Spatially Resolved Proteomic and Transcriptomic Profiling of Anaplastic Lymphoma Kinase-Rearranged Pulmonary Adenocarcinomas Reveals Key Players in Inter- and Intratumoral Heterogeneity.

Pulmonary adenocarcinomas (pADCs) with an ALK rearrangement are a rare cancer subtype, necessitating comprehensive molecular investigations to unravel their heterogeneity and improve therapeutic strategies. In this pilot study, we employed spatial transcriptomic (NanoString GeoMx) and proteomic profiling to investigate seven treatment-naïve pADCs with an ALK rearrangement. On each FFPE tumor slide, 12 smaller and 2-6 larger histopathologically annotated regions were selected for transcriptomic and proteomic analysis, respectively. The correlation between proteomics and transcriptomics was modest (average Pearson's r = 0.43 at the gene level). Intertumoral heterogeneity was more pronounced than intratumoral heterogeneity, and normal adjacent tissue exhibited distinct molecular characteristics. We identified potential markers and dysregulated pathways associated with tumors, with a varying extent of immune infiltration, as well as with mucin and stroma content. Notably, some markers appeared to be specific to the ALK-driven subset of pADCs. Our data showed that within tumors, elements of the extracellular matrix, including FN1, exhibited substantial variability. Additionally, we mapped the co-localization patterns of tumor microenvironment elements. This study represents the first spatially resolved profiling of ALK-driven pADCs at both the gene and protein expression levels. Our findings may contribute to a better understanding of this cancer type prior to treatment with ALK inhibitors.

High Tumor-Infiltrating Lymphocyte Count Is Associated with Distinct Gene Expression Profile and Longer Patient Survival in Advanced Ovarian Cancer.

Cancer-related immunity plays a significant role in the outcome of ovarian cancer, but the exact mechanisms are not fully explored. A retrospective, real-life observational study was conducted including 57 advanced ovarian cancer patients. Immunohistochemistry for CD4+, CD8+, and CD45+ was used for assessing tumor-infiltrating immune cells. Furthermore, an immune-related gene expression assay was performed on 12-10 samples from patients with less than and more than 1-year overall survival (OS), respectively. A higher number of CD4+ (p = 0.0028) and CD45+ (p = 0.0221) immune cells within the tumor microenvironment were associated with longer OS of patients. In a multivariate setting, higher CD4+ T cell infiltration predicted longer OS (p = 0.0392). Twenty-three differentially expressed genes-involved in antigen presentation, costimulatory signaling, matrix remodeling, metastasis formation, and myeloid cell activity-were found when comparing the prognostic groups. It was found that tumor-infiltrating immune cell counts are associated with peculiar gene expression patterns and bear prognostic information in ovarian cancer. SOX11 expression emerged and was validated as a predictive marker for OS.

[The occurrence and impact on survival of type 2 diabetes mellitus and thrombocytosis in colorectal cancer, before and after the surgical resection of the primary tumor]. / Colorectalis daganatokban a 2-es típusú cukorbetegség és a thrombocytosis elofordulása, a túlélésre gyakorolt hatásuk, a primer tumor mutéti eltávolítása elott és után.

