Second-line therapy in pancreatic ductal adenocarcinoma (PDAC) patients with germline BRCA1-2 pathogenic variants (gBRCA1-2pv).

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbouring germline BRCA1-2 pathogenic variants (gBRCA1-2pv) is a distinct nosological entity. Information on second-line therapy (2LT) outcome in this setting is lacking. METHODS: Data of gBRCA1-2pv metastatic PDAC patients treated with chemotherapy were collected. A primary analysis of 2LT RECIST response, median progression-free survival (mPFS2) and overall survival (mOS2), was performed. A secondary analysis addressed the impact of timing of platinum introduction on the outcome of patients receiving at least a first-line combination chemotherapy (1LT). RESULTS: Eighty-four gBRCA1-2pv metastatic PDAC patients were enrolled. The primary analysis, including 43 patients, highlighted a significant improvement of mPFS2 and a doubled response rate, in the platinum-based 2LT subgroup as compared to the platinum-free (8.8 versus 3.7 months, p = 0.013). Seventy-seven patients were included in the secondary analysis. Median PFS1 of 3- and 4-drug platinum-based 1LT significantly outperformed both platinum-free combinations and platinum-based doublets (11.4 versus 6.4 versus 7.9 months, p = 0.01). Albeit still immature, data on mOS paralleled those on mPFS. CONCLUSIONS: This study highlighted the beneficial role of platinum agents in gBRCA1-2pv PDAC patients also in second-line treatment setting. However, our data suggest that early use of 3- and 4-drug platinum-based chemotherapy combinations provides a survival outcome advantage.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real-world setting. METHODS: The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression-free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. RESULTS: From February 2022 to November 2022, 145 patients were enrolled. After a median follow-up of 8.5 months (95% CI: 7.9-13.6), the median PFS was 8.9 months (95% CI: 7.4-11.7). Median OS was 12.9 months (95% CI: 10.9-12.9). The investigator-assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3-4 AEs occurred in 51 patients (35.2%). The rate of immune-mediated AEs (imAEs) was 22.7%. Grades 3-4 imAEs occurred in 2.1% of the patients. In univariate analysis, non-viral aetiology, ECOG PS >0 and NLR ≥3 correlated with shorter PFS. CONCLUSION: The results reported in this first real-world analysis mostly confirmed the results achieved in the TOPAZ-1 trial in terms of PFS, ORR and safety.

Pattern of progression of intrahepatic cholangiocarcinoma: Implications for second-line clinical trials.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC-06 trial reported the superiority of FOLFOX vs clinical observation as a second-line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post-progression survival (PPS), similar to hepatocellular carcinoma. METHODS: Multicentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH). RESULTS: We included 206 patients from 5 centres. The median OS was 14.1 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509-0.961], performance status >2.445 [1.788-3.344], permanent first-line discontinuation 16.072 [5.102-50.633], registration of ascites 2.226 [1.448-3.420] or bilirubin >3 mg/dl 3.004 [1.935-4.664] during the follow-up, and disease progression 2.523 [1.261-5.050]. The appearance of NEH independently predicted OS 2.18 [1.55-3.06] in patients with radiological progression. Amongst 138 patients eligible for second-line treatment, PPS was 16.8 and 5.9 months in cases without and with NEH, respectively (P = .001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333-2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3 mg/dl and ascites. CONCLUSIONS: PPS of iCCA is influenced by progression pattern, with important implications for second-line trial design and analysis.

Statins increase pathological response in locally advanced rectal cancer treated with chemoradiation: a multicenter experience.

Aims: To investigate the influence of various concomitant medications on outcomes in patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. Materials & methods: The authors retrospectively identified 246 patients from 2003 to 2018, collecting demographic and clinicopathological data of interest. Odds ratio (OR) was used to assess the association between concomitant drugs and outcomes. Results: The authors found an association between statins and a Dworak regression grade of 3-4 (OR = 8.78; p = 0.01). Furthermore, statins were significantly associated with more frequent chemoradiation-related toxicity (OR = 2.39; p = 0.0098) and chemotherapy dose reduction or discontinuation (OR = 2.26; p = 0.03). Conclusion: Despite higher frequency of radiotherapy and chemotherapy interruption or dose reduction, the concomitant use of statins during neoadjuvant chemoradiation proved to be associated with better tumor regression.

