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Background: Hyperprogressive disease (HPD) is a new phenomenon that has emerged in the immunotherapy era. HPD is defined as a rapid tumour growth with detrimental effect on the patient condition and disease course. The management and treatment following HPD is not defined. We present here the case report of patient with HPD and review of the literature on putative mechanisms of HPD and following disease management., Methods and Results: A 60-year old male patient with metastatic melanoma was indicated for systemic treatment with anti-programmed cell death (PD)-1 antibody. Rapid tumour growth and detrimental effect on the patient general condition after administration of a single dose of anti-PD-1 antibody met the criteria of HPD. The patient underwent the second line taxane-based chemotherapy with good tolerance and disease stabilization. The third line treatment with anti- cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody ipilimumab was well tolerated and resulted in partial response. Re-challenge with anti-CTLA-4 antibody was feasible, but only with a modest clinical effect., Conclusion: Prompt recognition of HPD and administration of salvage chemotherapy with taxane-based regimens may be crucial. HPD is rarely observed with ipilimumab treatment. Administration of ipilimumab as well as an ipilimumab re-challenge are feasible after HPD on anti-PD-1 antibodies. Investigation of new predictive biomarkers of HPD is warranted as well as new agents that potentiate the immune response in patients affected with this insidious complication., Competing Interests: The authors report no conflicts of interest in this work.

DNA repair pathways are essential for maintaining genome stability, and understanding the regulation of these mechanisms may help in the design of new strategies for treatments, the prevention of platinum-based chemoresistance, and the prolongation of overall patient survival not only with respect to ovarian cancer. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) together with cytoreductive surgery (CRS) and adjuvant systemic chemotherapy is receiving more interest in ovarian cancer (OC) treatment because of the typical peritoneal spread of the disease. The aim of our study was to compare the expression level of 84 genes involved in the DNA repair pathway in tumors and the paired peritoneal metastasis tissue of patients treated with CRS/platinum-based HIPEC with respect to overall patient survival, presence of peritoneal carcinomatosis, treatment response, and alterations in the BRCA1 and BRCA2 genes. Tumors and metastatic tissue from 28 ovarian cancer patients collected during cytoreductive surgery before HIPEC with cisplatin were used for RNA isolation and subsequent cDNA synthesis. Quantitative real-time PCR followed. The most interesting findings of our study are undoubtedly the gene interactions among the genes CCNH , XPA , SLK , RAD51C , XPA , NEIL1 , and ATR for primary tumor tissue and ATM , ATR , BRCA2 , CDK7 , MSH2 , MUTYH , POLB , and XRCC4 for metastases. Another interesting finding is the correlation between gene expression and overall survival (OS), where a low expression correlates with a worse OS.

Objectives: The aim of this study is to evaluate the results of treatment of diffuse malignant peritoneal mesothelioma (DMPM) by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) at a single center., Methods: We conducted a retrospective single-center observational cohort study of consecutive patients with DMPM treated by CRS-HIPEC at the Department of Surgery I of the University Hospital in Olomouc, Czech Republic., Results: Data on a total of 16 patients were processed. The study group of 16 patients had six (37.5 %) women. The mean age was approximately 62 years. Complete cytoreduction was achieved in all patients (100 %) (CC0: 75 %, CC1: 25 %). All patients underwent a closed form of HIPEC with cisplatin and doxorubicin for 90 min. The mean hospital stay was 13.5 days, including 4.38 days in the ICU (13.5 ± 5.07 and 4.38 ± 1.49, respectively). Major postoperative complications (CD grades 3-4) occurred in four patients (25 %). In-hospital mortality was 6.25 %. In the study group, the median overall survival was 20 months, and the median disease-free survival was 10.3 months., Conclusions: Also under the conditions at our specialized center, CRS-HIPEC is considered as an effective, affordable, and safe therapy with OS, DFS, morbidity, and mortality rates comparable to those reported in the literature (Tab. 5, Fig. 2, Ref. 28). Text in PDF www.elis.sk Keywords: cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, malignant mesothelioma, cisplatin, doxorubicin.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment modality for peritoneal surface malignancies with efficacy reported in many trials. Discrepancies, however, in the indication criteria, the extent of the surgical procedure, HIPEC regimens and toxicity evaluation represent a problem when comparing this method with other therapeutic modalities., Methods: We describe the initial experience with CRS/HIPEC using different chemotherapy regimens (oxaliplatin, cisplatin, mitomycin C and doxorubicin) at the Comprehensive Oncology Centre Olomouc., Results: A perioperative mortality of 2% and perioperative morbidity of 11%, according to Clavien-Dindo were observed. Interestingly, all these patients underwent HIPEC with oxaliplatin 460 mg/m 2 . The median duration of admission to hospital was 6 days in the intensive care unit (range 2-28 days) and 7 days in the surgical ward (range 1-21 days). Hospital admission did not exceed 2 weeks in 75% of patients. These results are consistent with the published results of large centres performing this treatment modality mainly due to pre-operative preparation of patients and pre-treatment and post-treatment management of HIPEC/CRS toxicity. Evaluation of the efficacy in terms of time to progression and overall survival (OS) is limited by the short follow up period., Conclusion: CRS/HIPEC performed is a safe method with low perioperative mortality.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, and no targeted therapy is currently available. The aim of the present study was to investigate the prognostic significance of the expression of V-Ki-ras2 Κirsten rat sarcoma viral oncogene homolog ( KRAS ), downstream signaling pathway genes and the association with clinical characteristics in PDAC patients undergoing radical surgery. Tumors and adjacent non-neoplastic pancreatic tissues were examined in 45 patients with histologically verified PDAC. KRAS and B-Raf proto-oncogene, serine/threonine kinase ( BRAF ) gene mutation analysis was performed using the KRAS / BRAF /phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α array. The transcript profile of 52 KRAS downstream signaling pathway genes was assessed using quantitative-polymerase chain reaction. KRAS mutation was detected in 80% of cases. The genes of four signaling pathways downstream of KRAS, including the phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/V-akt murine thymoma viral oncogene homolog 1, RAL guanine nucleotide exchange factor, Ras and Rab interactor 1/ ABL proto-oncogene-1, non-receptor tyrosine kinase, and RAF proto-oncogene serine/threonine-protein kinase/mitogen-activated protein kinase pathways, exhibited differential expression in PDAC compared with that in the adjacent normal tissues. However, no significant differences in expression were evident between patients with KRAS -mutated and wild-type tumors. The expression of KRAS downstream signaling pathways genes did not correlate with angioinvasion, perineural invasion, grade or presence of lymph node metastasis. Additionally, the presence of KRAS mutations was not associated with overall survival. Among the KRAS downstream effective signaling pathways molecules investigated, only v-raf-1 murine leukemia viral oncogene homolog 1 expression was predictive of prognosis. Overall, KRAS mutation is present in the majority of cases of PDAC, but is not associated with changes in the expression of KRAS downstream signaling pathways and the clinical outcome. This may partly explain the failure of KRAS-targeted therapies in PDAC.

Aim: To analyze pancreatic cancer patients who developed metachronous pulmonary metastases (MPM) as a first site of recurrence after the curative-intent surgery., Methods: One-hundred-fifty-nine consecutive pancreatic ductal adenocarcinoma (PDAC) patients who underwent radical pancreatic surgery between 2006 and 2013 were included in this retrospective analysis. The clinical data including age, sex, grade, primary tumor location, pTNM stage, lymph node infiltration, microangioinvasion, perineural invasion, lymphovascular invasion, the therapy administered, and follow-up were all obtained from medical records. Further analysis covered only patients with metachronous metastases. Clinical and histopathological data (age, sex, grade, primary tumor location, pTNM stage, lymph node infiltration, microangioinvasion, perineural invasion, lymphovascular invasion, the therapy administered and follow-up) of patients with metachronous non-pulmonary metastases and patients with metachronous pulmonary metastases were statistically assessed. Disease-free survival (DFS) from pancreas resection until metastases onset and overall survival (OS) were calculated. Wilcoxon test, χ 2 test and survival functions computed by the Kaplan-Meier method were used. Statistical significance was evaluated by the log-rank test using SPSS. A P -value of less than 0.05 was considered statistically significant., Results: Metachronous pulmonary metastases were observed in 20 (16.9%) and were operable in 3 (2.5%) of PDAC patients after a prior curative-intent surgery. Patients with isolated pulmonary metastases (oligometastases and multiple metastases) had estimated prior DFS and OS of 35.4 and 81.4 mo, respectively, and those with metachronous pulmonary metastases accompanied by other metastases had prior DFS and OS of 17.3 and 23.4 mo, respectively. Patients with non-pulmonary metastases had prior DFS and OS of 9.4 and 15.8 mo, respectively. Different clinical scenarios according to the presentation of MPM were observed and patients could be divided to three subgroups with different prognosis which could be used for the selection of treatment strategy: isolated pulmonary oligometastases, isolated multiple pulmonary metastases and pulmonary metastases accompanied by other metastases., Conclusion: Surgery should be considered for all patients with isolated pulmonary oligometastases, but the risk of intervention has to be individually weighted for each patient., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest.

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease with very poor prognosis. Chemotherapy is the primary treatment modality for patients with locally advanced and metastatic PDAC, but the efficacy of currently available regimens is limited. Taxanes are widely used in many primary cancers including breast, ovarian and lung cancers. The activity of combined regimen of taxanes plus nucleoside analogue or platinum derivate in terms of response rate ranges between 20 and 57 % in PDAC and may prolong overall survival. Since 2013 nab-paclitaxel (paclitaxel-albumin-bound particles) became a new treatment option for patients with metastatic pancreatic cancer based on the results of MPACT trial. Moreover, encouraging activity in PDAC of the combination regimen of paclitaxel and carboplatin that is being widely used in other solid tumors has been reported recently. Biomarkers, including biomarkers predictive of taxane resistance, could allow individualized tailored therapy. BRCA mutation status could serve as predictor of better chemotherapy treatment outcome in PDAC. The present review summarizes the principal clinical trials evaluating the efficacy of taxanes both as monotherapy and in combination in view of the potential use in the treatment of PDAC.