INTRODUCTION: The relationship between platelets and metastatic tumor cells is an ongoing research area. Pre- and postoperative thrombocytosis are suggested predictive survival markers. Colorectal cancer and type 2 diabetes are characterized by various changes to platelets. The occurrence of colorectal cancer is more frequent in diabetes. AIM: Our aim was to determine the occurrence of type 2 diabetes in colorectal cancer patients, who attended the Semmelweis University 2nd Department of Internal Medicine's Oncology Department in the last three years. Further goals included the evaluation of anamnestic, pre- and postoperative laboratory data, and whether diabetes can be a significant survival factor. METHOD: A retrospective study was conducted with 86 randomly selected colorectal cancer patients' preoperative (86 patients) and paired postoperative (66, who were operable) data. Patients were monitored no later than September 30, 2017 or until their death. RESULTS: Preoperatively, elevated (over 400 Giga/L) platelet counts were present in 22.1% of the patients (323.5 ± 128.63 Giga/L, mean ± SD) which decreased to 10.6% postoperatively (χ2: p = 0.0351; 289.2 ± 82.45 Giga/L, p = 0.0232). Negative correlation was found between platelet counts and overall survival (R: -0.35, p = 0.0085). One third of the patients had diabetes. Laboratory results (i.e., blood counts, creatinine) between diabetic and non-diabetic patients were not significant. Diabetes is a significant five-fold postoperative risk factor for shorter overall survival (relative risk: 5.1612, p = 0.0165). Average survival was 30.6 ± 26.78 months. CONCLUSION: Persistent consequential postoperative thrombocytosis may indicate shorter survival time. Our observations suggest elevated platelet counts and type 2 diabetes as prognostic markers for survival at the recognition of colorectal tumors. Orv Hetil. 2018; 159(19): 756-767.

[The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus]. / A kromogranin-A és a belole lehasadó WE-14 szerepe az 1-es típusú cukorbetegség kialakulásában.

Chromogranin-A is a member of the granine protein family. It is produced in neuroendocrine cells via secretory granules. Many cleavage proteins are formed from chromogranin-A, from which some have well known biological activity, while the function of others is not yet fully known. Serum chromogranin-A levels are used in neuroendocrine tumour diagnostics. Recent studies showed that one of its cleavage protein, WE-14 may also play a role in the development of type 1 diabetes. WE-14 may function as an autoantigen for T-cells involved in the destruction of ß-cells. This mechanism was previously observed only in non-obese diabetic mice. Novel results show that WE-14 also serves as a target for autoreactive cells in newly diagnosed type 1 diabetic patients as well, which reaction can be increased with transglutaminase. In this paper the authors summarize the recent knowledge about chromogranin-A and its potential role in the pathomechanism of type 1 diabetes mellitus.

Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors.

Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.

Surgical Treatment and Outcome of Ovarian Cancer Patients With Liver Metastases: Experience of a Tertiary Hepatic and Peritoneal Surface Malignancy Center.

BACKGROUND/AIM: The aim of this study was to describe and evaluate the patterns, perioperative outcomes, and survival rates of patients subjected to hepatic resections for ovarian-derived liver metastasis as part of cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC). Furthermore, we investigated two subgroups of tumor patterns: hematogenous liver metastasis and infiltrative liver metastatic spread. PATIENTS AND METHODS: A retrospective study was conducted. Patients from a University Tertiary Hepatic and Peritoneal Surface Malignancy Center with primary or recurrent ovarian cancer, who underwent liver resection as part of cytoreductive surgery between January 1992 and December 2022, were included. RESULTS: Data from 35 patients were analyzed. Both median overall survival (OS) and disease-specific survival (DSS) were 24.97 months. In a multivariate setting, the combined effect of age, peritoneal carcinomatosis index, body mass index, hematogenous liver metastasis vs. infiltrative spread types, and HIPEC (HR=0.2372; 95%CI=0.0719-0.7823; p=0.0181) over OS was tested. Survival analysis revealed no differences between the two metastatic spread types (OS: p=0.9720; DSS: p=0.9610). Younger age (p=0.0301), splenectomy (p=0.0320), lesser omentectomy (p=0.0178), and right upper quadrant peritonectomy (p=0.0373) were more characteristic for those patients with infiltrative liver metastatic spread. CONCLUSION: Complete cytoreductive surgery, including hepatic resection is a feasible approach with or without additional HIPEC, which may provide survival benefit for patients with advanced and/or recurrent ovarian cancer. If metastatic and infiltrative liver involvement is suspected, liver-specific imaging is recommended.

Predicting Potentially Fatal COVID-19 Disease in Pregnant Patients Using the Neutrophil-to-Lymphocyte Ratio (NLR).

