The Impact of Sidedness on the Efficacy of Anti-EGFR-Based First-Line Chemotherapy in Advanced Colorectal Cancer Patients in Real-Life Setting-A Nation-Wide Retrospective Analysis (RACER).

Anti-EGFR antibodies combined with chemotherapy doublets are a cornerstone of the upfront treatment of colorectal cancer. RAS and BRAF mutations are established negative predictive factors for such therapy. The primary tumour located in the proximal colon has recently emerged as another negative predictive factor. We have conducted a retrospective multicentre study to collect data on real-world population characteristics, practice patterns, and outcomes in patients with metastatic colorectal cancer treated in a first-line setting with either cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI chemotherapy. The presented analysis focuses on the impact of the primary tumour location. 126 of 842 patients analysed (15.0%) had proximal primary. It was associated with a lower BMI at diagnosis, mucinous histology, and peritoneal metastases. It was also associated with inferior treatment outcomes in terms of response ratio: 59.4% vs. 74.22% (odds ratio [OR] 0.51, 95% CI 0.33-0.78, p = 0.010), and median depth of response: -36.7% vs. -50.0% (p = 0.038). There was only a borderline non-significant trend for inferior PFS in patients with proximal tumours. OS data was incomplete. The presented analysis confirms the negative impact of tumour sidedness on the efficacy of an upfront anti-EGFR-chemotherapy combination and provides valuable data on real-world population characteristics.

Clinical Characterization of Targetable Mutations (BRAF V600E and KRAS G12C) in Advanced Colorectal Cancer-A Nation-Wide Study.

BRAF V600E and KRAS mutations that occur in colorectal cancer (CRC) define a subpopulation of patients with an inferior prognosis. Recently, the first BRAF V600E-targeting therapy has been approved and novel agents targeting KRAS G12C are being evaluated in CRC. A better understanding of the clinical characteristics of the populations defined by those mutations is needed. We created a retrospective database that collects clinical characteristics of patients with metastatic CRC evaluated for RAS and BRAF mutations in a single laboratory. A total of 7604 patients tested between October 2017 and December 2019 were included in the analysis. The prevalence of BRAF V600E was 6.77%. Female sex, primary in the right colon, high-grade, mucinous, signet cell, partially neuroendocrine histology, perineural and vascular invasion, and surgical tissue sample were factors associated with increased mutation rates. The prevalence of KRAS G12C was 3.11%. Cancer of primary origin in the left colon and in samples from brain metastases were associated with increased mutation rates. The high prevalence of the BRAF V600E mutation in cancers with a neuroendocrine component identifies a potential candidate population for BRAF inhibition. The association of KRAS G12C with the left part of the intestine and brain metastases of CRC are new findings and require further investigation.

Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer.

Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the availability of active therapies and their applicability to often fragile, exhausted patients with poor performance status. Metronomic chemotherapy (MC) is a concept of a continuous administration of cytotoxic drugs, which is characterized by multidirectional activity (anti-proliferative, anti-angiogenic, and anti-immunosuppressive) and low toxicity. We have performed a retrospective analysis of consecutive, advanced, chemo-refractory OC patients treated with MC based on single-agent topotecan (1 mg p.o. q2d) or on a topotecan (1 mg q2d) and cyclophosphamide (50 mg p.o. qd) combination (CyTo). Metronomic chemotherapy demonstrated promising activity, with 72% and 86% of patients achieving biochemical or objective disease control and 18% and 27% of patients achieving a biochemical or objective response, respectively. The median PFS in the whole population was 3.65 months, but the median PFS in patients with a biochemical response to MC (18.2% of patients) reached 10.7 months. The study also suggested that overweight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m2. This article is the first report in the literature on metronomic chemotherapy based on a topotecan + cyclophosphamide combination (CyTo). The CyTo regimen demonstrated safety, clinical activity, and potential broad clinical applicability in advanced OC patients and will be evaluated in a forthcoming clinical trial.

