with locally advanced SCCHN was found to be an effective and tolerable one-day regimen. Further prospective evidence from larger trials is warranted.

Evaluation of personalized cancer therapies based on comprehensive genomic profiling in a middle-sized oncologic center in Austria, the University Clinic Krems.

BACKGROUND AND AIM: To successfully apply personalized cancer therapies, thorough understanding of the patient's tumor is needed. In-depth, comprehensive genomic profiling systems allow gathering this knowledge by testing hundreds of cancer-related genes. Several large institutions have established precision oncology programs in recent years with promising results for patients. However, especially middle-sized oncologic institutions face challenges to implement such programs. This study aims to retrospectively analyze the effects of comprehensive genomic tumor profiling with respect to feasibility and effectiveness in a middle-sized oncologic center in Austria. METHODS: From May 1st, 2016 to December 31st, 2019 patients at the University Clinic Krems, who suffered from CUP-syndromes plus patients, who were resistant to conventional therapy or have progressed after all available therapy lines, were offered to get their tumors analyzed by comprehensive genomic profiling in order to establish a customized therapy. RESULTS: Of 69 considered patients, 64 patients' samples could be profiled. The median number of detected alterations was 4 (minimum 0; maximum 23). Most frequent alterations were reported for TP53, KRAS and CDKN2A/B. In 13 patients (20% of 64 successful profiles), personalized therapies could be initiated. 22 patients were treated with another line of chemotherapy as no actionable alteration could be detected. Effectiveness, determined by a PFS of the newly initiated therapy longer than 130% of the last conventional therapy line, could be seen in 8 of 13 patients (61,5%) of the precision oncology cohort compared to only 3 of 22 patients (13,5%) in the chemotherapy group. Additionally, Kaplan-Meier curves of PFS demonstrate a significant benefit for personalized treated patients (p = 0,0165 with a median PFS of 151 days, compared to 83 days in the chemotherapy group). CONCLUSION: In summary, personalized cancer therapy based on comprehensive genomic profiling is effective and feasible also in the setting of a middle-sized oncologic center.

Comparison of nab-paclitaxel plus gemcitabine in elderly versus younger patients with metastatic pancreatic cancer: Analysis of a multicentre, prospective, non-interventional study.

BACKGROUND: Pancreatic cancer (PC) ranks among the deadliest malignancies worldwide. In the MPACT study, first-line nab-paclitaxel plus gemcitabine (nab-P/G) demonstrated activity (median overall survival [OS], 8.7 months) and tolerability in patients with metastatic PC (mPC). However, the clinical evidence of nab-P/G in the elderly (>70 years), who account for the majority of patients with mPC, is limited. This is the first prospective, multicentre, non-interventional study evaluating the tolerability and effectiveness of nab-P/G in younger (≤70 years) versus elderly (>70 years) patients with mPC in the daily clinical routine. METHODS: Eligible patients with mPC were treated with nab-P/G and observed until disease progression or unacceptable toxicity. The primary objectives were safety and tolerability of nab-P/G, and the secondary objectives were efficacy and real-life dosing. RESULTS: A total of 317 patients with mPC (median age, 70 years) were recruited, of which 299, aged ≤70 (n = 162) and >70 (n = 137) years, were eligible for analysis. Baseline characteristics and the safety profile were comparable between the groups. However, fatigue (22.8% versus 13.0%) and decreased appetite (8.8% versus 1.2%) were more frequent in elderly patients. Younger versus elderly patients equally benefited in terms of objective response rate (36% versus 48%), median progression-free survival (5.6 versus 5.5 months; hazard ratio [HR] = 1.03; p = 0.81) and OS (10.6 versus 10.2 months; HR = 0.89; p = 0.4). In addition, the median treatment duration (5 versus 4 cycles), relative dose intensity (70% versus 74%) or reasons for treatment discontinuation were similar. Most patients (56.2% versus 47.4%) benefited from a second-line therapy. CONCLUSION: This prospective real-world analysis confirms the feasibility and tolerability of nab-P/G treatment and reveals OS data similar for younger patients and elderly patients aged >70 years. CLINICALTRIALS. GOV REGISTRATION: NCT02555813. AUSTRIAN NIS REGISTRY: NIS005071.

Efficacy and safety of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC): a systematic literature review.

