Repeated Cytoreduction Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Selected Patients Affected by Peritoneal Metastases: Italian PSM Oncoteam Evidence.

The reiteration of surgical cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients affected by recurrent peritoneal metastases is still questioned regarding safety and effectiveness. This study evaluates the safety, efficacy, and associated factors of iterative CRS combined with HIPEC. This multicentric retrospective study collected data from four surgical oncology centers, on iterative HIPEC. We gathered data on patient and cancer characteristics, the peritoneal cancer index (PCI), completeness of cytoreduction (CC), postoperative complications, and overall survival (OS). In the study period, 141 CRS-plus-HIPECs were performed on 65 patients. Nine patients underwent three iterative procedures, and one underwent five. No increased incidence of complications after the second or third procedure was observed. Furthermore, operative time and hospitalization stay were significantly shorter after the second than after the first procedure (p < 0.05). Optimal cytoreduction was achieved in more than 90% of cases in each procedure, whether first, second, or third. A five-year (5 y) OS represented 100% of the cases of diffuse malignant-peritoneal-mesotheliomas, 81.39% of pseudomyxoma peritonei, 34.67% of colorectal cancer (CRC), and 52.50% of ovarian cancer. During the second CRS combined with HIPEC, we observed a lower rate of complete cytoreduction and a non-significantly better survival in cases with complete cytoreduction (5 y-OS CC-0 56.51% vs. 37.82%, p = 0.061). Concomitant hepatic-CRC-metastasis did not compromise the CRS-plus-HIPEC safety and efficacy. This multicentric experience encourages repeated CRS-plus-HIPEC, showing promising results.

Diagnostic and Therapeutic Pathway in Diffuse Malignant Peritoneal Mesothelioma.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare form of mesothelioma that carries a very poor prognosis. The 5-year overall survival is about 20% (±5.9). Survival is optimal for patients suitable for cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), with a median OS ranging from 34 to 92 months. However, selecting patients for surgery remains a complex task and requires a careful preoperative workup, rational analysis of prognostic profiles, and risk prediction models. Systemic chemotherapy could be offered: (1) in the adjuvant setting for high-risk patients; (2) for patients not eligible for CRS; and (3) for those with recurrent disease. It mainly includes the combination of Platin compound with Pemetrexed or immunotherapy. The biology of DMPM is still largely unknown. However, progress has been made on some fronts, such as telomere maintenance mechanisms, deregulation of apoptosis, tyrosine kinase pathways, and mutation of BRCA1-associated protein 1 (BAP1). Future perspectives should include translational research to improve our understanding of the disease biology to identify druggable targets. We should also clear the role of immune checkpoint inhibitors and investigate new locoregional technologies, such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) or normothermic intraperitoneal chemotherapy (NIPEC).

Diagnostic and Therapeutic Pathway of Advanced Ovarian Cancer with Peritoneal Metastases.

Over two thirds of ovarian cancer patients present with advanced stage disease at the time of diagnosis. In this scenario, standard treatment includes a combination of cytoreductive surgery and carboplatinum-paclitaxel-based chemotherapy. Despite the survival advantage of patients treated with upfront cytoreductive surgery compared to women undergoing neo-adjuvant chemotherapy (NACT) and interval debulking surgery (IDS) due to high tumor load or poor performance status has been demonstrated by multiple studies, this topic is still a matter of debate. As a consequence, selecting the adequate treatment through an appropriate diagnostic pathway represents a crucial step. Aiming to assess the likelihood of leaving no residual disease at the end of surgery, the role of the CT scan as a predictor of cytoreductive outcomes has shown controversial results. Similarly, CA 125 level as an expression of tumor load demonstrated limited applicability. On the contrary, laparoscopic assessment of disease distribution through a validated scoring system was able to identify, with the highest specificity, patients undergoing suboptimal cytoreduction and therefore best suitable for NACT-IDS. Against this background, with this article, we aim to provide a comprehensive review of available evidence on the diagnostic and treatment pathways of advanced ovarian cancer.