Metronomic Chemo-Endocrine Therapy (FulVEC) as a Salvage Treatment for Patients with Advanced, Treatment-Refractory ER+/HER2-Breast Cancer-A Retrospective Analysis of Consecutive Patients Data.

BACKGROUND: Breast cancer, with 2.3 million new cases and 0.7 million deaths every year, represents a great medical challenge worldwide. These numbers confirm that approx. 30% of BC patients will develop an incurable disease requiring life-long, palliative systemic treatment. Endocrine treatment and chemotherapy administered in a sequential fashion are the basic treatment options in advanced ER+/HER2- BC, which is the most common BC type. The palliative, long-term treatment of advanced BC should not only be highly active but also minimally toxic to allow long-term survival with the optimal quality of life. A combination of metronomic chemotherapy (MC) with endocrine treatment (ET) in patients who failed earlier lines of ET represents an interesting and promising option. METHODS: The methodology includes retrospective data analyses of pretreated, metastatic ER+/HER2- BC (mBC) patients who were treated with the FulVEC regimen combining fulvestrant and MC (cyclophosphamide, vinorelbine, and capecitabine). RESULTS: Thirty-nine previously treated (median 2 lines 1-9) mBC patients received FulVEC. The median PFS and OS were 8.4 and 21.5 months, respectively. Biochemical responses (CA-15.3 serum marker decline ≥50%) were observed in 48.7%, and any increase in CA-15.3 was observed in 23.1% of patients. The activity of FulVEC was independent of previous treatments with fulvestrant of cytotoxic components of the FulVEC regimen. The treatment was safe and well tolerated. CONCLUSIONS: Metronomic chemo-endocrine therapy with FulVEC regimen represents an interesting option and compares favorably with other approaches in patients' refractory to endocrine treatments. A phase II randomized trial is warranted.

Reduction of Cancer-Induced Thrombocytosis as a Biomarker of Improved Outcomes in Advanced Gastric Cancer.

BACKGROUND: Interplay between non-specific inflammatory reaction and tumor microenvironment in gastric cancer (GC) can be measured indirectly by assessing fluctuations in concentration of platelets. Cytotoxic chemotherapy affects these morphotic elements directly by inducing myelosuppression. It was hypothesized that chemotherapy not only directly affects malignant cells, but also through immunomodulation related to myelosuppression. METHODS: Metastatic GC patients (N: 155) treated with chemotherapy +/- trastuzumab were enrolled in this retrospective study. Platelet pretreatment concentration (PLT-count) and the deepest level of platelet reduction, as well as other inflammatory and general confounders were collected in the first 12 weeks of treatment (PLT-red). Martingale residuals were used to visualize the relationship between PLT-count, PLT-red, and overall survival (OS). Multiple multivariate Cox regression models were built to assess the impact of platelet reduction on OS and progression-free survival (PFS). RESULTS: Reduction of PLT (PLT-red) to 60% of baseline concentration was associated with improved survival rates (HR = 0.60, p = 0.026 for OS and HR 0.56, p = 0.015 for PFS). Cross-classification into four groups based on PLT-count (high vs low) and PLT-red (high vs low) showed significantly worse survival rates in both high PLT-count (HR = 3.60, p = 0.007 for OS and HR = 2.97, p = 0.024 for PFS) and low PLT-count (HR = 1.75, p = 0.035 for OS and HR = 1.80, p = 0.028 for PFS) patients with insufficient platelets reduction. CONCLUSION: Thrombocytosis reduction represents a novel, clinically important, prognostic factor for OS and PFS in patients with stage IV GC.

Combined Neutrophil-to-Lymphocyte and Platelet-Volume-to-Platelet Ratio (NLR and PVPR Score) Represents a Novel Prognostic Factor in Advanced Gastric Cancer Patients.

BACKGROUND: Chemotherapy is a cornerstone of treatment in advanced gastric cancer (GC) with a proven impact on overall survival, however, reliable predictive markers are missing. The role of various inflammatory markers has been tested in gastric cancer patients, but there is still no general consensus on their true clinical applicability. High neutrophil-to-lymphocyte (NLR) and low (medium)-platelets-volume-to-platelet ratio (PVPR) are known markers of unspecific immune system activation, correlating significantly with outcomes in advanced GC patients. METHODS: Metastatic GC patients (N:155) treated with chemotherapy +/- trastuzumab were enrolled in this retrospective study. Pre-treatment NLR and PVPR, as well as other inflammatory markers were measured in peripheral blood. Univariate Cox regression was conducted to find markers with a significant impact on overall survival (OS) and progression-free survival (PFS). Spearman correlation and Cohen's kappa was used to analyze multicollinearity. Multiple multivariable Cox regression models were built to study the combined impact of NLR and PVPR, as well as other known prognostic factors on OS. RESULTS: Elevated NLR was significantly associated with increased risk of death (HR = 1.95; 95% CI: 1.17-3.24), and lower PVPR was significantly associated with improved outcomes (HR = 0.53; 95% CI: 0.32-0.90). A novel inflammatory marker, based on a combination of NLR and PVPR, allows for the classification of GC patients into three prognostic groups, characterized by median OS of 8.4 months (95% CI 5.8-11.1), 10.5 months (95% CI 8.8-12.1), and 15.9 months (95% CI 13.5-18.3). CONCLUSION: The NLR and PVPR score (elevated NLR and decreased PVPR) is a marker of detrimental outcome of advanced GC patients treated with chemotherapy.

Anthracycline-induced cardiotoxicity prevention with angiotensin-converting enzyme inhibitor ramipril in women with low-risk breast cancer: results of a prospective randomized study.

BACKGROUND: Anthracycline­induced cardiotoxicity (AIC) remains the main long­term irreversible side effect in malignancy survivors. Cardiotoxicity prevention is one of the most reasonable approaches. AIMS: In this prospective randomized open­label study, we aimed to verify whether ramipril protects from early­onset AIC in women with breast cancer (BC). METHODS: We analyzed data from 96 women (median age, 47 years) with BC after breast surgery, without significant cardiovascular diseases, who were eligible for adjuvant anthracyclines. They were randomized to a ramipril or control arm. Cardiotoxicity was estimated with repeat echocardiography and themeasurement of troponin I and N­terminal fragment of the prohormone brain natriuretic peptide (NT­proBNP) levels over 1­year follow­up. Anthracycline­induced cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF), elevated biomarker levels, and/or occurrence of heart failure (HF) or cardiac death. RESULTS: A decrease in LVEF above 10­percent points occurred in 6.3% of ramipril patients and 18.5% ofcontrols (P = 0.15). No cases of HF, cardiac death, or LVEF decline below 50% were reported. The percentage of patients with elevated NT­proBNP levels increased with time in controls (P = 0.003) and remained unchanged in the ramipril arm. At the end of follow­up, an increase in NT­proBNP levels was more common and decline was less common in the control than ramipril arm (P = 0.01). No significant differences in troponin levels were found between the study arms. Ramipril was well tolerated in normotensive women. CONCLUSIONS: In relatively young women with BC without serious comorbidities, who received anthracyclines, 1­year treatment with ramipril exerts potentially protective effects on cardiotoxicity assessed with NT­proBNP levels.

Postoperative complications are associated with worse survival after laparoscopic surgery for non-metastatic colorectal cancer - interim analysis of 3-year overall survival.