OBJECTIVE: To evaluate the neutrophil-to-lymphocyte ratio (NLR) values' possible predictive role in fatal and severe cases of COVID-19 disease in pregnant women. Design and data collection: A case-control study was conducted with the inclusion of 45 pregnant COVID-19 patients. All the data were obtained from the hospital information system of Semmelweis University by two of the authors. RESULTS: Statistical analyses showed that NLR values were significantly higher in patients with fatal COVID-19 compared to those who survived the disease, with or without mechanical ventilation. The study also assessed whether NLR values measured on the first day of hospitalization or at their peak provided better markers of disease severity. While both the first-day and peak NLR values were evaluated in patients who did not survive the disease, only the peak NLR values had predictive value regarding patient death. CONCLUSION: Based on our results, the peak NLR values appear to be useful markers of COVID-19 severity, with a cut-off value of 18.05. However, the authors suggest and hope that larger sample size studies will be conducted to further validate the findings of their research.

Changes in the cochlear and retrocochlear parts of the auditory system in 19-39 and 40-60 years old patients with type 1 diabetes mellitus.

Pathophysiological alterations in the cochlea and functional tests of the auditory pathway support that in diabetes both vasculopathy and neural changes could be present. The aim of our research was to study the differential effect of type 1 diabetes mellitus (T1DM) on two different age groups. Audiological investigation was carried out in 42 patients and 25 controls at the same age groups. Investigation of the conductive and sensorineural part of the hearing system by pure tone audiometry, distortion product otoacoustic emission measurement and acoustically evoked brainstem response registration were evaluated. Among the 19-39-year-old people the incidence of hearing impairment was not different in the diabetes and control groups. Among the 40-60-year-old people hearing impairment was more common in the diabetes group (75%) than in the control group (15,4%). Among patients with type 1 diabetes, the mean threshold values were higher in both age groups at all frequencies although significant difference was in 19-39 years old group: 500-4000Hz right ear, 4000Hz left ear, in 40-60 years old group: 4000-8000 Hz both ears. In the 19-39 years old diabetes group only at 8000 Hertz on the left side was a significant (p<0,05) difference in otoacoustic emissions. In the 40-60 years old diabetes group significantly less otoacoustic emissions at 8000 Hz on the right side (p<0,01) and at 4000-6000-8000 Hertz on the left side, (p<0,05, p<0,01, p<0,05 respectively) was present compared to the control group. According to ABR (auditory brainstem response) latencies and wave morphologies, a possible retrocochlear lesion arose in 15% of the 19-39 years old and 25% of the 40-60 years old diabetes group. According to our results, T1DM affects negatively the cochlear function and the neural part of the hearing system. The alterations are more and more detectable with aging.

[Electromagnetic procedures in the treatment of pancreatic cancer: eminent or resentful?] / Elektromágneses eljárások a hasnyálmirigyrák kezelésében: eminens vagy renitens?

The treatment of advanced-stage pancreatic cancers is limited. Previous studies have found that the use of modulated electro-hyperthermia (mEHT) is beneficial in this patient population. However, there is no data on the optimal treatment number and initiation period. Therefore, a retrospective study was conducted with the inclusion of 96 mEHT-treated and 86 age- and sex-matched control pancreatic cancer patients. 76, 57, 38 and 33 patient pairs were enrolled into propensity score matched cohorts, whether they received at least 10, 20, 30 and 40 mEHT treatments, respectively. The survival of patients with at least 30 (HR: 0.5011; p = 0.0041) and 40 (HR: 0.5048; p = 0.0085) mEHT treatments was significantly longer, median survival was almost twice as long (10 vs. 18 months). The introduction of mEHT had the greatest benefit in the first (HR: 0.5382; p = 0.0056) and second (HR: 0.7861; p = 0.0031) 6 months after diagnosis.

Meta-Analysis of Modulated Electro-Hyperthermia and Tumor Treating Fields in the Treatment of Glioblastomas.

