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In 2020, the Global Cancer Observatory estimated the incidence of colorectal cancer (CRC) at around 10.7% coupled with a mortality rate of 9.5%. The explanation for these values lies in the tumor microenvironment consisting of the extracellular matrix and cancer-associated fibroblasts (CAFs). Fibroblast activation protein (FAP) offers a promising target for cancer therapy since its functions contribute to tumor progression. Immunohistochemistry examination of FAP, fibronectin ED-B, and CXCR4 in primary tumors and their respective synchronous and/or metachronous metastases along with semiquantitative analysis have been carried out on histological samples of 50 patients diagnosed with metastatic CRC. The intensity of FAP, articulated by both “Intensity %” and “Intensity score”, is lower in the first metastasis compared to the primary tumor with a statistically significant correlation. No significant correlations have been observed regarding fibronectin ED-B and CXCR4. Tumors that produce FAP have an ambivalent relationship with this protein. At first, they exploit FAP, but later they reduce its expressiveness. Although our study has not directly included FAP-Inhibitor (FAPI) PET/CT, the considerable expression of FAP reveals its potential as a diagnostic and therapeutic tool worthy of further investigation. This dynamic relationship between cancer and FAP has substantial diagnostic and therapeutic implications.

Introduction: Studies have shown that the Ki-67 index is a valuable biomarker for the diagnosis, and classification of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). We re-evaluated the expression of Ki-67 based on the intensity of the stain, basing our hypothesis on the fact that the Ki-67 protein is continuously degraded. Background: The aim was to evaluate whether a new scoring method would be more effective in classifying NETs by reducing staining heterogeneity. Methods: Patients with GEP-NET (n = 87) were analyzed. The classification difference between the two methods was determined. Results: The classification changed significantly when the Ki-67 semiquantal index was used. The percentage of G1 patients increased from 18.4% to 60.9%, while the G2 patients decreased from 66.7% to 29.9% and the G3 patients also decreased from 14.9% to 9.2%. Moreover, it was found that the traditional Ki-67 was not significantly related to the overall survival (OS), whereas the semiquantal Ki-67 was significantly related to the OS. Conclusions: The new quantification was a better predictor of OS and of tumor classification. Therefore, it could be used both as a marker of proliferation and as a tool to map tumor dynamics that can influence the diagnosis and guide the choice of therapy.

Vasopressin (AVP) plays a key function in controlling body water and salt balance through the activation of the vasopressin receptors V1aR and V2R. Abnormal secretion of AVP can cause the syndrome of inappropriate antidiuresis that leads to hyponatremia, which is an electrolyte disorder often observed in the elderly hospitalized and oncologic patients. Beyond kidneys, the colonic epithelium modulates water and salt homeostasis. The water channel AQP3, expressed in villus epithelial cells is implicated in water absorption across human colonic surface cells. Here, the action of dDAVP, a stable vasopressin analog, was evaluated on the AQP3 expression and function using human colon HCT8 cells as an experimental model. Confocal and Western Blotting analysis revealed that HCT8 cells express both V1aR and V2R. Long-term (72 h) treatment with dDAVP reduced glycerol uptake and cell viability. These effects were prevented by SR49059, a synthetic antagonist of V1aR, but not by tolvaptan, a specific V2R antagonist. Of note, the SR49059 action was impaired by DFP00173, a selective inhibitor of AQP3. Interestingly, compared to the normal colonic mucosa, in the colon of patients with adenocarcinoma, the expression of V1aR was significantly decreased. These findings were confirmed by gene expression analysis with RNA-Seq data. Overall, data suggest that dDAVP, through the V1aR dependent pathway, reduces AQP3 mediated glycerol uptake, a process that is reversed in adenocarcinoma, suggesting that the AVP-dependent AQP3 pathway may represent a novel target in colon diseases associated with abnormal cell growth.

Hyperthermic intraperitoneal chemotherapy (HIPEC) has been widely investigated in patients with peritoneal carcinomatosis, including those with epithelial ovarian cancer (EOC), with conflicting results. The hyperthermia enhances drug tissue penetration, synergizes with several cytotoxic drugs including cisplatin, degrades BRCA2, suppresses homologous recombination, and elicits an anticancer immune response. A meta-analysis of retrospective studies including both patients with primary advanced EOC and those with recurrent platinum-sensitive EOC failed to detect a benefit in terms of progression-free survival (PFS) or overall survival (OS) from the addition of HIPEC after surgery. The aim of the present review was to analyze the recent randomized clinical trials designed to assess the value of HIPEC in the management of patients with primary advanced EOC. Although not free from criticism and bias, the available data from two phase III trials seem to suggest that the addition of HIPEC to interval debulking surgery after neoadjuvant chemotherapy significantly improves PFS and OS. Conversely, HIPEC does not appear to offer any advantage after primary debulking surgery. Several phase III trials are currently ongoing on these issues and the use of HIPEC is still a matter of debate in the scientific community. Additional translational research is strongly warranted to detect biological variables able to identify a subset of patients who may have a major benefit from this therapeutic approach. In particular, the clinical outcome of patients who undergo HIPEC should be correlated with BRCA status and homologous recombination repair status.

BackgroundCytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.MethodsData were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).ResultsThe study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4–51.2 months], and the median DFS was 13.6 months (95% CI, 12.3–14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4–24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.ConclusionFor patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

Purpose Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC. Methods Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors. Results A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger ( p = 0.02) and node-positive ( p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS ( p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026). Conclusions In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset.

High-grade serous carcinoma (HGSC) of the ovary is characterized by two major histological patterns: a classic papillary/micropapillary architecture and a solid pseudo-endometrioid transitional (SET) variant. We investigated whether the distinct morphologic subtypes are underpinned by transcriptomic differences in the tumor microenvironment (TME). We profiled 21 HGSC tumors (7 SET, 14 classic) using a 770-gene NanoString PanCancer Progression panel. Differential expression analysis revealed ~20 genes with significantly different expression (>4-fold, adjusted p < 0.01) between SET and classic tumors. Unsupervised clustering partially separated SET and classic tumors, suggesting that global gene expression patterns correlate with histologic subtype. SET tumors exhibited upregulation of cell-cycle and epithelial genes (e.g., PTTG1, TRAIL, HER3) and downregulation of genes involved in epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) organization, and angiogenesis (e.g., TWIST2, FGF2, decorin) relative to classic tumors. Notably, PTTG1 and TRAIL were upregulated ~6–9-fold in SET tumors, whereas TWIST2 was ~7-fold downregulated, consistent with reduced EMT in SET tumors. Pathway analysis indicated that SET tumors appear to have an immune-active, stroma-poor microenvironment, in line with an “immunoreactive” phenotype, whereas classic tumors showed a mesenchymal, stroma-rich profile. These molecular distinctions could have diagnostic utility and may inform therapeutic stratification, with key dysregulated genes (e.g., HER3, TRAIL, FGF2) representing potential prognostic or predictive biomarkers. For example, high HER3 expression in SET tumors might predict sensitivity to ERBB3/PI3K inhibitors, whereas stromal factors (e.g., FGF2) enriched in classic HGSC could be targeted with microenvironment-modulating therapies. These preliminary findings require validation before translation into pathology practice via immunohistochemical (IHC) assays (e.g., for HER3 or TRAIL), potentially enabling improved classification and personalized treatment of HGSC. We report effect sizes as log2 fold change with 95% confidence intervals and emphasize FDR-adjusted q-values. Given the small sample size and the absence of outcome data (OS/PFS/PFI), results are preliminary and hypothesis-generating. Orthogonal protein-level validation and replication in larger, independent cohorts are required before any translational inference.

BackgroundTumors develop within an organism operating in a specific social and physical environment. Cortisol and dehydroepiandrosterone (DHEA), two of the most abundant steroid hormones in humans, are involved in both emotional regulation and the tumor progression. Several studies reported preclinical findings that DHEA can have preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, although the mechanisms of action are not yet defined. The main aim of current study was to investigate the relationship between psychological and physiological emotional regulation and cancer development.MethodThis study assessed the quality of life of urogenital cancer male patients using several validated tools, including the Functional Assessment of Cancer Therapy-General and the Profile of Mood States. Saliva samples were collected to monitor peripheral activity of both cortisol and DHEA. It was hypothesized that patients with a better quality of life would have higher levels of the DHEA/cortisol ratios.ResultsWe found that the quality of life was positively related to DHEA, but not cortisol levels. Negative mood increases were related to lower levels of DHEA. Logistic regression of the predictors of metastases indicated three main independent factors involved: DHEA, age, and cortisol. In other words, the higher the DHEA levels in comparison to cortisol levels, controlling for age, the lower the probability of metastases.ConclusionOur results appear to support the hypothesis that emotional dysregulation mediated by DHEA/cortisol activity is a key factor in the probability of metastasis in urogenital cancers.

Enhanced recovery after surgery (ERAS) program refers to a multimodal intervention to reduce the length of stay and postoperative complications; it has been effective in different kinds of major surgery including colorectal, gynaecologic and gastric cancer surgery. Its impact in terms of safety and efficacy in the treatment of peritoneal surface malignancies is still unclear. A systematic review and a meta-analysis were conducted to evaluate the effect of ERAS after cytoreductive surgery with or without HIPEC for peritoneal metastases. MEDLINE, PubMed, EMBASE, Google Scholar and Cochrane Database were searched from January 2010 and December 2021. Single and double-cohort studies about ERAS application in the treatment of peritoneal cancer were considered. Outcomes included the postoperative length of stay (LOS), postoperative morbidity and mortality rates and the early readmission rate. Twenty-four studies involving 5131 patients were considered, 7 about ERAS in cytoreductive surgery (CRS) + HIPEC and 17 about cytoreductive alone; the case histories of two Italian referral centers in the management of peritoneal cancer were included. ERAS adoption reduced the LOS (−3.17, 95% CrI −4.68 to −1.69 in CRS + HIPEC and −1.65, 95% CrI −2.32 to –1.06 in CRS alone in the meta-analysis including 6 and 17 studies respectively. Non negligible lower postoperative morbidity was also in the meta-analysis including the case histories of two Italian referral centers. Implementation of an ERAS protocol may reduce LOS, postoperative complications after CRS with or without HIPEC compared to conventional recovery.