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.

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.

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.

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.

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.

Tolerability of obinutuzumab therapy in patients with rituximab-relapsed/refractory B-cell malignancies - a retrospective single center cohort study.

BACKGROUND & AIM: In randomised clinical trials, the type II anti-CD20 antibody obinutuzumab has been shown to be more effective than rituximab for therapy of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). However, this enhanced efficacy was linked with elevated rates of high-grade adverse events. The aim of this study was to assess the tolerability and toxicity profile of obinutuzumab treatment in routine patients with CLL and FL, of whom the majority had experienced toxicity or resistance to rituximab. METHODS: This retrospective cohort study investigated fifteen obinutuzumab-treated patients, eight with CLL and seven with FL. The course of the disease, comorbidities and treatment-related toxicities were recorded. All patients with CLL and all but three FL patients had any form of pre-treatment with rituximab. RESULTS: Between October 2014 and August 2017, 15 patients were treated with obinutuzumab at the University Hospital Krems. In the CLL-cohort, 1 patient (12,5%) developed pneumonia, 2 (25%) febrile neutropenia, 6 (75%) anemia and 7 (87,5%) thrombocytopenia, respectively. One patient exhibited an infusion-related allergic reaction. In the FL-cohort, 6 patients (85,7%) presented with thrombocytopenia, 3 (42,9%) with anemia and one patient with neutropenia. No sepsis or consecutive solid tumors were seen in any of the patients. CONCLUSION: Obinutuzumab was mostly well tolerated in mild to heavily pre-treated patients with CLL and therapy-naïve or pre-treated patients with FL. The frequency and profile of adverse events and toxicity was comparable to data from previous clinical studies and could be managed adequately in the setting of a University Clinic.

Evaluation of vascular events in patients with myeloproliferative syndromes and mutations of either the januskinase-2 or calreticulin gene at the university hospital Krems from 2008 to 2015.

Myeloproliferative neoplasms (MPN), classified as polycythemia vera (PV), essential thrombocytosis (ET) and myelofibrosis (MF) are stem-cell derived disorders. Mutations in either the januskinase-2 (JAK-2) or the calreticulin (CALR) gene are characteristic for MPN and may result in enhanced proliferation of red blood cells, white blood cells and platelets, and thus increase the risk for vascular events. This study is a retrospective and descriptive analysis of records of patients, who underwent treatment for myeloproliferative syndromes at the Department of Hemato-Oncology of the University hospital Krems from 2008 to the end of 2015. Out of 250 patients, who were suspected for MPN, 51 patients displayed a JAK-2 V617F mutation. These were analyzed with regard to their blood values, gender, age at diagnosis, therapy and vascular events before and after diagnosis (during therapy). Of the 51 patients diagnosed with MPN and a JAK-2 V617F mutation, 33 suffered from PV, 15 from ET and 3 from MF. More men than women were diagnosed with MPN and the median age at diagnosis was 72 years. Acetylsalicylic acid, phlebotomy and Hydroxyurea were the most frequent therapies applied. In our study cohort, the most common vascular events were acute coronary syndrome and transitory ischemic attack. Thromboembolic events were effectively reduced by MPN therapy while no elevation in bleeding events could be observed.

A single-center retrospective analysis of first-line therapy of multiple myeloma with bendamustine-bortezomib-dexamethasone.

The aim of this retrospective study was to evaluate the efficacy and toxicity profile of bendamustine, bortezomib, and dexamethasone (BBD) combination treatment of patients with newly diagnosed multiple myeloma (MM). BBD treatment had a response rate of 80% regarding patients with ≥ partial response (PR). Median time to best response was 87.5 days and PFS was 22 months. Median of OS was not reached. PFS of non-responding patients was significantly shortened compared to those with ≥ PR. No statistically significant differences were determined concerning age (≥ vs. < 68 years) and ISS stage (ISS stage I/II vs. III). Grade 3 hematological effects and grade 3/4 non-hematological effects occurred in 20% and 35% of patients, respectively. Most pronounced hematological adverse event was leukopenia, the most severe non-hematological ones affected the cardiovascular system. In summary, BBD treatment was of acceptable efficacy in patients with newly diagnosed MM and exhibited rather low toxicity.