BACKGROUND: Glioblastoma is one of the most difficult to treat and most aggressive brain tumors, having a poor survival rate. The use of non-invasive modulated electro-hyperthermia (mEHT) and Tumor Treating Fields (TTF) devices has been introduced in the last few decades, both of which having proven anti-tumor effects. METHODS: A meta-analysis of randomized and observational studies about mEHT and TTF was conducted. RESULTS: A total of seven and fourteen studies about mEHT and TTF were included, with a total number of 450 and 1309 cases, respectively. A 42% [95% confidence interval (95% CI): 25-59%] 1-year survival rate was found for mEHT, which was raised to 61% (95% CI: 32-89%) if only the studies conducted after 2008 were investigated. In the case of TTF, 1-year survival was 67% (95% CI: 53-81%). Subgroup analyses revealed that newly diagnosed patients might get extra benefits from the early introduction of the devices (mEHT all studies: 73% vs. 37%, p = 0.0021; mEHT studies after 2008: 73% vs. 54%, p = 0.4214; TTF studies: 83% vs. 52%, p = 0.0083), compared with recurrent glioblastoma. CONCLUSIONS: Our meta-analysis showed that both mEHT and TTF can improve glioblastoma survival, and the most benefit may be achieved in newly diagnosed cases.

Influence of the duration of type 2 diabetes mellitus on colorectal cancer outcomes.

Type 2 diabetes mellitus (T2DM) is a progressive disease, which affects colorectal cancer (CRC) survival. However, data on the relationship between CRC survival and T2DM duration is scarce and controversial. A retrospective observational study was conducted. Sub-cohorts were created based on the duration of T2DM as follows, ≤ or > 5/10/15/20 years. 204 of the 817 (24.95%) included study participants had T2DM at any point of CRC. 160 of the 204 CRC + T2DM patients had detailed T2DM duration data. At the time of CRC diagnosis, 85, 50, 31, and 11 patients had T2DM for > 5/10/15/20 years, respectively, which increased to 110, 71, 45, and 17 during the course of the study. Despite constant glycated hemoglobin values throughout the study, shorter overall and disease-specific survival times were observed for the > 5/10/15 years cohorts and longitudinal survival modeling techniques confirmed the significant effect of T2DM duration in all cohorts. While in the first 3 years after CRC diagnosis, the best survival was found for the ≤ 5 years cohort, all diabetes cohorts had the same survival thereafter. T2DM duration affected CRC survival significantly, therefore, a closer follow-up of this sub-populations is suggested.

Prolonged hyperthermic intraperitoneal chemotherapy duration with 90 minutes cisplatin might increase overall survival in gastric cancer patients with peritoneal metastases.

BACKGROUND: Advanced gastric cancer with synchronous peritoneal metastases (GC-PM) is associated with a poor prognosis. Although cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a promising approach, only a limited number of Western studies exist. AIM: To investigate the clinicopathological outcomes of patients who underwent CRS-HIPEC for GC-PM. METHODS: A retrospective analysis of patients with GC-PM was conducted. All patients were seen at the Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, Germany between January 2011 and July 2021 and underwent CRS-HIPEC. Preoperative laboratory results, the use of neoadjuvant trastuzumab, and the details of CRS-HIPEC, including peritoneal carcinomatosis index, completeness of cytoreduction, and surgical procedures were recorded. Disease-specific (DSS), and overall survival (OS) of patients were calculated. RESULTS: A total of 73 patients were included in the study. Patients treated with neoadjuvant trastuzumab (n = 5) showed longer DSS (P = 0.0482). Higher white blood cell counts (DSS: P = 0.0433) and carcinoembryonic antigen levels (OS and DSS: P < 0.01), and lower hemoglobin (OS and DSS: P < 0.05) and serum total protein (OS: P = 0.0368) levels were associated with shorter survival. Longer HIPEC duration was associated with more advantageous median survival times [60-min (n = 59): 12.86 mo; 90-min (n = 14): 27.30 mo], but without statistical difference. To obtain additional data from this observation, further separation of the study population was performed. First, propensity score-matched patient pairs (n = 14 in each group) were created. Statistically different DSS was found between patient pairs (hazard ratio = 0.2843; 95% confidence interval: 0.1119-0.7222; P = 0.0082). Second, those patients who were treated with trastuzumab and/or had human epidermal growth factor receptor 2 positivity (median survival: 12.68 mo vs 24.02 mo), or had to undergo the procedure before 2016 (median survival: 12.68 mo vs 27.30 mo; P = 0.0493) were removed from the original study population. CONCLUSION: Based on our experience, CRS-HIPEC is a safe and secure method to improve the survival of advanced GC-PM patients. Prolonged HIPEC duration may serve as a good therapy for these patients.

