ONCOLOGY

Polypoidal giant cancer cells in metastatic castration-resistant prostate cancer: observations from the Michigan Legacy Tissue Program Abstract Despite early diagnosis and established protocols, a subset of prostate cancer patients will eventually be categorized as castration-resistant prostate cancer. Recently, it has been reported that these multi-modal therapy cases may harbor a special subset of cancer cells termed as polypoidal giant cancer cells (PGCC). These cells are phenotypically described either as possessing highly irregular polylobated nuclei or multiple pleomorphic nuclei. To identify and characterize the distribution of these cells, we created a cohort of 5 randomly selected cases of multi-modal therapy failure prostate cancer (16 selected non-osseous and osseous tumor sites) enrolled in Michigan Legacy Tissue Program. In all cases, specific “regions of interest” or “hot spots” within tumor areas showing an increased proportion of these multi-nucleated/polylobated cells under light microscopy were labeled as PGCC-rich area. On microscopic evaluation, overall mean count of PGCC was 42.4 ± 3.91 with case 2 in the study cohort with the highest number of average PGCC count of 17 ± 4.04. Site wise analysis showed retroperitoneal lymph node as the tissue with highest number of average PGCC number/site (5.0 ± 0.32). On correlating the average number of PGCC recorded with the time elapsed from last dose of chemotherapy administered to autopsy, the spearman correlation value (R) was 0.67, but the result was not statistically significant (p = 0.22). A systematic assessment of PGCC in a large stratified cohort of prostate cancer patients integrated with various histopathological and clinical parameters along with discovery of specific biomarkers for PGCC are the future studies suggested.

Could the kinetin riboside be used to inhibit human prostate cell epithelial–mesenchymal transition? Abstract The epithelial–mesenchymal transition (EMT) is a molecular process connected to higher expression of vimentin and increased activity of transcription factors (Snail, Twist) which restrains E-cadherin. EMT has been linked to prostate cancer metastatic potential, therapy resistance, and poor outcomes. Kinetin riboside (9-(b-dribofuranosyl)-6-furfurylaminopurine, KR) is a naturally occurring cytokinin, which induces apoptosis and shows strong antiproliferative activity against various human cancer cell lines. To establish the effect of KR on human prostate cell lines, expression of, e.g. AR, E-, N-cadherins, Vimentin, Snail, Twist, and MMPs, was analysed at mRNA and protein levels using Western Blot and RT-PCR and/or RQ-PCR techniques. KR inhibited the growth of human prostate cancer cells, but also, to a small extent, of normal cells. This effect depended on the type of the cells and their androgen sensitivity. KR also decreased the level of p-Akt, which takes part in androgen signalling modulation. The antiapoptotic Bcl-2 protein was down-regulated in cancer cell lines, while that of Bax is up-regulated upon KR exposure. KR contributed to re-expression of the E-cadherin as well as to significant changes in cell migration. Taken together, our results indicate for the first time that KR can be proposed as a factor for signalling pathways regulation that participates in the inhibition of development of aggressive forms of prostate cancer, and may alter the approach to therapeutic interventions. We propose KR as a potent inhibitor of EMT in human prostate cells.

To be or not to be: whether anti-angiogenic agent combined with immune checkpoint inhibitoris necessary in the treatment of advanced or metastatic renal cell carcinoma Abstract Although it’s widely known that targeted therapy against angiogenesis and immunotherapy agents showed survival benefit over chemoradiotherapy in advanced or metastatic renal cell carcinoma, some patients still cannot receive a satisfied prognosis. We performed a systematic review and meta-analysis to explore the efficacy and safety of anti-angiogenic agents combined with immune checkpoint inhibitors. We conducted a search for randomized controlled trials in Pubmed, Embase, Cochrane, and major conference. Enrolled eligible studies and extracted data were completed by two investigators to compare OS, PFS, and ORR both in PD-L1 and ITT subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. Besides, we assessed the heterogeneity through subgroup and sensitivity analysis. A total of three RCTs covering 2662 patients were enrolled. In PFS analysis, the estimated HR for ITT subset was 0.74 with 95% CI of 0.65 to 0.84 and for PD-L1 subset was 0.65 with 95% CI of 0.56 to 0.76. And in OS analysis, the result was 0.74 with 95% CI of 0.53 to 1.03 in ITT subset and 0.74 with 95% CI of 0.56 to 0.96 in PD-L1 subset. As for ORR analysis, combination therapy showed advantage rather than monotherapy in ITT subset (RR 1.54; 95% CI 1.11 to 2.14), but conversely in PD-L1 positive subset (RR 1.64; 95% CI 0.94 to 2.84). Additionally, combination therapy failed to show obvious safety in most immune-related adverse events, whatever in all-grade or high grade.