Background: Therapeutic strategies with immune checkpoint inhibitors (ICIs) counteract the immunosuppressive effects of programmed cell death protein-1 (PD-1) and ligand-1 (PD-L1). ICI treatment has emerged in first- and second-line therapy of non-small cell lung cancer (NSCLC). As immunotherapeutic treatment with ICIs is a dynamic field where new drugs and combinations are constantly evaluated, we conducted an up-to-date systematic review on comparative efficacy and safety in patients with advanced NSCLC. Methods: We searched PubMed up to February 2020 and Embase, CENTRAL, and clinical trial registries up to August 2018. Additionally, we checked reference lists. We dually screened titles, abstracts and, subsequently, full-texts for eligibility. Two reviewers assessed the risk of bias and graded the certainty of evidence following GRADE (Grading of Recommendations Assessment, Development and Evaluation). For second-line therapy, we performed random-effects meta-analyses. Due to considerable clinical heterogeneity, we reported first-line results narratively. Results: Of 1497 references, we identified 22 relevant publications of 16 studies. For first-line therapy, a combination of an ICI with chemotherapy improved progression-free survival and overall survival compared to chemotherapy but increased the risk of serious adverse events. Single-agent pembrolizumab increased overall and progression-free survival in patients with PD-L1 expression of ≥50% and resulted in less TRAE than chemotherapy. Compared to placebo, maintenance therapy with durvalumab increased overall and progression-free survival at the downside of higher risk of TRAE. For second-line therapy, a random-effects meta-analysis yielded a statistically significantly improved overall survival (OS) and progression-free survival (PFS) for ICIs compared to docetaxel (HR 0.69; 95% CI: 0.63-0.75 for OS; HR 0.85; 95% CI: 0.77 - 0.93 for PFS; 6 studies, 3478 patients; median OS benefit in months: 2.4 to 4.2). In meta-analysis, risk of any treatment-related adverse events of any grade was lower for ICI than docetaxel as second-line therapy (RR 0.76, 95% CI: 0.73-0.79; 6 studies, 3763 patients). Conclusion: In first-line therapy of patients with advanced NSCLC, ICI is effective when combined with chemotherapy not depending on PD-L1 expression, or as monotherapy in high PD-L1 expressing tumors. For second-line therapy, single-agent ICI improves efficacy and safety compared to docetaxel.

Retrospective analysis of the prevalence of specialised palliative care services for patients with metastatic breast cancer.

BACKGROUND: Patients with metastatic breast cancer (MBC) have a considerable symptom burden and may require extensive care for a long period of time. Palliative care (PC) has the potential to improve their quality of care and reduce their use of medical services. However, the role of specialised PC (SPC) in patients with MBC remains unclear. PATIENTS AND METHODS: We performed a retrospective analysis of the medical records of patients diagnosed with breast cancer (BC) from 2008 to 2018 at an university-based referral centre to examine the extent of early and late integration of SPC services for patients with MBC. A descriptive analysis of the patients was also established. RESULTS: In all, 932 patients were diagnosed with BC from 2008 to 2018; 225 of these patients had or developed metastases related to their BC. In addition, 132 patients received SPC (58.7%) and 93 patients did not receive SPC (41.3%). The median probability of overall survival (OS) for patients who did not receive SPC services was 3.6 years (95% CI 2.0 to 5.1) and 1.8 years (95% CI 1.3 to 2.3) (p<0.0001) for patients who did receive SPC. In multivariate analysis, referral to SPC services was independently associated with OS (HR 1.60, 95% CI 1.16 to 2.22, p=0.004). CONCLUSION: Patients who received SPC lived significantly shorter amounts of time than patients not referred for SPC services at our hospital. We concluded that the referral to SPC services was often too late and should be implemented earlier in the course of the disease. We suggest that patients with MBC should participate in a consultation by a SPC team ≤60 days after the start of systemic palliative anticancer therapy in addition to endocrine treatment. Larger prospective studies are needed to evaluate the benefit of the early integration of SPC services for patients with MBC.

Reduced LDL-Cholesterol and Reduced Total Cholesterol as Potential Indicators of Early Cancer in Male Treatment-Naïve Cancer Patients With Pre-cachexia and Cachexia.

Cancer cachexia is characterized by the impairment of glucose and lipid homeostasis, the acceleration of processes promoting the mobilization of energy-rich compounds (e.g., insulin resistance, gluconeogenesis, and lipolysis) and the simultaneous activation of highly energy-demanding processes (e.g., systemic inflammation and activation of brown adipose tissue). We hypothesized that these processes might themselves change during cancer cachexia progression, such that plasma levels of glucose and lipids might be used to distinguish between the non-malignant state, pre-cachexia and cachexia. We performed an initial cross-sectional study including 60 treatment naïve cancer patients (38 with cancer cachexia and 22 with cancer pre-cachexia) and 61 patients without malignancy (21 with metabolic syndrome and 40 controls). Differences in lipids (total cholesterol, LDL and HDL cholesterol) and plasma fasting glucose were analyzed across various group configurations, with adjustments to age and antidiabetic or lipid-lowering drugs. Our study showed that levels of LDL cholesterol and total cholesterol might indicate cachexia stages irrespective of the presence of metabolic syndrome or lipid-lowering medication. High levels of plasma glucose were only seen in cachectic cancer patients on antidiabetics. These observations indicate that markers of metabolic dysregulation associated with cachexia progression might be exploited for early detection of malignancy.

The AST/ALT (De Ritis) ratio predicts clinical outcome in patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine: post hoc analysis of an Austrian multicenter, noninterventional study.

BACKGROUND: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. METHODS: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. RESULTS: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06-1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00-1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31-0.94, p = 0.020). CONCLUSIONS: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial.

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL-8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab-containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m2 q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non-obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non-obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.

Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer.

PURPOSE: Recent studies have emphasized a key role for the anti-apoptotic Bcl-2 family member Mcl-1 in conferring tumor cell survival and drug resistance in breast cancer (BC). Mcl-1 inhibitors, such as the BH3-mimetic EU-5346, therefore represent an exciting new class of targeting agents and are a current focus of widespread cancer-drug development efforts. METHODS: ONCOMINE analysis was utilized to compare expression profiles of Bcl-2 family members across all major BC subgroups. Potential toxicities of EU-5346 were evaluated using iPS-generated cardiomyocytes, blood cells and astrocytes. The anti-BC cell activity of EU-5346-based therapies was evaluated using [3H]-thymidine uptake and spheroid-forming assays as well as immunoblotting and the Chou-Talalay method. Protein level-based activity of EU-5346, the specific anti-Bcl-2 inhibitor ABT-199 and the specific anti-Bcl-xL inhibitor WEHI-539 was verified in Mcl-1Δ/null versus Mcl-1wt/wt MEFs. RESULTS: We previously demonstrated significant anti-tumor activity of EU-5346 in all BC subtypes. Our present results go further and suggest that EU-5346 may induce limited adverse events such as cardiotoxicity, hematotoxicity, and neurotoxicity, frequently observed with other BH3 mimetics. As demonstrated by our mathematical scoring model, the prediction of EU-5643-induced IC50 not only relies on the protein level of Mcl-1 but also on Bak, Bim, and Noxa. Synergistic anti-BC activity of low-dose EU-5346 with the BH3 mimetics ABT-199 or WEHI-539 was observed only in those BC cells expressing Bcl-2 or Bcl-xL, respectively. Similarly, when combined with tamoxifen or trastuzumab, low-dose EU-5346 induced significant anti-BC activity in hormone receptor positive or Her2-positive BC cells, respectively. Finally, EU-5346 in combination with paclitaxel induced synergistic anti-BC activity in both paclitaxel-sensitive and paclitaxel-resistant TNBC cells. CONCLUSION: These data strongly support the further clinical development of EU-5346 to improve BC patient survival.

Is Neuronal Histamine Signaling Involved in Cancer Cachexia? Implications and Perspectives.

In this paper, we present evidence in support of our hypothesis that the neuronal histaminergic system might be involved in cancer cachexia. To build our premise, we present the research and the reasonable inferences that can be drawn from it in a section by section approach starting from one of the key issues related to cachexia, increased resting energy expenditure (REE), and progressing to the other, anorexia. Based on an extensive survey of the literature and our own deliberations on the abovementioned topics, we investigate whether histamine signaling might be the mechanism used by a tumor to hijack the body's thermogenic machinery. Our hypothesis in short is that hypothalamic histaminergic neurons are stimulated by inputs from the parasympathetic nervous system (PSNS), which senses tumor traits early in cancer development. Histamine release in the preoptic area of the hypothalamus primarily activates brown adipose tissue (BAT), triggering a highly energy demanding mechanism. Chronic activation of BAT, which, in this context, refers to intermittent and/or low grade activation by the sympathetic nervous system, leads to browning of white adipose tissue and further enhances thermogenic potential. Aberrant histamine signaling not only triggers energy-consuming processes, but also anorexia. Moreover, since functions such as taste, smell, and sleep are governed by discrete structures of the brain, which are targeted by distinct histaminergic neuron populations even relatively minor symptoms of cachexia, such as sleep disturbances and taste and smell distortions, also might be ascribed to aberrant histamine signaling. In late stage cachexia, the sympathetic tone in skeletal muscle breaks down, which we hypothesize might be caused by a reduction in histamine signaling or by the interference of other cachexia related mechanisms. Histamine signaling thus might delineate distinct stages of cachexia progression, with the early phase marked by a PSNS-mediated increase in histamine signaling, increased sympathetic tone and symptomatic adipose tissue depletion, and the late phase characterized by reduced histamine signaling, decreased sympathetic tone and symptomatic muscle wasting. To support our hypothesis, we review the literature from across disciplines and highlight the many commonalities between the mechanisms underlying cancer cachexia and current research findings on the regulation of energy homeostasis (particularly as it relates to hypothalamic histamine signaling). Extrapolating from the current body of knowledge, we develop our hypothetical framework (based on experimentally falsifiable assumptions) about the role of a distinct neuron population in the pathophysiology of cancer cachexia. Our hope is that presenting our ideas will spark discussion about the pathophysiology of cachexia, cancer's devastating and intractable syndrome.