Optimal dose of silymarin for the management of drug­induced liver injury in oncology.

Systemic oncological treatment may cause drug-induced liver injury (DILI). Therefore, there is a pressing need for an active drug able to accelerate liver regeneration. Silymarin mitigates oxidative stress, and inhibits pro-inflammatory and pro-apoptotic cytokines and the fibrotic transformation of liver tissue. Currently, there are a lack of data regarding the optimal dosage of silymarin and its efficacy. Thus, the present retrospective study aimed to determine the optimal dose of silymarin for use in oncological DILI treatment. For this purpose, 180 patients with solid malignancies treated with systemic oncological therapy and silymarin between January, 2015 and November, 2021 were enrolled in the study. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (Bil) levels, as well as the dose of silymarin were assessed at the initiation of silymarin treatment, after 3-6 weeks and after 6-12 weeks. Pearson's correlation analysis was performed to evaluate the correlation between the initial dose of silymarin (IDoS), and the ALT, AST and Bil levels. The effects of four independent variables, namely IDoS, the initial dose reduction of systemic treatment, the systemic treatment dose reduction at first assessment (DR1M) and the elevation of the silymarin dose at first control on the ALT, AST and Bil levels were evaluated using regression analysis. The median IDoS was 450 mg. A decrease in or the stabilization of the ALT, AST and Bil levels after 6-12 weeks were observed in 68.63, 65.85 and 53.25% of patients, respectively. There was a weak correlation between IDoS and the decrease in ALT and AST levels after 6-12 weeks (correlation coefficient, R=0.361 and 0.277 respectively, P<0.001). No significant correlation between the IDoS and a decrease in Bil levels was observed. DR1M was a negative predictor for a decrease in Bil levels in patients with liver tumors. On the whole, the present study demonstrates that silymarin appears to be efficient in alleviating DILI at a dose of 300-450 mg. A further increase in the dose of silymarin may not lead to an adequate increase in its efficacy.

Randomized double-blind, placebo-controlled multicenter phase III study of prevention of irinotecan-induced diarrhea by a probiotic mixture containing Bifidobacterium BB-12®Lactobacillus rhamnosus LGG® in colorectal cancer patients.

Background: The incidence of irinotecan-induced diarrhea varies between 60-90%, by which the incidence of severe diarrhea is 20-40%. The objective of this phase III trial was to determine the effectiveness of the probiotic mixture containing Bifidobacterium, BB-12® and Lactobacillus rhamnosus, LGG® in the prophylaxis of irinotecan-induced diarrhea in metastatic colorectal cancer patients due to a reduction in the activity of intestinal beta-D-glucuronidase. Methods: From March 2016 to May 2022, a total of 242 patients with colorectal cancer starting a new line of irinotecan-based therapy were registered to the study in 11 cancer centers in Slovakia. Patients were randomized in a ratio 1:1 to probiotic formula vs. placebo that was administered for 6 weeks. Each capsule of Probio-Tec® BG-Vcap-6.5 contained 2.7x109 colony-forming units (CFU) of 2 lyophilized probiotic strains Bifidobacterium, BB-12® (50%) and Lactobacillus rhamnosus GG, LGG® (50%). Results: Administration of probiotics compared to placebo was not associated with a significant reduction of grade 3/4 diarrhea (placebo arm 11.8% vs. probiotic arm 7.9%, p=0.38). Neither the overall incidence of diarrhea (46.2% vs. 41.2%, p=0.51) nor the incidence of enterocolitis (3.4% vs. 0.9%, p=0.37) was different in the placebo vs. probiotic arm. Subgroup analysis revealed that patients with colostomy had higher incidence of any diarrhea and grade 3/4 diarrhea in the placebo arm compared to the probiotic arm (48.5% vs. 22.2%, p=0.06 and 15.2% vs. 0%, p=0.06, respectively). Moreover, patients on probiotic arm had significantly better diarrhea-free survival (HR = 0.41, 95%CI 0.18 - 0.95, p=0.05) and needed less loperamide (p=0.01) compared to patients on placebo arm. We did not observe any infection caused by probiotic strains used in this study. Conclusion: This study failed to achieve its primary endpoint, and results suggest a lack of benefit of administered probiotic formula for the prevention of irinotecan-induced diarrhea. However, subgroup analysis suggests a possible benefit in patients with colostomy.