Ketogenic diets in medical oncology: a systematic review with focus on clinical outcomes Abstract Preclinical data provide evidence for synergism between ketogenic diets (KDs) and other oncological therapies. The aim of this systematic review was to summarize data from clinical studies that have tested KDs along with other treatments used within medical oncology. The PubMed database was searched using the key words "ketogenic" AND ("cancer" OR "glioblastoma"). A secondary search was conducted by screening the reference lists of relevant articles on this topic. Relevant studies for this review were defined as studies in which KDs were used complementary to surgery, radio-, chemo-, or targeted therapy and at least one of the following four outcomes were reported: (i) Overall survival (OS); (ii) progression-free survival (PFS); (iii) local control rate; (iv) body composition changes. Twelve papers reporting on 13 clinical studies were identified. Nine studies were prospective and six had a control group, but only two were randomized. KD prescription varied widely between studies and was described only rudimentarily in most papers. Adverse events attributed to the diet were rare and only minor (grade 1–2) except for one possibly diet-related grade 4 event. Studies reporting body composition changes found beneficial effects of KDs in both overweight and frail patient populations. Beneficial effects of KDs on OS and/or PFS were found in four studies including one randomized controlled trial. Studies in high-grade glioma patients were not sufficiently powered to prove efficacy. Evidence for beneficial effects of KDs during cancer therapy is accumulating, but more high-quality studies are needed to assess the overall strength of evidence.

Adult soft tissue myoepithelial carcinoma: treatment outcomes and efficacy of chemotherapy Abstract Soft tissue myoepithelial carcinomas are a rare, malignant subgroup of myoepithelial tumours mostly arising in the extremities with equal predilection for women and men. The mainstay of management of localised disease is complete surgical resection. Despite optimal treatment, 40–45% of tumours recur. Data regarding the efficacy of systemic therapy for advanced and metastatic disease are lacking. The primary aim of this study was to evaluate the outcome of all patients with soft tissue myoepithelial carcinoma treated at a single referral centre. The secondary aim was to establish the efficacy of systemic therapies in patients with advanced disease. A retrospective review of the prospectively maintained Royal Marsden Sarcoma Unit database was performed to identify soft tissue myoepithelial carcinoma patients treated between 1996 and 2019. Patient baseline characteristics and treatment history were recorded. Response to systemic therapy was evaluated using RECIST 1.1. We identified 24 patients treated at our institution between 1996 and 2019,12 males and 12 females. Median age at presentation was 49.6 years [interquartile range (IQR) 40.5–63.3 years]. Twenty-two out of 24 patients (91.7%) underwent primary surgical resection. Nine patients (37.5%) received systemic treatment. A partial response was documented in one patient treated with doxorubicin. The median progression-free survival for first-line chemotherapy was 9.3 months. Myoepithelial carcinoma frequently recurs after complete surgical resection. Conventional chemotherapy demonstrated some activity in myoepithelial carcinoma, however, more effective systemic therapies are required and enrolment in clinical trial should be encouraged.

Prospective assessment of the clinical benefit of a tailored cancer gene set built on a next-generation sequencing platform in patients with recurrent or metastatic head and neck cancer Abstract We performed a prospective trial to assess the clinical benefit of a tailored gene set built on a next-generation sequencing (NGS) platform in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Archived tumor tissue obtained from patients with recurrent or metastatic HNSCC was analyzed for variants by a tailored Comprehensive Cancer Gene set of 40 genes (CCG-40) performed on a NGS platform. These data were provided to clinicians to inform treatment decisions. The primary endpoint was clinical benefit (disease control) that resulted from selection and administration of a targeted therapy based on results of the CCG-40. Barriers to performance and implementation of the assay were recorded. Forty patients enrolled. Primary tumor sites included oropharynx (14), larynx/hypopharynx (14), oral cavity (9), and nasopharynx (3). The CCG-40 assay was performed in 23 patients (57.5%), but not in 17 patients due inadequate financial coverage (12) or insufficient tumor tissue (5). Potentially actionable tumor variants were identified in 3 patients (7.5%); all were PIK3CA variants. Due to inability to obtain access to candidate drugs (2) or rapid decline in performance status (1), none of these patients received targeted therapy informed by the CCG-40 results. The CCG-40 assay did not provide clinical benefit to the patients on this trial. Identification of limitations of the assay and barriers to the test’s performance and application may be used to optimize this strategy in future trials.

Venous thromboprophylaxis in urological cancer surgery Abstract Venous thromboembolism (VTE) represents a major complication of cancer and its treatment, contributing to increased morbidity and mortality. The appropriate choice of thromboprophylaxis method and duration is, therefore, of utmost importance. We conducted an extensive review of the literature concerning VTE in patients undergoing surgery for urological cancers. Special attention was paid to risk factors, different types of surgery (transurethral, pelvic, abdominal—open, laparoscopic and robot-assisted) and different medications used (heparins, vitamin K antagonists and new oral anticoagulants). Original papers, reviews and guidelines were identified in Medline database. The available data were then summarised for the purpose of this article. Venous thromboprophylaxis is obligatory in urological cancer patients undergoing surgical treatment. Unless individual contraindications are recognised, the available guidelines should be followed. The variety of clinical scenarios and patients’ comorbidities necessitate cooperation with other specialists (cardiologists, neurologists, etc.) in choosing the optimal management. Thrombosis risk must be carefully weighed against bleeding risk.

Cancer gene profiling explores the possible precision medicine for diffuse-type gastric adenocarcinoma Abstract Diffuse type gastric cancer (DGC), a pathological subtype, is one of the most common malignant solid tumors, and mortality of this tumor is not negligible, especially in early-onset cancer patients. In fact, affirmative personalized treatments based on gene profile have not been established yet. The aim of this study was to provide the possible genotype-matched treatment for DGC through comprehensive examination of genomic variants and analysis of clinicopathological characteristics. We retrospectively studied 23 formalin-fixed, paraffin-embedded samples of patients diagnosed as DGC between January 2003 and December 2015 at the Department of Cancer Pathology, Hokkaido University Graduate School of Medicine. The cases were divided into two groups: early-onset (< 50 years old) and elderly-onset (≥ 50 years old) DGC groups. We performed targeted genomic sequencing using a 163 cancer-related gene panel. The sequencing data were analyzed using an original bioinformatics pipeline called GenomeJack and were clinicopathologically evaluated. Intestinal metaplasia and atrophy were highly observed in the adjacent non-cancerous mucosa in the elderly-onset DGC group compared with those in the early-onset DGC group. The number of somatic variants was significantly higher in the elderly-onset DGC group than in the early-onset DGC group. Fifteen patients (65.2%) harbored at least one genomic alteration of the potential target for genotype-matched treatment. In addition, one patient with hypermutation phenotype was diagnosed as Lynch syndrome due to MLH1 mutation, suggesting the sensitivity for the treatment with immune checkpoint inhibitors. Not only does our study demonstrated the potential utility of the targeted genomic sequencing approach for making informed therapeutic decisions, but it also sheds light on DGC pathogenesis and progression.

Pentoxifylline and vitamin E reduce the severity of radiotherapy-induced oral mucositis and dysphagia in head and neck cancer patients: a randomized, controlled study Abstract The purpose of this study was to assess the impact of pentoxifylline and vitamin E on the incidence and severity of radiotherapy-induced oral mucositis and dysphagia in head and neck cancer patients. This is a prospective, randomized, controlled study. Head and neck cancer patients receiving 30–35 radiotherapy fractions with or without concurrent chemotherapy excluding those intolerant to xanthines, with any bleeding tendency were included. Sixty patients were enrolled; 30 patients received radiotherapy (control group) and 30 patients received radiotherapy with pentoxifylline and vitamin E (intervention group). The incidence, severity, onset and duration of oral mucositis and/or dysphagia were assessed. Locoregional control, quality of life, need for hospitalization, radiotherapy breaks, and adverse events were recorded and compared between groups. Pentoxifylline and vitamin E combination did not affect the incidence or the onset of oral mucositis or dysphagia. After adjusting for age, the combination reduced the incidence of severe oral mucositis (p = 0.01) and dysphagia (p = 0.012). The combination decreased the duration of oral mucositis and dysphagia by 5 weeks (p = 0.002) and 4 weeks (p = 0.003), respectively. The study drugs reduced the need for hospitalization (p = 0.002) and for radiotherapy breaks (p = 0.002) with improvement of FOIS (p = 0.014), EQ-5D index (p = 0.009) and VAS score (p = 0.012). Pentoxifylline and vitamin E decreased the occurrence of dysgeusia (p = 0.026) and fatigue (p = 0.026) without compromising locoregional control. Pentoxifylline/vitamin E combination reduced the severity and duration of acute radiotherapy-induced oral mucositis and dysphagia in head and neck cancer patients. Trial registry ClinicalTrials.gov registration number: NCT02397486.

Prognostic impact of C-reactive protein-albumin ratio for the lethality in castration-resistant prostate cancer Abstract This study aimed to assess the clinical value of C-reactive protein-albumin ratio (CAR) at the initiation of first-line treatment for castration-resistant prostate cancer (CRPC). We identified 221 CRPC patients treated with either androgen-signaling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as the first-line treatment. The value of CAR was evaluated at the initiation of first-line treatment. The optimal cutoff value of CAR for the prediction of lethality was defined by the receiver operating characteristic curve and the Youden Index. The primary endpoints of the study included overall survival (OS) and cancer-specific survival (CSS). The median age was 74 years. The optimal cutoff value of CAR in newly diagnosed CRPC patients was 0.5 (CAR > 0.5: n = 77 and CAR ≤ 0.5: n = 144). The 3-year OS and CSS rate in patients with CAR > 0.5 were significantly lower than those with CAR ≤ 0.5 (OS: 30.9% vs 55.5%, p < 0.001) (CSS: 42.5% vs 65.4%, p < 0.001). A multivariate analysis consistently demonstrated that CAR was an independent predictor for both OS and CSS. When stratified by the first-line treatments, patients with CAR > 0.5 has significantly shorter CSS than those with CAR ≤ 0.5 in abiraterone (median of 23 vs 49 months, p < 0.001) and enzalutamide (median of 23 vs 41 months, p = 0.0016), whereas no difference was observed in patients treated with docetaxel as the first-line treatment (median of 34 and 37 months, p = 0.7708). Despite the limited cohort size and retrospective design, increased CAR seemed to serve as an independent predictor of OS and CSS for patients newly diagnosed with CRPC.