Comparison of the effectiveness of integrative immunomodulatory treatments and conventional therapies on the survival of selected gastrointestinal cancer patients.

In the last decade, the use of immunomodulating treatments (IMT) at integrative oncology providers (IOP) increased. IMTs are used to modulate the tumor microenvironment, which might lead to increased response-to-treatment, and the indication of immune checkpoint inhibitors might also be widened. The efficacy and safety of IMTs in advanced/metastatic gastrointestinal cancers were compared with conventional chemo(radio)therapy (CT). 21 colorectal- (CRC), 14 pancreatic- (PC), 5 cholangiocellular- (CCC), 5 gastric- (GC) and 4 esophageal cancer (EC) patients received IMT. IMT and CT were compared in CRC and PC. CT was administered at an academic oncology center. After the initiation of IMT, a median survival of ~ 20 (CRC, PC and EC) and ~ 10 months (CCC and GC) was observed. Of the IMTs, locoregional modulated electro-hyperthermia had the most positive effect on overall survival (HR: 0.3055; P = 0.0260), while fever-inducing interleukin-2, and low-dose ipilimumab showed a positive tendency. IMT was superior to CT in PC (HR: 0.1974; P = 0.0013), while modest effect was detected in CRC (HR: 0.7797; P = 0.4710). When the whole study population was analyzed, IMTs showed minimal effect on patient survival, still CT had the greatest effect if introduced as early as possible (HR: 0.0624; P < 0.0001). The integrative IMTs in the presented form have mild impact on gastrointestinal cancer patients' survival, however, we observed its benefit in PC, which warrants further investigations.

Prognostic Factors in Pseudomyxoma Peritonei with Emphasis on the Predictive Role of Peritoneal Cancer Index and Tumor Markers.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare peritoneal condition where mucus-secreting tumorous cells progressively produce a thick, gelatin-like substance. The prognosis of patients with PMP is determined by the degree of cellularity within the mucin (low-grade (LAMN) vs. high-grade (HAMN) histologic features) and by the extent of the disease. METHODS: Prognostic relevance of tumor markers CA19-9 and CEA, gender, Peritoneal Cancer Index (PCI), and completeness of cytoreduction (CC) after cytoreductive surgery were evaluated on 193 consecutive PMP patients, based on a retrospective analysis of prospectively gathered data from a German tertial referral center. RESULTS: We demonstrated that low PCI, CC0 status, low-grade histology, and female gender were independent positive prognostic factors for both overall survival (OS) and progression-free survival (PFS). Furthermore, LAMN patients with achieved CC0 status show significantly better OS and PFS compared to those with CC1 status (p = 0.0353 and p = 0.0026 respectively). In contrast, the duration and drug of hyperthermic intraperitoneal chemotherapy (HIPEC) were not prognostic in any comparison. Increased CA19-9 and CEA levels were significantly associated with HAMN cases, but also predicted recurrence in patients with low-grade histologies. CONCLUSION: Our study confirmed the prognostic role of tumor markers and emphasized the importance of CC status and PCI in a large cohort of PMP- and LAMN patients.

The Prediction Analysis of Microarray 50 (PAM50) Gene Expression Classifier Utilized in Indeterminate-Risk Breast Cancer Patients in Hungary: A Consecutive 5-Year Experience.