Risk factors for anastomotic leakage after anterior resection for rectal cancer (RALAR study): A nationwide retrospective study of the Italian Society of Surgical Oncology Colorectal Cancer Network Collaborative Group.

AIM: Anastomotic leakage after restorative surgery for rectal cancer shows high morbidity and related mortality. Identification of risk factors could change operative planning, with indications for stoma construction. This retrospective multicentre study aims to assess the anastomotic leak rate, identify the independent risk factors and develop a clinical prediction model to calculate the probability of leakage. METHODS: The study used data from 24 Italian referral centres of the Colorectal Cancer Network of the Italian Society of Surgical Oncology. Patients were classified into two groups, AL (anastomotic leak) or NoAL (no anastomotic leak). The effect of patient-, disease-, treatment- and postoperative outcome-related factors on anastomotic leak after univariable and multivariable analysis was measured. RESULTS: A total of 5398 patients were included, 552 in group AL and 4846 in group NoAL. The overall incidence of leaks was 10.2%, with a mean time interval of 6.8 days. The 30-day leak-related mortality was 2.6%. Sex, body mass index, tumour location, type of approach, number of cartridges employed, weight loss, clinical T stage and combined multiorgan resection were identified as independent risk factors. The stoma did not reduce the leak rate but significantly decreased leak severity and reoperation rate. A nomogram with a risk score (RALAR score) was developed to predict anastomotic leak risk at the end of resection. CONCLUSIONS: While a defunctioning stoma did not affect the leak risk, it significantly reduced its severity. Surgeons should recognize independent risk factors for leaks at the end of rectal resection and could calculate a risk score to select high-risk patients eligible for protective stoma construction.

A New Score to Assess the Perioperative Period of the Cancer Patient Undergoing Non-Palliative Elective Surgery: A Retrospective Evaluation of a Case Report by PERIDIA Score.

The complexity of cancer patients and the use of advanced and demolitive surgical techniques frequently need post-operatory ICU hospitalization. To increase safety and to select the best medical strategies for the patient, a multidisciplinary team has performed a new peri-operatory assessment, arising from evidence-based literature data. Verifying that most of the cancer patients, admitted to the intensive care unit, undergo major surgery with localizations in the supramesocolic thoraco-abdominal area, the team focused the attention on supramesocolic peridiaphragmatic cancer surgery. Some scores already in use in clinical practice were selected for the peri-operatory evaluation process. None of them evaluate parameters relating to the entire peri-operative period. In detail, only a few study models were found that concern the assessment of the intra-operative period. Therefore, we wanted to see if using a mix of validated scores, it was possible to build a single evaluation score (named PERIDIAphragmatic surgery score or PERIDIA-score) for the entire peri-operative period that could be obtained at the end of the patient's hospitalization period in post-operative ICU. The main property sought with the creation of the PERIDIA-score is the proportionality between the score and the incidence of injuries, deaths, and the length of stay in the ward. This property could organize a tailor-made therapeutic path for the patient based on pre-rehabilitation, physiotherapy, activation of social assistance services, targeted counseling, collaborations with the continuity of care network. Furthermore, if the pre-operative score is particularly high, it could suggest different or less invasive therapeutic options, and if the intra-operative score is particularly high, it could suggest a prolongation of hospitalization in ICU. The retrospective prospective study conducted on 83 patients is still ongoing. The first data would seem to prove an increase of clinical complications in patients who were assigned a one-third score with respect to the maximum (16/48) of PERIDIA-score. Moreover, patients with a 10/16 score within each phase of the evaluation (pre, peri, and post) more frequently develop injuries. In the light of these evidence, the 29-point score assigned to our patient can be considered as predictive for the subsequent critical and fatal complications the patient faced up.

Remote mentoring in laparotomic and laparoscopic cancer surgery during Covid-19 pandemic: an experimental setup based on mixed reality.