INTRODUCTION: Postoperative morbidity after colorectal resections for cancer remains a significant problem. Data on the influence of complications on survival after laparoscopic colorectal resection are still limited. AIM: To analyze the impact of postoperative complications on long-term survival after radical laparoscopic resection for colorectal cancer. MATERIAL AND METHODS: Two hundred and sixty-five consecutive non-metastatic colorectal cancer patients undergoing laparoscopic colorectal resection for cancer were included in the analysis. The entire study group was divided into two subgroups based on the occurrence of postoperative complications. Group 1 included patients without postoperative morbidity and group 2 included patients with complications. The primary outcome was overall survival. RESULTS: Median follow-up was 45 (IQR: 34-55) months. Group 1 consisted of 187 (70.5%) patients and group 2 comprised 78 (29.5%) patients. Studied groups were comparable in terms of sex, age, body mass index, ASA class, cancer staging, localization of the tumor and operative time. Patients in group 1 had significantly better overall 3-year survival compared to those with complications (84.9% vs. 69.8%, p = 0.022). Kaplan-Meier curves showed significantly improved survival rates in patients without complications compared with complicated cases. The Cox proportional multivariate model showed that postoperative complications (HR = 2.83; 95% CI: 1.35-5.92; p = 0.0058) and AJCC III (HR = 3.17; 95% CI: 1.52-6.6; p = 0.0021) were independent predictors of worse survival after laparoscopic colorectal cancer surgery. CONCLUSIONS: Our analysis of interim results after 3 years confirms that complications after laparoscopic colorectal cancer surgery have an impact on survival. For this reason, these patients should be carefully monitored after surgery aiming at early detection of recurrence.

The relationship between breast cancer treatment, tumour type and vitamin D level in pre- and postmenopausal women.

OBJECTIVE: Vitamin D deficiency has been linked to a higher risk of cancer. There is insufficient data regarding the influence of treatment on vitamin D status. The aim of this study was to compare pre- and post-treatment levels of 25(OH)D in premenopausal and postmenopausal women with breast cancer with a different receptor status (ER-estrogen receptors, PR-progesterone receptors) and in healthy controls. METHODS: 49 patients with breast cancer (23 premenopausal), and 28 healthy controls matched for age, menopausal status and BMI. RESULTS: The pre-treatment levels of 25(OH)D in patients with breast cancer were significantly lower in comparison to the control group (19 ng/mL vs. 30 ng/mL, p<0.001), the lowest in premenopausal women (18.4 ng/mL). After the treatment period, a significant decrease in 25(OH)D level (mean 15.8 ng/mL) was observed. The pre-treatment level of 25(OH)D was significantly lower in patients with ER (16.1 vs. 23.9 ng/mL, p=0.02) and with PR (15 vs. 24.4 ng/mL, p=0.003). The mean pre- and post-treatment levels of 25(OH)D were lower in patients with Ki67 <21% (16.7 vs. 20.1 ng/mL, p=0.15; 12.5 vs. 18.1 ng/mL, p=0.02 respectively). CONCLUSIONS: 25(OH)D level is lower in patients with breast cancer in comparison to healthy women, regardless of their menopausal status. The lowest levels are found in patients with ER and PR positive tumours. While a significant decrease in 25(OH)D level during the course of therapy is observed, the supplementation of vitamin D should be considered.

Electrochemotherapy in the Treatment of Massive, Multisite Breast Cancer Metastasis to the Skin and Subcutaneous Tissue: A Case Report.

BACKGROUND: Chest wall recurrence (CWR) from breast cancer after mastectomy is a difficult to treat disease. Electrochemotherapy (ECT) provides a safe, efficient, and non-invasive locoregional treatment approach in this setting. CASE REPORT: A 61-year-old woman presented with unresectable breast cancer recurrence to the skin and subcutaneous tissue for which numerous lines of treatment were unsuccessful. Between February 2015 and May 2015, the patient underwent 3 courses of ECT after which a spectacular regression of the cutaneous metastatic foci was observed. After an overall observation period of 12 weeks, complete clinical remission was achieved. CONCLUSION: ECT can be proposed as an effective and safe locoregional therapy for breast cancer CWR and provides an alternative treatment modality to conventional therapies, especially in the case of multiple cutaneous and subcutaneous lesions.

Which aspects of long-term outcome are predicted by positive and negative symptoms in early-onset psychosis? An exploratory eight-year follow-up study.