A multicenter study of skin toxicity management in patients with left-sided, RAS/BRAF wild-type metastatic colorectal cancer treated with first-line anti-EGFR-based doublet regimen: is there room for improvement?

BACKGROUND: Skin toxicity in patients affected by metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors is well known. However, ad hoc ESMO guidelines have only recently been published. AIM AND METHODS: To describe the management (pre-emptive or reactive) of anti-EGFR-related cutaneous adverse events (AEs), in a real-life clinical context, in a selected population of patients with left-sided, metastatic RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR monoclonal antibody (i.e., panitumumab or cetuximab) as first-line regimen at 22 Institutions. The measured clinical outcomes were treatment-related adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 515 patients included in the analysis, 173 (33.6%) received a pre-emptive and 342 (66.4%) a reactive treatment. The median follow-up period for the overall population was 30.0 months. A significantly lower incidence of any grade acneiform rash was found in the pre-emptive compared to the reactive cohort both in the overall population (78.6% vs 94.4%, p < 0.001) and in patients treated with panitumumab (76.1% vs 93.7%, p < 0.001) or cetuximab (83.3% vs 95.4%, p = 0.004), respectively. A lower incidence of any grade (41.6% vs 50.9%, p = 0.047) but a higher incidence of G3-G4 (9.2% vs 4.7%, p = 0.042) paronychia/nail disorders were found in the pre-emptive compared to the reactive cohort. Nevertheless, a lower rate of patients within the reactive compared to the pre-emptive cohort was referred to dermatological counseling (21.4% vs 15.3%, respectively, p = 0.001). A higher rate of anti-EGFR therapy modification was needed in the pre-emptive compared to the reactive cohort (35.9% vs 41.6%, respectively, p < 0.001). The pre-emptive approach did not reduce the efficacy of antineoplastic therapy compared to the reactive in terms of ORR (69.2% vs 72.8%), median PFS (12.3 vs 13.0 months), and median OS (28.8 vs 33.5 months). CONCLUSION: Although recommended by international guidelines, the pre-emptive approach of anti-EGFR-related skin toxicity in mCRC patients still appears less adopted in daily clinical practice, compared to the reactive one. A wider reception and application of this indication is desirable to improve patients' quality of life without compromising the continuity and efficacy of antineoplastic therapy.

Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles. SUMMARY BACKGROUND DATA: FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed. METHODS: We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin. RESULTS: Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability. CONCLUSIONS: Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.

Brain Metastases from Biliary Tract Cancer: A Monocentric Retrospective Analysis of 450 Patients.

OBJECTIVE: Brain metastases (BMs) from biliary tract cancer (BTC) are extremely rare. The aim of our study was to report the incidence of BMs in patients with BTC. METHODS: We retrospectively analyzed a series of 450 patients with BTC. Presence of brain lesions was investigated only when symptoms were evident. Cumulative incidence, median overall survival (OS) from detection of BMs, median OS from cancer diagnosis, and median time from cancer diagnosis to detection of BMs were evaluated. RESULTS: In our series, 6 patients developed BMs with an incidence of about 1.4%. Median OS from detection of BMs and from cancer diagnosis was, respectively, 3.7 (0.9-17.8) and 23 (9.9-57.6) months. Median time between cancer diagnosis and detection of BMs was 13.6 (7.3-52.8) months. Moreover, we observed a significant association between BMs and bone metastases (particularly vertebral lesions). DISCUSSION: Despite the retrospective design, this is the first study evaluating the incidence of BMs among patients with BTC in Western countries. BMs from BTC remain atypical, although their incidence is probably a little higher than previously assumed. Patients with BMs had poor prognosis. Unpredictably, bone involvement occurred in 5 out of 6 patients.

Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial.

The search for systemic therapies for hepatocellular carcinoma has been characterized by difficulties and failures. Despite recent progresses, many issues are still to be settled. In particular, the development of drugs inhibiting different neoplastic pathways remains a priority for patients intolerant or resistant to antiangiogenic drugs. This task may be daunting, as previous failures extensively demonstrated. We aimed to identify the future perspective of postsorafenib trials analyzing the strengths and the critical points of past and currently undergoing studies, in the light of the most recent evidences in the field. We identified various points (including stratification, biomarkers, end points, radiologic criteria of response, treatment beyond radiologic progression) that should be considered by future trials to reduce the risks of failure.