In this paper, Mixed Reality (MR) has been exploited in the operating rooms to perform laparoscopic and open surgery with the aim of providing remote mentoring to the medical doctors under training during the Covid-19 pandemic. The employed architecture, which has put together MR smartglasses, a Digital Imaging Player, and a Mixed Reality Toolkit, has been used for cancer surgery at the IRCCS Hospital 'Giovanni Paolo II' in southern Italy. The feasibility of using the conceived platform for real-time remote mentoring has been assessed on the basis of surveys distributed to the trainees after each surgery.

The Interaction between Reactive Peritoneal Mesothelial Cells and Tumor Cells via Extracellular Vesicles Facilitates Colorectal Cancer Dissemination.

Advanced colorectal cancer (CRC) is highly metastatic and often results in peritoneal dissemination. The extracellular vesicles (EVs) released by cancer cells in the microenvironment are important mediators of tumor metastasis. We investigated the contribution of EV-mediated interaction between peritoneal mesothelial cells (MCs) and CRC cells in generating a pro-metastatic environment in the peritoneal cavity. Peritoneal MCs isolated from peritoneal lavage fluids displayed high CD44 expression, substantial mesothelial-to-mesenchymal transition (MMT) and released EVs that both directed tumor invasion and caused reprogramming of secretory profiles by increasing TGF-ß1 and uPA/uPAR expression and MMP-2/9 activation in tumor cells. Notably, the EVs released by tumor cells induced apoptosis by activating caspase-3, peritoneal MC senescence, and MMT, thereby augmenting the tumor-promoting potential of these cells in the peritoneal cavity. By using pantoprazole, we reduced the biogenesis of EVs and their pro-tumor functions. In conclusion, our findings provided evidence of underlying mechanisms of CRC dissemination driven by the interaction of peritoneal MCs and tumor cells via the EVs released in the peritoneal cavity, which may have important implications for the clinical management of patients.

Study Protocol: Phase I Dose Escalation Study of Oxaliplatin, Cisplatin and Doxorubicin Applied as PIPAC in Patients with Peritoneal Metastases.

Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel laparoscopic intraperitoneal chemotherapy approach offered in selected patients affected by non-resectable peritoneal carcinomatosis. Drugs doses currently established for nebulization are very low: oxaliplatin (OXA) 120 mg/sm, cisplatin (CDDP) 10.5 mg/sm and doxorubicin (DXR) 2.1 mg/sm. A model-based approach for dose-escalation design in a single PIPAC procedure and subsequent dose escalation steps is planned. The starting dose of oxaliplatin is 100 mg/sm with a maximum estimated dose of 300 mg/sm; an escalation with overdose and under-dose control (for probability of toxicity less than 16% in case of under-dosing and probability of toxicity greater than 33% in case of overdosing) will be further applied. Cisplatin is used in association with doxorubicin: A two-dimensional dose-finding design is applied on the basis of the estimated dose limiting toxicity (DLT) at all combinations. The starting doses are 15 mg/sm for cisplatin and 3 mg/sm for doxorubicin. Safety is assessed according to Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Secondary endpoints include radiological response according to Response Evaluation Criteria in Solid Tumor (version 1.1) and pharmacokinetic analyses. This phase I study can provide the scientific basis to maximize the optimal dose of cisplatin, doxorubicin and oxaliplatin applied as PIPAC.