Spontaneous Regression of Merkel Cell Carcinoma: Case Report.

Merkel cell carcinoma (MCC) is a rare skin neuroendocrine tumor presumably arising from Merkel cells in the basal layer of epidermis. It is an aggressive tumor predominantly found on the head and neck area of elderly people, with a mortality rate around 41% for all stages. Complete spontaneous regression of MCC is seldom observed, mostly in elderly women. We describe complete spontaneous regression of large, histologically confirmed MCC in an elderly woman after biopsy, which occurred incidentally, while waiting for radical surgery with skin flap. Next-generation sequencing with SOPHiA Solid Tumor Plus Solution did not reveal any relevant gene mutations or rearrangements. An update of literature for these very rare cases is provided.

Hypotension as a symptom of autonomic neuropathy in patients with advanced malignancies.

AIMS: Hypotension can be a symptom of paraneoplastic autonomic neuropathy (PAN). Onconeural antibodies (OA) provide strong evidence for the paraneoplastic origin of neurological syndromes. Our goal was to assess the frequency of PAN among patients with advanced malignancies and hypotension using OA. METHODS: Patients with advanced malignancies and hypotension were screened and enrolled as per protocol. Plasma levels of six classical OAs were assessed in these patients. We prospectively evaluated other symptoms of PAN in these patients. RESULTS: 31 patients out of 740 screened met the criteria of this cross-sectional study. OAs were present in 4 patients (12.9%). Anti-amphiphysin was found in 1 patient (3.23%), anti- CV2 (anti-CRPM5, anti- collapsin- response mediator protein) was present in 1 patient (3.23%), 1 patient (3.23%) was positive for anti-Hu and anti-Ma2 was present in 1 patient (3.23%). No patient was positive for 2 or more OAs. Normalization of blood pressure in concordance with partial remission occurred in 5 patients. The most used criteria for PAN were fulfilled in 9 patients. CONCLUSION: The frequency of PAN may be underestimated in a busy oncology clinic. Assessing OAs may aid in the differential diagnosis of hypotension of unknown origin.

Global cancer control: responding to the growing burden, rising costs and inequalities in access.

The cancer burden is rising globally, exerting significant strain on populations and health systems at all income levels. In May 2017, world governments made a commitment to further invest in cancer control as a public health priority, passing the World Health Assembly Resolution 70.12 on cancer prevention and control within an integrated approach. In this manuscript, the 2016 European Society for Medical Oncology Leadership Generation Programme participants propose a strategic framework that is in line with the 2017 WHO Cancer Resolution and consistent with the principle of universal health coverage, which ensures access to optimal cancer care for all people because health is a basic human right. The time for action is now to reduce barriers and provide the highest possible quality cancer care to everyone regardless of circumstance, precondition or geographic location. The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if we are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible.

Circulating tumor cells and coagulation-Minireview.

Venous thromboembolic events in cancer patients signify poor prognosis. Prophylactic treatment of ambulatory patients with anticoagulants is currently not recommended. Circulating tumor cells, either directly or indirectly, are associated with prothrombotic state. In this review, we discuss various interactions of circulating tumor cells with the coagulation pathway in cancer patient.

Relationship Between Circulating Tumor Cells and Annexin A2 in Early Breast Cancer Patients.

BACKGROUND/AIM: Annexin A2 (ANXA2) is a phospholipid-binding protein involved in fibrinolysis, cell proliferation, migration and metastatic dissemination. Circulating tumor cells (CTCs) are cells responsible for tumor dissemination and have a prognostic value in several types of cancers including breast cancer. Previously, we found correlation between CTCs and activation of coagulation. This study aimed to correlate CTCs with ANXA2 expression on CTCs, tumor cells and tumor associated stroma in primary breast cancer (PBC) patients. PATIENTS AND METHODS: This prospective study included 101 PBC patients treated by primary surgery. CTCs were detected by quantitative real-time polymerase chain reaction (qRT-PCR) assay for the expression of epithelial (CK19) or epithelial-mesenchymal transition (EMT) genes [TWIST1, SNAI1, SNAI2, zinc finger E-box-binding homeobox 1 (ZEB1)]. ANXA2 expression on CTCs was detected by qRT-PCR, while expression of ANXA2 in tumor specimen was evaluated by immunohistochemistry and expressed by a weighted histoscore, evaluating both the percentage of positive cells and the intensity of membrane and cytoplasmic staining. Results of hormone receptors, HER2 status, B-cell lymphoma 2 (bcl-2) protein expression and protein p53 were reported as either positive or negative on histopathology report without further quantification. RESULTS: CTCs were detected in 24.8% patients. Patients with epithelial CTCs had a significantly higher ANXA2 expression on CTCs than those of patients without CTCs (p=0.01). There was no association between CTCs and ANXA2 protein expression in tumor cells. However, patients, whom CTCs with EMT phenotype were detected in, had higher ANXA2 expression in tumor stroma when compared to those with absent EMT CTCs (p=0.04). Hormone-negative tumors had significantly higher ANXA2 expression in tumor cells compared to hormone-positive tumors (p=0.03). Similarly, tumors without bcl-2 protein expression had higher tumor levels of ANXA2 compared to tumor cells that were bcl-2 positive (p=0.05). CONCLUSION: ANXA2 stromal expression might play a key role in aggressive tumor phenotype associated with increased EMT CTCs release, however, other factors beyond ANXA2 are responsible for coagulation activation mediated by CTCs in breast cancer patients.

Relationship Between Circulating Tumor Cells and Tissue Plasminogen Activator in Patients with Early Breast Cancer.

AIM: Cancer increases the risk of venous thromboembolism (VTE) and circulating tumor cells (CTCs) are associated with an increased risk of VTE and, thus, with increased D-dimers as a product of fibrinolysis. Tissue plasminogen activator (tPA) is one of the key enzymes in the fibrinolytic pathway. Its activity is crucial in maintaining the balance between blood coagulation and fibrinolysis. This study aimed to analyze the association between CTCs and tPA in patients with primary breast cancer before surgery. PATIENTS AND METHODS: This prospective study included 110 patients in whom CTCs were detected by quantitative reverse transcription polymerase chain reaction targeted at epithelial (CK19) or epithelial-mesenchymal transition (EMT)-associated genes[TWIST1, SNAI1, SNAI2, zinc finger E-box-binding homeobox 1 (ZEB1), forkhead box protein C2 (FOXC2)]. Plasma tPA protein was detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: CTCs were detected in 31 (28.2%) patients. There was no association between plasma tPA and CTCs. Although on average, higher levels of tPA were detected in patients with CTCs expressing EMT-associated genes, this difference did not reach statistical significance. There was no association of plasma tPA with any of the observed patient or tumor characteristics. CONCLUSION: Even though the blood coagulation pathway may be activated in more aggressive disease related to an elevated CTC count, in this study, we did not find any association between CTCs and plasma concentrations of tPA.

Male breast cancer - a single center experience.

Due to its rarity, male breast cancer remains a poorly characterized disease. The present study obtained retrospective clinicopathological data, treatment patterns and outcomes for all male patients diagnosed with breast cancer in the Oncology Department, Faculty Hospital Trencín (Trencín, Slovakia) over the last 20 years from January 1995 to December 2015. A total of 21 patients with male breast cancer were analyzed, with a median patient age of 65.6 years. Two patients were diagnosed with lobular invasive cancer; all others were diagnosed with cancer of a ductal origin. One patient presented with metastatic disease in the pleural cavity. The primary tumors in 8 patients were staged as pT1, whilst 6 patients were staged as pT2 and 7 as pT4. Axillary lymph node involvement was present in 11 patients (52%) and 15 patients were hormone receptor-positive (83%). All but 1 patient underwent mastectomy and surgical staging of the axilla. Adjuvant chemotherapy, radiotherapy and hormone treatment was administered in the same manner as breast cancer treatment in female patients. The median follow-up time was 4.5 years. The 5- and 10-year overall survival rates were 87 and 74%, respectively, and the estimated median disease-free survival for the same population was 9.5 years (95% confidence interval, 6.2-14.6). The survival rates reported in the present retrospective study are comparable with previously published studies. In addition, the current study reported predominant hormone-positive characteristics and rare expression of human epidermal growth factor receptor 2. However, further multi-institutional trials are required to allow for informed treatment decisions in this uncommon disease.

Small Cell Carcinoma of the Ovary (Hypercalcemic Type): Malignant Rhabdoid Tumor.

We present a rare case of malignant rhabdoid tumor (ovarian small cell carcinoma of hypercalcemic type) in a 24-year-old female with fulminant course. Clinically, hypercalcemia was not found at the time of primary diagnosis. However, it appeared later during the course of tumor progression. Histologically, the tumor showed classical features of small cell carcinoma of hypercalcemic type. Therapy included radical surgery with adjuvant chemotherapy. Despite this intensive therapy, the disease recurred and the patient died 10 months after the diagnosis. We discuss the diagnosis and therapy of this tumor, as well as its recent classification as malignant rhabdoid tumor.

Primary Angiosarcoma of the Spleen: Rare Diagnosis with Atypical Clinical Course.

Primary angiosarcoma of the spleen is a rare diagnosis with poor prognosis. Morphologically, it demonstrates conventional blood vessel differentiation. We present a case of 65-year-old female who underwent radical splenectomy for primary angiosarcoma of the spleen. After three-year disease-free interval, she was diagnosed with bone-only metastatic disease. Palliative radiotherapy and bisphosphonates kept her disease reasonably stable for another four years. After development of lung metastases, six cycles of single agent doxorubicin kept her progression-free for six years. Upon further progression in lungs, thirteen years after original diagnosis, lung biopsy confirmed metastatic splenic angiosarcoma in the lungs. She started weekly paclitaxel chemotherapy. Although splenic angiosarcoma generally carries grave prognosis, some patients may enjoy prolonged periods of disease stabilization. Durable benefit can be achieved in some patients with multimodality management. We review the literature focusing on systemic treatment for this rare tumor.

First-line treatment of nonsquamous NSCLC using gemcitabine: a retrospective study of real-life practice.

We present results of retrospective real-life data of nonsquamous lung cancer patients treated in first-line (platinum-based chemotherapy with gemcitabine without bevacizumab). 56 patients with satisfactory performance status for cytotoxic chemotherapy were treated in 2010-2014. Median progression-free survival was 6.48 months (95% CI: 4.44-9.48), time to progression was 10.19 months (95% CI: 7.59-12.19). Median overall survival was 10.8 months (95% CI: 6.72-14.52). Although our group of patients had higher proportion of elderly patients with somewhat limited performance status, progression-free survival rate was comparable to large registration studies. Overall survival, despite intervening comorbidities and subsequent limited use of second-line treatment was analogous to large gemcitabine/platinum Phase III studies in nonsquamous population. We believe our data represent real-life survival rates of unselected patients with advanced NSCLC of nonsquamous type from mostly rural catchment area.

Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study.

PURPOSE: Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development, which is excreted in glucuronidated form into the intestine. This study aimed to determine the effectiveness of the probiotics in the prevention of irinotecan induced diarrhea due to reduction of intestinal beta-d-glucuronidase activity. METHODS: Between January 2011 and December 2013, 46 patients with colorectal cancer starting a new line of irinotecan based therapy were included. Patients were randomized 1:1 to probiotics (PRO) or placebo (PLA). Probiotic formula Colon Dophilus™, was administered at a dose of 10×10(9)CFU of bacteria tid, orally for 12 weeks of chemotherapy. The study was prematurely terminated due to slow accrual, when 46 of 220 planned patients were accrued. RESULTS: Twenty-three patients were randomized to PRO and 23 patients to PLA. Administration of probiotics compared to placebo led to a reduction in the incidence of severe diarrhea of grade 3 or 4 (0% for PRO vs. 17.4% for PLA, p=0.11), as well as reduction of the overall incidence of diarrhea (39.1% for PRO vs. 60.9% for PLA, p=0.24) and incidence of enterocolitis (0% for PRO vs. 8.7% for PLA). Patients on PRO used less antidiarrheal drugs compared to PLA. There was no infection caused by probiotic strains recorded. CONCLUSIONS: Administration of probiotics in patients with colorectal cancer treated with irinotecan-based chemotherapy is safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity.

Patupilone in cancer treatment.

IMPORTANCE OF THE FIELD: Since the introduction of taxane-based chemotherapy for advanced solid tumors in the 1990s, the median overall survival of patients with metastatic breast cancer increased from 2 years to almost 5 years. Similarly, the 5-year overall survival for ovarian cancer has increased from 30% to more than 40%. AREAS COVERED IN THIS REVIEW: Patupilone is a novel cytotoxic compound, with similar microtubule-binding and apoptotic properties of taxanes and is active in taxane-resistant cell lines. Over 1200 patients have been treated with patupilone in Phase I - III clinical trials and a wealth of knowledge has accumulated about this compound. This review discusses current pharmacology and data from clinical trials with patupilone from the last seven years. WHAT THE READER WILL GAIN: We present a comprehensive summary of data from Phase II and III trials, as well as an overview of currently accruing trials. TAKE HOME MESSAGE: Although patupilone has not demonstrated superiority over pegylated liposomal doxorubicin in a large Phase III trial in relapsed or refractory ovarian cancer, its evaluation is continuing in a range of other malignancies, especially in primary or secondary tumors of the CNS.

Optimal therapeutic strategies for resectable oesophageal or oesophagogastric junction cancer.

Oesophageal cancer is the eighth most common cancer diagnosed worldwide, with almost half a million new cases diagnosed each year. Despite improvements in surgical and radiotherapy techniques and refinements of chemotherapeutic regimens, long-term survival, even from localized oesophageal cancer, remains poor. Surgical resection alone remains the standard approach for very early stage disease (stage I), but whilst surgery remains fundamental to the treatment of stage II-III resectable adenocarcinoma, multimodality therapy with chemotherapy or chemoradiation (CRT) is internationally accepted as the standard of care. Data from two large, randomized phase III trials support the use of perioperative combination chemotherapy in lower oesophageal and oesophagogastric junction adenocarcinomas, but the contribution of the adjuvant therapy is uncertain. There are conflicting data from randomized studies of a purely neoadjuvant approach; however, recent meta-analyses have demonstrated that chemotherapy or CRT given prior to radical surgery improves survival in patients with adenocarcinoma of the oesophagus. Neoadjuvant CRT but not chemotherapy alone is also beneficial for patients with squamous cell carcinoma. Definitive CRT has emerged as a useful option for the treatment of resectable squamous cell carcinoma of the oesophagus, avoiding potential surgical morbidity and mortality for most patients, with salvage surgery reserved for those with persistent disease. In this review, we focus on the pharmacotherapy of resectable oesophageal and oesophagogastric junction cancers and how clinical trials and meta-analyses inform current clinical practice.