BACKGROUND: Early-onset psychoses show substantial variability of diagnostic and functional outcome. Finding reliable prognostic factors may allow to allocate resources to those with the worst prognosis. The aim of the study was to gain new insights regarding the potential value of baseline negative and positive symptoms as predictors of outcome in psychoses of early onset. METHOD: Sixty-three patients with early-onset schizophrenia spectrum psychosis hospitalized in an adolescent psychiatry unit were assessed with the Positive and Negative Syndrome Scale during the index admission. Associations with diagnosis, illness course and functional outcome were analysed in mean 8 years of follow-up (range 3.4-13.5 years). RESULTS: The mean age at the index admission and the follow-up was 16.6 ± 1.2 and 24.5 ± 3.0 years, respectively. A significant majority of subjects continued psychiatric treatment (95%) and had been readmitted (71%). The mortality rate was 3% (suicide and accident). Negative symptoms were related to mental health service utilization during the follow-up. General severity of symptoms, specifically positive and cognitive factors were associated with the diagnosis of schizophrenia and inversely with diagnostic shift outside the schizophrenia spectrum at the catamnesis. Poor impulse control at baseline was associated with worse functional outcome. The drug-free subgroup with no occupational/educational activity compared with the drug-treated subjects showed lower levels of baseline negative symptomatology. CONCLUSION: The study findings suggest that in patients with early-onset psychosis negative and positive symptoms show a differential prognostic value. Pharmacotherapy may attenuate the effect of symptoms on functional outcome. These hypotheses need to be tested in future studies using confirmatory approaches.

[Retrospective analysis of psychopathological presentation of psychotic episodes in adolescent inpatients]. / Retrospektywna analiza obrazu psychopatologicznego epizodów psychotycznych u hospitalizowanej mlodziezy.

AIM: Analysis of a clinical presentation and course of psychotic episodes in adolescent inpatients. METHOD: A retrospective analysis of charts of all (n=104) inpatients diagnosed with one of the schizophrenia-spectrum disorders (schizophrenia, schizotypal disorder and acute and transient psychotic disorders: F20, F21 and F23 according to ICD-10) and assessed with the Positive and Negative Syndrome Scale (PANSS) over a 10-year period (1998-2008) in the Child and Adolescent Psychiatry Department. A psychopathological profile of different disorders and correlation between symptoms and demographic and clinical data were analysed. RESULTS: Severity of symptoms correlated with length of hospitalisation. In schizophrenia higher PANSS total score and more severe some general symptoms then in schizotypal disorders were observed. Also in schizophrenia more negative symptoms then in acute and transient psychotic disorders were detected. In all three disorders, the psychopathological profile included negative symptoms. CONCLUSION: In schizophrenia psychopathological symptoms were more severe than in other disorders. Presence of negative symptoms may indicate that all schizophrenia spectrum disorders may have a neurodevelopmental component.

[Psychiatric symptoms and coeliac disease]. / Niektóre zaburzenia psychiczne wspólistniejace z choroba trzewna.

Psychiatric symptoms and psychological behavioral pathologies are common in patients with untreated coeliac disease. There are several case reports of coexistence of coeliac sprue and depression, schizophrenia and anxiety. Views on association between coeliac disease and psychiatric disturbances and results of the most important studies are discussed. Biological background is referred. Malabsorption and deficiency of aminoacids and vitamins implicate reduction of synthesis of neurotransmitters in the central nervous system. Psychiatric symptoms could also be linked to immunological disregulation in coeliac patients. Psychological pathologies do appear in treated and untreated coeliacs, the need of psychological support is stressed. Coeliac disease should be taken into consideration in patients with psychiatric disorders, particularly if they are not responsive to psychopharmacological therapy, because withdrawal of gluten from the diet usually results in disappearance of symptoms. In recent years, an increased incidence of subclinical/silent coeliac disease has been reported. Psychiatric symptoms and psychological behavioral pathologies could be the only clinical manifestation of coeliac disease, but the epidemiological aspects need further investigation.