A Phase I Dose Escalation Study of Oxaliplatin, Cisplatin and Doxorubicin Applied as PIPAC in Patients with Peritoneal Carcinomatosis.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an innovative laparoscopic intraperitoneal chemotherapy approach with the advantage of a deeper tissue penetration. Thus far, oxaliplatin has been administered at an arbitrary dose of 92 mg/m2, cisplatin at 7.5 mg/m2 and doxorubicin 1.5 mg/m2. This is a model-based approach phase I dose escalation study with the aim of identifying the maximum tolerable dose of the three different drugs. The starting dose of oxaliplatin was 100 mg/m2; cisplatin was used in association with doxorubicin: 15 mg/m2 and 3 mg/m2 were the respective starting doses. Safety was assessed according to Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Thirteen patients were submitted to one PIPAC procedure. Seven patients were treated with cisplatin and doxorubicin and 6 patients with oxaliplatin; no dose limiting toxicities and major side effects were found. Common adverse events included postoperative abdominal pain and nausea. The maximum tolerable dose was not reached. The highest dose treated cohort (oxaliplatin 135 mg/m2; cisplatin 30 mg/m2 and doxorubicin 6 mg/m2) tolerated PIPAC well. Serological analyses revealed no trace of doxorubicin at any dose level. Serum levels of cis- and oxaliplatin reached a peak at 60-120 min after PIPAC and were still measurable in the circulation 24 h after the procedure. Cisplatin and doxorubicin may be safely used as PIPAC at a dose of 30 mg/m2 and 6 mg/m2, respectively; oxaliplatin can be used at an intraperitoneal dose of 135 mg/m2. The dosages achieved to date are the highest ever used in PIPAC.

Transanal reinforcement of low rectal anastomosis versus protective ileostomy after total mesorectal excision for rectal cancer. Preliminary results of a randomized clinical trial.

AIM: The study aimed to show if transanal reinforcement of the suture line can prevent anastomotic leakage (AL) after rectal cancer surgery, thus avoiding the need for a covering ileostomy. METHODS: This is a prospective, multicentre, parallel-arm randomized controlled equivalence trial. After standard total mesorectal excision, patients with anastomotic line at 1-3 cm from the dentate line were randomized to have transanal suture reinforcement (TAR group) or protective ileostomy (PI group). RESULTS: Twenty-nine patients had PI, 25 had TAR. The two groups were comparable both for baseline characteristics and intra-operative aspects. Clinically evident AL occurred in four (16%) and five (17.24%) patients of the TAR and PI group, respectively, resulting in a difference of -1.20% (90% CI -17.93, 15.45), while subclinical AL at proctography was absent in 15 (65.22%) and 13 (50%) patients of the TAR and PI groups, respectively, resulting in a difference of 15% (90% CI -7.74 to 38.17). CONCLUSION: Preliminary data suggest that transanal reinforcement of the suture line performed in rectal cancer patients with suture line at 1-3 cm from the dentate line carries a similar (even if not equivalent) AL rate to covering ileostomy, suggesting that a covering ileostomy could be avoided in this selected group of patients. This indication needs to be addressed with future larger trials (clinicaltrials.gov ID number NCT02279771).

Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience.

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010-2018) in two different centers. Fifty patients (median age 52.5 years, range 34-75) were included; the median number of previous chemotherapy lines was three (range 1-7) and the median number of previous surgeries was one (range 1-4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC > 0 subgroup (median OS 32.9 months (95% CI 21.6-44.2) vs. 4.8 months (95% CI n.a.-9.8), hazard ratio (HR) 4.21 (95% CI 2.07-8.60), p < 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease.

Improved Outcome Prediction for Appendiceal Pseudomyxoma Peritonei by Integration of Cancer Cell and Stromal Transcriptional Profiles.

In recent years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have substantially improved the clinical outcome of pseudomyxoma peritonei (PMP) originating from mucinous appendiceal cancer. However, current histopathological grading of appendiceal PMP frequently fails in predicting disease outcome. We recently observed that the integration of cancer cell transcriptional traits with those of cancer-associated fibroblasts (CAFs) improves prognostic prediction for tumors of the large intestine. We therefore generated global expression profiles on a consecutive series of 24 PMP patients treated with CRS plus HIPEC. Multiple lesions were profiled for nine patients. We then used expression data to stratify the samples by a previously published "high-risk appendiceal cancer" (HRAC) signature and by a CAF signature that we previously developed for colorectal cancer, or by a combination of both. The prognostic value of the HRAC signature was confirmed in our cohort and further improved by integration of the CAF signature. Classification of cases profiled for multiple lesions revealed the existence of outlier samples and highlighted the need of profiling multiple PMP lesions to select representative samples for optimal performances. The integrated predictor was subsequently validated in an independent PMP cohort. These results provide new insights into PMP biology, revealing a previously unrecognized prognostic role of the stromal component and supporting integration of standard pathological grade with the HRAC and CAF transcriptional signatures to better predict disease outcome.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Oxaliplatin, Cisplatin, and Doxorubicin in Patients with Peritoneal Carcinomatosis: An Open-Label, Single-Arm, Phase II Clinical Trial.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative approach for treating peritoneal carcinomatosis that applies chemotherapeutic drugs into the peritoneal cavity as an under-pressure airflow. It improves local bioavailability of cytostatic drugs as compared to conventional intraperitoneal chemotherapy. The aim of this study is to prove feasibility, efficacy and safety of this new treatment. Patients included in the analysis underwent at least two single port PIPAC procedures; drugs used were Oxaliplatin for colorectal cancers and Cisplatin + Doxorubicin for ovarian, gastric, and primary peritoneal cancers. The primary endpoint was the Disease Control Rate according to the RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Secondary significant endpoints were overall and progression free survival, tumor regression on histology, and quality of life. Safety and tolerability were assessed according to the Common Terminology Criteria for Adverse Events 4. Sixty-three patients were enrolled in this trial. Forty patients (100 PIPAC) were eligible for analysis. Twenty patients were undergoing systemic chemotherapy. Fourteen patients reported an objective response (35%). Median overall survival was 18.1 months; median progression-free survival was 7.4 months. Minor morbidity was observed in seven procedures. Grade 3 complications occurred in two patients, and grade 4 in one patient submitted to reoperation. Single-port PIPAC is feasible, safe, and easy to perform. The combined treatment based on systemic chemotherapy and PIPAC does not induce significant hepatic and renal toxicity and can be considered a valid therapeutic option in patients with advanced peritoneal disease. Further studies on the use of PIPAC alone, possibly with different drug dosages, may define the real effectiveness of the procedure.

An Intrapancreatic accessory spleen presenting as a neuroendocrine tumor.

Although the second most common site of the accessory spleen is the tail of the pancreas, intrapancreatic accessory spleens (IPAS) are rarely recognized radiologically. When an accessory spleen is located in the pancreas, it may mimic a hypervascular pancreatic tumor. We report a case of intrapancreatic accessory spleen which radiologically (on TC) mimicked a neuroendocrine pancreatic tumor (PNET). It was not possible to be sure that the pancreatic nodule had no malignant potential; because of the close proximity to splenic vessel we performed en bloc resection of the spleen and distal pancreas. Postoperative course was uneventful. IPAS must be considered in the differential diagnosis of pancreatic tail tumors, particulary an asymptomatic small PNET; new and adequate diagnostic studies have demonstrated utility in defining these lesions. We review pertinent literature. KEY WORD: Intrapancreatic accessory spleen, Pancreatic neuroendocrine tumor.

Precision oncotherapy based on liquid biopsies in multidisciplinary treatment of unresectable recurrent rectal cancer: a retrospective cohort study.

BACKGROUND: Third line innovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have both been proposed for the treatment of unresectable not responsive recurrent rectal cancer (URRC). In the present study, we have compared the safety and efficacy of HPP/target therapy, using drug regimens selected by liquid biopsy precision oncotherapy, to third-line systemic therapy based on tissue specimens precision oncotherapy. METHODS: HPP/target therapy regimens were selected based on precision oncotherapy, including assays for chemosensitivity and viability, and qRT-PCR for tumor-related gene expression. In the control group, systemic third-line and further lines of therapy were defined according to clinical and biological parameters. RESULTS: From 2007 to 2019, 62 URRC patients were enrolled, comprised of 43 patients in the HPP/target-therapy group and 19 patients in the systemic therapy control group. No HPP related complications were reported and the most common adverse events were skin and bone marrow toxicity. In the HPP/target-therapy group, the ORR was 41.8% whereas in the systemic therapy control group was 15.8%. DCR of the HPP/target-therapy group was significantly improved over the systemic therapy group (P = 0.001), associated with a PFS of 8 vs 4 months (P = 0.009), and OS of 20 vs 8 months (P = 0.046). CONCLUSIONS: The present data indicate that in URCC patients, the integration of HPP/target-therapy and precision oncotherapy based upon liquid biopsy is as effective and efficacious as third-line treatment in local disease control and, therefore, deserves to be further assessed and compared to conventional systemic treatments in future prospective randomized trials.

Short-term outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy used as treatment of colo-rectal carcinomatosis: a multicentric study.

The aim of this study is to assess the morbidity and mortality related to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colo-rectal carcinomatosis. A retrospective multi-institutional study from seven Italian Centers was performed. One hundred and seventy-two patients, submitted to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) to treat carcinomatosis of colorectal origin, were recorded. Postoperative morbidity was evaluated in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Post-operative mortality was evaluated as patients' death within 60 days from surgical procedures. Predictors of morbidity were evaluated with univariate and multivariate analyses. Post-operative morbidity occurred in 83 patients (48.3%): grades 1-2 in 29 cases (16.9%), and grades 3-4 in 54 (31.4%). Mortality occurred in four cases (2.3%). Number of anastomoses (OR 1.45; 95% CI 1.05-2.00; p = 0.024), number of blood transfusions (OR 1.31; 95% CI 1.11-1.54; p = 0.001) and chemotherapy regimen [Oxaliplatin (OX): OR 2.87; 95% CI 1.22-6.75; p = 0.015] remained, in multivariate analysis, in a statistically significant correlation with overall morbidity. The only variable that was proven to have statistically significant correlation with 3-4 morbidity was the number of blood transfusions (OR 1.25; 95% CI 1.07-1.46; p = 0.005). Morbidity and mortality do not preclude the use of CRS plus HIPEC in the treatment of peritoneal carcinomatosis of colorectal origin.

Synergism of Adipocytokine Profile and ADIPOQ/TNF-α Polymorphisms in NAFLD-associated MetS Predict Colorectal Liver Metastases Outgrowth.

BACKGROUND/AIM: The aim of this study was to evaluate whether the altered profile of adipocytokine and genetic fingerprint in NAFLD-associated metabolic syndrome "cluster" represents synergistic risk factors predicting onset of liver colorectal cancer metastases. MATERIALS AND METHODS: A total of 165 colorectal cancer patients were enrolled, 56,3% were with metabolic syndrome/NAFLD. Serum samples were assayed for ADIPOQ, leptin and TNF-a levels by ELISA. ADIPOQ rs266729 C/G and TNF-308 A/G genotypes were analyzed in DNA isolated from whole blood. RESULTS: Reduction in adiponectin levels and increase in leptin and TNF-α was shown in patients with liver metastases. This trend was influenced by BMI, MetS/NAFLD, and insulin resistance. ADIPOQ G rs266729 and TNF- 308 A allele are associated with obesity, MetS/NAFLD and insulin resistance. ADIPOQ CG/GG and GA/AA TNF-alpha genotypes confer susceptibility to liver metastases. CONCLUSION: Obesity and hepatic steatosis significantly favor the development of colorectal cancer liver metastases and the individual adipocytokines genetic profile may play an important predictive role.

A Comprehensive PDX Gastric Cancer Collection Captures Cancer Cell-Intrinsic Transcriptional MSI Traits.

Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell-intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell-intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis. SIGNIFICANCE: This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.