BACKGROUND: Breast cancer has been categorized into molecular subtypes using immunohistochemical staining (IHC) and fluorescence in situ hybridization (FISH) since the early 2000s. However, recent research suggests that gene expression testing, specifically Prosigna® Prediction Analysis of Microarray 50 (PAM50), provides more accurate classification methods. In this retrospective study, we compared the results of IHC/FISH and PAM50 testing. We also examined the impact of various PAM50 parameters on overall survival (OS) and progression-free survival (PFS). RESULTS: We analyzed 42 unilateral breast cancer samples, with 18 classified as luminal A, 10 as luminal B, 8 as Human epidermal growth factor receptor 2 (HER2)-positive, and 6 as basal-like using PAM50. Interestingly, 17 out of the 42 samples (40.47%) showed discordant results between histopathological assessment and the PAM50 classifier. While routine IHC/FISH resulted in classification differences for a quarter to a third of samples within each subtype, all basal-like tumors were misclassified. Hormone receptor-positive tumors (hazard rate: 8.7803; p = 0.0085) and patients who had higher 10-year recurrence risk scores (hazard rate: 1.0539; p = 0.0201) had shorter OS and PFS. CONCLUSIONS: Our study supports the existing understanding of molecular subtypes in breast cancer and emphasizes the overlap between clinical characteristics and molecular subtyping. These findings underscore the value of gene expression profiling, such as PAM50, in improving treatment decisions for breast cancer patients.

New therapeutic approaches for type 1 diabetes: Disease-modifying therapies.

It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of ß-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent ß-cell destruction. T1DM patients with better ß-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting ß cells are usually lost. Therefore, to maximize the salvageable ß-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.

High plasma CD40 ligand level is associated with more advanced stages and worse prognosis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is often associated with elevated platelet count (> 400 × 109/L), known as thrombocytosis. The role of CD40 ligand (CD40L), a member of the tumor necrosis factor family, is controversial in CRC. Circulating CD40L is higher in CRC, but its relationship with disease staging and local and distant metastasis is not clear. Although most of the circulating CD40L is produced by platelets, no previous study investigated its relationship with CRC-related thrombocytosis. AIM: To investigate the role of CD40L to predict the outcome of CRC and its relation to thrombocytosis. METHODS: A total of 106 CRC patients and 50 age and sex-matched control subjects were enrolled for the study. Anamnestic data including comorbidities and histopathological data were collected. Laboratory measurements were performed at the time of CRC diagnosis and 1.5 mo and at least 6 mo after the surgical removal of the tumor. Plasma CD40L and thrombopoietin were measured via enzyme-linked immunosorbent assay, while plasma interleukin-6 was measured via electrochemiluminescence immunoassay. Patient follow-ups were terminated on January 31, 2021. RESULTS: Plasma CD40L of CRC patients was tendentiously higher, while platelet count (P = 0.0479), interleukin-6 (P = 0.0002), and thrombopoietin (P = 0.0024) levels were significantly higher as opposed to the control subjects. Twelve of the 106 CRC patients (11.3%) had thrombocytosis. Significantly higher CD40L was found in the presence of distant metastases (P = 0.0055) and/or thrombocytosis (P = 0.0294). A connection was found between CD40L and platelet count (P = 0.0045), interleukin-6 (P = 0.0130), and thrombocytosis (P = 0.0155). CD40L was constant with the course of CRC, and all baseline differences persisted throughout the whole study. Both pre- and postoperative elevated platelet count, CD40L, and interleukin-6 level were associated with poor overall and disease-specific survival of patients. The negative effect of CD40L and interleukin-6 on patient survival remained even after the stratification by thrombocytosis. CONCLUSION: CD40L levels of CRC patients do not change with the course of the disease. The CD40L level is strongly correlated with platelet count, interleukin-6, thrombocytosis, and the presence of distant metastases.

Prolonged Exposition with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) May Provide Survival Benefit after Cytoreductive Surgery (CRS) in Advanced Primary Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancer.