Non-Coding RNAs as Predictive Biomarkers to Current Treatment in Metastatic Colorectal Cancer.

The onset and selection of resistant clones during cancer treatment with chemotherapy or targeted therapy is a major issue in the clinical management of metastatic colorectal cancer patients. It is possible that a more personalized treatment selection, using reliable response-to-therapy predictive biomarkers, could lead to an improvement in the success rate of the proposed therapies. Although the process of biomarker selection and validation could be a long one, requiring solid statistics, large cohorts and multicentric validations, non-coding RNAs (ncRNAs) and in particular microRNAs, proved to be extremely promising in this field. Here we summarize some of the main studies correlating specific ncRNAs with sensitivity/resistance to chemotherapy, anti-VEGF therapy, anti-EGFR therapy and immunotherapy in colorectal cancer (CRC).

Membrane Localization of Human Equilibrative Nucleoside Transporter 1 in Tumor Cells May Predict Response to Adjuvant Gemcitabine in Resected Cholangiocarcinoma Patients.

BACKGROUND: The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. METHODS: Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. RESULTS: Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24-0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI 0.34-2.68; three to four cycles: HR 0.99, 95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77). CONCLUSION: hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting. IMPLICATIONS FOR PRACTICE: Gemcitabine is becoming an increasingly used adjuvant modality in cholangiocarcinoma (CC), but limited data are available on predictive biomarkers of response. In this study, patients receiving more than four cycles of adjuvant gemcitabine and harboring Human equilibrative nucleoside transporter 1 (hENT-1, the major transporter involved in gemcitabine intracellular uptake) on tumor cell membrane had a longer disease-free survival compared with patients negative or positive for hENT-1 only in the cytoplasm of tumor cells. Overall these results may lay the basis for further prospective randomized trials based on a larger population of patients and may prove useful for tailoring appropriate gemcitabine-based chemotherapy for CC patients in the adjuvant setting.

Unraveling the Connection: Pancreatic Cancer Cells and Schwann Cells.

Pancreatic ductal adenocarcinoma is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. Progress in the management of metastatic disease has been modest. A robust connection between nervous system and tumor progression exists, with prominent neural alterations having been observed during pancreatic cancer's progression, including neural hypertrophy, neural density, and neural remodeling. The pancreatic tumor microenvironment includes s set of cells and structures that constantly dialogue with cancer cells, influencing its growth and behavior. The microglia is key cellular components of the tumor microenvironment, and Schwann cells are the principal glial cells in the peripheral neural system. Schwann cells can regulate changes in the tumor microenvironment and immune responses by secreting a variety of factors and can support a tumor's invasion of nerves and distant metastasis, with further pain exacerbation. Schwann cells secrete various pain-related molecules, such as the neural growth factor, to mediate the activation of primary sensory neurons, leading to pain induction. The binding of the neural growth factor to tropomyosin receptor kinase A is an important signaling mechanism for pain perception in humans. Consequently, directing efforts towards targeting neural invasion may provide an alternative strategy to improve the prognosis of and alleviate pain in patients with pancreatic cancer.

ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it. METHODS: Three paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance. RESULTS: Upregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel. CONCLUSION: Upregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.

Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab.

BACKGROUND: The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma. OBJECTIVE: We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes. METHODS: We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis. RESULTS: Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188). CONCLUSIONS: By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.

Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). OBJECTIVE: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. PATIENTS AND METHODS: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. RESULTS: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. CONCLUSION: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

Focus on Therapeutic Options for Surgically Resectable Pancreatic Adenocarcinoma Based on Novel Biomarkers.