Background: The usage of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gynecological cancers is increasing. Methods: Prospectively collected data of 85 advanced primary ovarian/fallopian tube cancer and peritoneal carcinoma patients of a single center were investigated. Results: A total 48, 37, 62, and 25 patients were enrolled into the HIPEC with/without neoadjuvant chemotherapy (upfront vs. interval) and into the 60 min and 90 min long HIPEC groups, respectively. Better overall survival (OS) was observed in the 90 min HIPEC group (p = 0.0330), compared to the 60 min HIPEC group. Neither OS (p = 0. 2410), disease-specific (p = 0. 3670), nor recurrence-free survival (p = 0.8240) differed between upfront and interval HIPEC. Higher peritoneal carcinomatosis index (PCI) values were associated with worse disease-specific survival (p = 0.0724). Age (p = 0.0416), body mass index (p = 0.0044), PCI (p < 0.0001), the type (p = 0.0016) and duration (p = 0.0012) of HIPEC, and increased perioperative morbidity (p < 0.0041) had the greatest impact on OS. Conclusions: Increasing data support the value of HIPEC in the treatment of advanced ovarian cancer. Ongoing prospective studies will definitively clarify the role and timing of this additional therapeutic approach.

Longitudinal Analysis of 1α,25-dihidroxyvitamin D3 and Homocysteine Changes in Colorectal Cancer.

BACKGROUND: 1α,25-dihydroxycholecalciferol (1,25(OH)2D3) and homocysteine are known to play a role in the pathophysiology of colorectal cancer (CRC). In health, the two changes are inversely proportional to each other, but little is known about their combined effect in CRC. METHODS: The serum 1,25(OH)2D3 and the homocysteine levels of eighty-six CRC patients were measured, who were enrolled into four cohorts based on the presence of metastases (Adj vs. Met) and vitamin D3 supplementation (ND vs. D). RESULTS: 1,25(OH)2D3 was constant (Adj-ND), increased significantly (Adj-D, p = 0.0261), decreased (Met-ND), or returned close to the baseline after an initial increase (Met-D). The longitudinal increase in 1,25(OH)2D3 (HR: 0.9130, p = 0.0111) positively affected the overall survival in non-metastatic CRC, however, this effect was cancelled out in those with metastasis (p = 0.0107). The increase in homocysteine negatively affected both the overall (HR: 1.0940, p = 0.0067) and the progression-free survival (HR: 1.0845, p = 0.0073). Lower 1,25(OH)2D3 and/or higher homocysteine level was characteristic for patients with higher serum lipids, albumin, total protein, white blood cell and platelet count, male sex, and right-sided tumors. No statistically justifiable connection was found between the target variables. CONCLUSIONS: A measurement-based titration of vitamin D3 supplementation and better management of comorbidities are recommended for CRC.

Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?

BACKGROUND: A large variety of factors can affect colorectal cancer (CRC) survival, including type 2 diabetes mellitus (T2DM) and paraneoplastic thrombocytosis. Although several common factors play a role in their development and platelets are damaged in both diseases, the combined relationship of the three conditions was never investigated previously. METHODS: A prospective, real-life observational cohort study was conducted with the inclusion of 108 CRC patients and 166 voluntary non-CRC subjects. Plasma interleukin-6 and thrombopoietin levels were measured. RESULTS: Study participants were divided into cohorts based on the presence of T2DM. Platelet count (p < 0.0500) and interleukin-6 (p < 0.0100) level were significantly higher in the CRC groups. Thrombopoietin level was higher in the T2DM, CRC, and CRC + T2DM groups (p < 0.0500). Analysis of parameter changes over time and survival models revealed that neither platelet count, interleukin-6, nor thrombopoietin levels were affected by T2DM. Death of patients was associated with higher baseline platelet count (p = 0.0042) and interleukin-6 level (p < 0.0001). CONCLUSION: Although the independent, disease-worsening effect of paraneoplastic thrombocytosis and T2DM is known, the coexistence of the two did not further impair the survival of CRC patients, suggesting that T2DM has no significant effect over paraneoplastic thrombocytosis.