Pancreatic ductal adenocarcinoma remains associated with a poor prognosis, even when diagnosed at an early stage. Consequently, it is imperative to carefully consider the available therapeutic options and tailor them based on clinically relevant biomarkers. In our comprehensive review, we specifically concentrated on the identification of novel predictive and prognostic markers that have the potential to be integrated into multiparametric scoring systems. These scoring systems aim to accurately predict the efficacy of neoadjuvant chemotherapy in surgically resectable pancreatic cancer cases. By identifying robust predictive markers, we can enhance our ability to select patients who are most likely to benefit from neoadjuvant chemotherapy. Furthermore, the identification of prognostic markers can provide valuable insights into the overall disease trajectory and inform treatment decisions. The development of multiparametric scoring systems that incorporate these markers holds great promise for optimizing the selection of patients for neoadjuvant chemotherapy, leading to improved outcomes in resectable pancreatic neoplasia. Continued research efforts are needed to validate and refine these markers and scoring systems, ultimately advancing the field of personalized medicine in pancreatic adenocarcinoma management.

A Simple Overview of Pancreatic Cancer Treatment for Clinical Oncologists.

Pancreatic cancer (PDAC) is one of the most aggressive solid tumors and is showing increasing incidence. The aim of our review is to provide practical help for all clinical oncologists and to summarize the current management of PDAC using a simple "ABC method" (A-anatomical resectability, B-biological resectability and C-clinical conditions). For anatomically resectable PDAC without any high-risk factors (biological or conditional), the actual standard of care is represented by surgery followed by adjuvant chemotherapy. The remaining PDAC patients should all be treated with initial systemic therapy, though the intent for each is different: for borderline resectable patients, the intent is neoadjuvant; for locally advanced patients, the intent is conversion; and for metastatic PDAC patients, the intent remains just palliative. The actual standard of care in first-line therapy is represented by two regimens: FOLFIRINOX and gemcitabine/nab-paclitaxel. Recently, NALIRIFOX showed positive results over gemcitabine/nab-paclitaxel. There are limited data for maintenance therapy after first-line treatment, though 5-FU or FOLFIRI after initial FOLFIRINOX, and gemcitabine, after initial gemcitabine/nab-paclitaxel, might be considered. We also dedicate space to special rare conditions, such as PDAC with germline BRCA mutations, pancreatic acinar cell carcinoma and adenosquamous carcinoma of the pancreas, with few clinically relevant remarks.

Bone Metastases from Intrahepatic Cholangiocarcinoma Confer Worse Prognosis.

BACKGROUND: Metastatic intrahepatic cholangiocarcinoma still has a dismal prognosis. The aim of our study was to investigate the prognostic role of bone metastases in patients affected by intrahepatic cholangiocarcinoma. METHODS: A total of 186 metastatic intrahepatic cholangiocarcinoma patients were retrospectively reviewed. Clinicopathologic and survival data were collected and reviewed, in particular overall survival, progression-free survival after first-line treatment and time from end of first-line therapy to cancer death. RESULTS: Around 11% of intrahepatic cholangiocarcinoma patients developed bone metastases. This subgroup of patients showed no differences in progression-free survival to first-line chemotherapy but had a shorter median overall survival of 4 months compared to the group with liver involvement only (p = 0.03). If treated, the outcome for ECOG PS 2 patients with bone metastases was worse in comparison to patients with liver involvement only with poor performance status (p = 0.003). The presence of bone metastases, poor performance status and no subsequent second-line treatment was associated with a worse outcome in multivariate analysis. CONCLUSIONS: Patients with intrahepatic carcinoma and bone metastases with poor ECOG performance status might be treated with best supportive care and not active chemotherapy treatment, the decisions which have to be shared with patients.

Early Onset Metastatic Colorectal Cancer: Current Insights and Clinical Management of a Rising Condition.

Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include not only genetic syndromes but also other risk factors, such as microbiome alteration, antibiotic exposure, obesity, diabetes mellitus, and inflammatory bowel disease. EOCRC tends to be diagnosed later than in the older counterpart because of a lack of awareness and the fact that screening for CRC usually starts at the age of 50. Furthermore, CRC in young adults seems to be related to unique molecular features and more aggressive clinical behavior. This paper aims to provide an in-depth review of this poorly understood subject, with a comprehensive review of the state of the art and considerations for future perspectives.

Prognostic Impact of Metastatic Site in Patients Receiving First-Line Sorafenib Therapy for Advanced Hepatocellular Carcinoma.

Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate.