Total Versus Subtotal Gastrectomy for Distal Gastric Poorly Cohesive Carcinoma.

BACKGROUND: Gastric poorly cohesive carcinoma (PCC) in advanced stages has a poor prognosis. Total gastrectomy (TG) remains the common treatment for distal gastric PCC, but subtotal gastrectomy (SG) may improve quality of life without compromising outcomes. Currently, no clear recommendation on the best surgical strategy for distal PCC is available. This study aimed to compare overall survival (OS) and disease-free survival (DFS) at 5 years for patients with antropyloric PCC treated by total versus subtotal gastrectomy. METHODS: A large retrospective European multicenter cohort study analyzed 2131 patients treated for gastric cancer between 2007 and 2017 by members of the French Association of Surgery (AFC). The study compared a group of patients who underwent TG with a group who underwent SG for antropyloric PCC. The primary outcomes were 5 year OS and DFS. RESULTS: The study enrolled 269 patients: 140 (52.0%) in the TG group and 129 (48.0%) in the SG group. The baseline characteristics and pTNM stage were similar between the two groups. According to Dindo-Claven classification, the patients treated with TG had more postoperative complications than the patients treated with SG (p < 0.001): grades I to IIIa (77.1% vs 59.5%) and grades IIIb to IVb (14.4% vs 9.0%). No difference in 5-year OS was observed between TG (53.8%; 95 % confidence interval [CI], 43.2-63.3%) and SG (53.0%; 95% CI, 41.4-63.3%) (hazard ratio [HR], 0.94; 95% CI, 0.68-1.29). The same was observed for 5-year DFS: TG (46.0%; 95% CI, 35.9-55.5%) versus SG (45.3%; 95% CI, 34.3-55.6%) (HR, 0.97; 95% CI, 0.70-1.34). CONCLUSIONS: At 5 years, SG was not associated with worse OS and DFS than TG for distal PCC. Surgical morbidity was higher after TG. Subtotal gastrectomy is a valuable option for distal PCC gastric cancer.

Signet ring cells and conditional survival after trimodality therapy for esophageal adenocarcinoma.

BACKGROUND AND METHODS: Although signet ring cell (SRC) histology is associated with resistance to neoadjuvant chemoradiotherapy and worse overall survival (OS) in esophageal adenocarcinoma (EAC), its prognostic relationship among patients who survive the early period following resection is unknown. EAC patients who underwent trimodality therapy at a single institution (2006-2018) were identified. Bayesian multivariable regression (BMR) analyses of OS and additional OS from a 3-year landmark were performed. RESULTS: Of 631 patients, SRCs were present in 16.0% (N = 101). SRC was associated with shorter median OS (45.8 [95% confidence interval: 31.0-96.7] vs. 79.8 [63.0-107.2] months; p = 0.014). In BMR analysis, the absence of an SRC component was moderately associated with improved OS (probability of beneficial effect, PBE = 0.879). Three-year conditional BMR analysis of additional OS (N = 357) showed that SRC status no longer had a prognostic effect (PBE = 0.546); higher pathological stage was strongly associated with worse additional OS (PBE < 0.001). CONCLUSIONS: The presence of SRC portends worse OS following trimodality therapy for EAC. However, this prognostic impact is dynamic and abates by 3 years postoperatively. In contrast, a higher pathological stage is strongly associated with poor overall and 3-year conditional survival. DISCUSSION: These findings may inform postoperative patient counseling and surveillance protocols.

The correlation between the margin of resection and prognosis in esophagogastric junction adenocarcinoma.

Adenocarcinoma of the gastroesophageal junction (AEG) has become increasingly common in Western and Asian populations. Surgical resection is the mainstay of treatment for AEG; however, determining the distance from the upper edge of the tumor to the esophageal margin (PM) is essential for accurate prognosis. Despite the relevance of these studies, most have been retrospective and vary widely in their conclusions. The PM is now widely accepted to have an impact on patient outcomes but can be masked by TNM at later stages. Extended PM is associated with improved outcomes, but the optimal PM is uncertain. Academics continue to debate the surgical route, extent of lymphadenectomy, preoperative tumor size assessment, intraoperative cryosection, neoadjuvant therapy, and other aspects to further ensure a negative margin in patients with gastroesophageal adenocarcinoma. This review summarizes and evaluates the findings from these studies and suggests that the choice of approach for patients with adenocarcinoma of the esophagogastric junction should take into account the extent of esophagectomy and lymphadenectomy. Although several guidelines and reviews recommend the routine use of intraoperative cryosections to evaluate surgical margins, its generalizability is limited. Furthermore, neoadjuvant chemotherapy and radiotherapy are more likely to increase the R0 resection rate. In particular, intraoperative cryosections and neoadjuvant chemoradiotherapy were found to be more effective for achieving negative resection margins in signet ring cell carcinoma.

Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma - the phase III "PREVENT"- (FLOT9) trial of the AIO /CAOGI /ACO.

BACKGROUND: The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40-50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60-70% of tumors of diffuse type, compared to only 20-30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since pts. with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. METHODS: This is a multicenter, randomized, controlled, open-label study including a total of 200 pts. with localized and locally advanced diffuse or mixed type (Laurens's classification) adenocarcinoma of the stomach and Type II/III GEJ. All enrolled pts. will have received 3-6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m2; Oxaliplatin 85 mg/m2; Leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (control arm) or surgery + intraoperative HIPEC (cisplatin 75 mg/m2 solution administered at a temperature of 42 °C for 90 min) and postoperative FLOT (experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, rate of pts. with peritoneal relapse at 2 and 3 years, perioperative morbidity/mortality and quality of life. The trial starts with a safety run-in phase. After 20 pts. had curatively intended resection in Arm B, an interim safety analysis is performed. Recruitment has already started and first patient in was on January 18th, 2021. DISCUSSION: If the PREVENT concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, pts. with gastric cancer and no peritoneal involvement will not be treated with HIPEC during surgery. TRIAL REGISTRATION: The study is registered on June 25th, 2020 under ClinicalTrials.gov Identifier: NCT04447352 ; EudraCT: 2017-003832-35 .

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer.

BACKGROUND: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin-eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. METHODS: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. RESULTS: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. CONCLUSIONS: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.

Pathological features of total gastrectomy specimens from asymptomatic hereditary diffuse gastric cancer patients and implications for clinical management.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant syndrome characterised by multigenerational diffuse gastric cancer, and is mainly caused by germline alterations in the CDH1 gene. Currently, endoscopy has limited diagnostic accuracy, and total gastrectomy (TG) is the treatment of choice for asymptomatic CDH1 carriers. In this study, we aimed to obtain a better understanding of HDGC syndrome by exploring the histopathological findings of TG specimens from asymptomatic HDGC patients. A comprehensive literature review was carried out, searching for TGs performed in asymptomatic HDGC patients. Fourteen unpublished cases, analysed in our institution, were also included. The series encompassed 174 CDH1 carriers. Preoperative endoscopic biopsies were positive in 28.3%. A macroscopic lesion was apparent in 11.7% of TGs. Histopathological analysis revealed intraepithelial lesions and/or intramucosal signet ring cell carcinoma in 87.9% of TGs. When we explored the type of protocol used for handling the specimens, we found that microscopic cancer foci were detected in 95.3% of TGs when a total-embedding protocol (assessment of the totality of gastric mucosa) was applied, and only in 62.5% when no specific protocol was used (P < 0.001). Helicobacter pylori infection was found in 23.4% cases. In conclusion, a thorough histopathological examination of gastric mucosa remains the gold standard for detection of cancer foci in HDGC gastrectomy specimens, requiring experienced pathologists for an accurate diagnosis. A better understanding of the natural history of HDGC will enable better clinical management of HDGC patients, particularly regarding the optimal timing for the performance of TG.

Gastric Adenocarcinomas in Central Tunisia: Evolution Specificities through Two Decades and Relation with Helicobacter pylori.

INTRODUCTION: In developed countries, authors have reported variations over time in the seat and histological type of gastric adenocarcinomas, which were explained by Helicobacter pylori infection (HPI) incidence changes. In North-African countries and the Arabic world, epidemiological changes in gastric adenocarcinomas are still unknown. Our study aims to explore and to describe those changes in central Tunisia. MATERIALS AND METHODS: This is a retrospective observational and descriptive study including 876 cases based on the National Central Tunisian Register of Cancers over a period of 21 years. Two groups were formed and compared (group A: 337 patients from 1995 to 2005; group B: 539 patients from 2006 to 2015). RESULTS: HPI decreased from 32.6% in group A to 11.2% in group B (p < 0.05). Signet ring cell carcinomas increased in 2 decades from 14% in group A to 36% in group B (p < 0.05). Proximal cancers were 16.61% in group A and increased to 19.66% in group B (p = 0.3). Total gastrectomy rate was 10.4% in group A versus 23.2% in group B (p < 0.05). CONCLUSION: This study has shown a significant increase of signet ring cell carcinomas with a simultaneous decrease in HPI in the last decade in central Tunisia.

Contemporary rates of pathological features and mortality for adenocarcinoma of the urinary bladder in the USA.

OBJECTIVES: To examine contemporary rates of pathological features and mortality for adenocarcinoma of the urinary bladder in the USA using population-based data analysis. METHODS: We relied on 10 024 patients with non-metastatic bladder cancer diagnosed between 2004 and 2013 within the Surveillance, Epidemiology and End Results registries. Logistic regression analyses focused on grade and stage. Kaplan-Meier analyses assessed cancer-specific mortality rates in adenocarcinoma and urothelial carcinoma of the bladder. Cox regression analyses assessed the impact of histological subtype on cancer-specific mortality. RESULTS: Overall, 215 (2.1%) adenocarcinoma and 9809 (97.9%) urothelial carcinoma patients were identified. The rate of non-organ-confined disease was higher in adenocarcinoma (64.7% vs 50.8%, P < 0.001). In multivariable logistic regression analyses, adenocarcinoma patients had a 2.2-fold higher risk of harboring non-organ-confined disease (95% confidence interval 1.7-3.0; P < 0.001) than urothelial carcinoma patients. Cancer-specific mortality-free survival rates were lower in adenocarcinoma (P < 0.01). This disadvantage only applied to non-organ-confined disease (P = 0.044), and not to organ-confined disease (P = 0.9). In multivariable Cox regression analyses, adenocarcinoma conferred a 1.3-fold higher rate of cancer-specific mortality (hazard ratio 1.30, 95% confidence interval 1.05-1.60; P = 0.01). Among adenocarcinoma patients, 30.7% harbored signet-ring cell adenocarcinoma and portended particularly poor cancer-specific mortality rates. CONCLUSIONS: In bladder cancer, adenocarcinoma presents at higher stages than urothelial carcinoma. However, cancer-specific mortality rates do not differ. A more unfavorable stage at diagnosis and higher cancer-specific mortality apply to the signet-ring cell variant.

Appendiceal Neoplasm: It's Never What It Seems.

Appendiceal neoplasms are a rare and heterogeneous condition with a non-specific clinical presentation, often concealing intricate predicaments; hence they require complex and diverse management. The present case report aims not only to describe a less usual form of presentation and its orientation but also to provide a modest literature review in a rather demanding pathology.

A Rare Case of Cutaneous Gastric Adenocarcinoma With Signet Ring Cell Features.

Cutaneous metastatic disease from primary gastric cancer is quite scarce, often going unrecognized. In this case, the patient presented with an expanding rash that was biopsied, with findings concerning for metastatic adenocarcinoma from a suspected luminal upper gastrointestinal origin. Subsequent biopsies during an esophagogastroduodenoscopy confirmed poorly differentiated adenocarcinoma with signet ring cell features, most likely from an upper gastrointestinal primary (gastric vs gastroesophageal junction). We review this case to help providers identify signet cell type cutaneous metastases of gastric cancer quickly to improve patient outcomes.

Krukenberg Tumour in a 34-Year-Old Female: A Case Report.

A metastatic condition involving signet ring cells rich in mucin is the Krukenberg tumor, which affects the ovaries. Usually, the metastatic disease does not include both ovaries and usually originates from the stomach side, while it can also occur less frequently from other locations. Krukenberg tumors are uncommon in younger age groups and usually occur after the age of 40. We report a case of a 34-year-old female patient with a primary form of past medical history. The patient was treated with multiple rounds of chemotherapy.

The impact of the length of proximal margin on the prognosis in adenocarcinoma of gastroesophageal junction: A real-world study and strategies.

BACKGROUND: The optimal proximal margin (PM) length for Siewert II/III adenocarcinoma of the esophagogastric junction (AEJ) remains unclear. This study aimed to determine the optimal PM length using an abdominal approach to guide surgical decision-making. METHODS: A prospective study analyzed 304 consecutive patients diagnosed with Siewert II/III AEJ between January 2019 and December 2021. Total gastrectomy was performed via the abdominal approach, and PM length was measured on fixed gross specimens. X-Tile software determined the optimal PM cut-point based on progression-free survival (PFS). Univariate analyses compared baseline characteristics across PM groups, while survival analyses utilized Kaplan-Meier estimation and Cox proportional hazards regression for assessing the impact of margin length on survival. Multivariable analyses were conducted to adjust for confounding variables. RESULTS: The study included 264 AEJ cases classified as Siewert II (71.97%) or III (28.03%). The median gross PM length was 1.0 cm (IQR: 0.5 cm-1.5 cm, range: 0 cm-6 cm). PM length ≥1.2 cm was associated with a lower risk of disease progression compared to PM length 0.4 cm on PFS (HR = 0.41, 95% CI 0.20-0.84, P = 0.015). Moreover, PM ≥ 1.2 cm improved prognosis in subgroups of T4 or N3, tumor size <4 cm, Siewert II, and Lauren classification. CONCLUSIONS: For Siewert type II/III AEJ, a proximal margin length ≥1.2 cm (1.65 cm in situ) is associated with improved outcomes. These findings offer valuable insights into the association between PM length and outcomes in Siewert II/III AEJ, providing guidance for surgical approaches and aiding clinical decision-making to enhance patient outcomes.

Primary Testicular Mucinous Adenocarcinoma-a Case Report and Review of Literature.

Testicular tumors include germ cell tumors, sex cord stromal tumors, and ovarian type epithelial tumors. Testicular mucinous tumors belong to ovarian type epithelial tumors and are extremely rare with only 31 cases reported in literature so far. Among those, mucinous adenocarcinoma constitutes only 9 cases. There are no standard treatment guidelines owing to their rarity. We report a case of primary testicular mucinous adenocarcinoma managed by orchidectomy, chemotherapy, and retroperitoneal lymph node dissection. A 44-year-old gentleman presented with right testicular tumor with infiltration and ulceration of scrotal skin. Tumor markers were within normal limits. Patient underwent orchidectomy with excision of involved scrotal skin. HPE suggested mucinous adenocarcinoma of testis. Patient was then administered chemotherapy but had progression of disease and hence taken up for retroperitoneal, bilateral pelvic, and bilateral inguinal lymph node dissection with revision of spermatic cord. Patient recovered uneventfully and is on regular follow-up 6 months now since surgery. There are no standard guidelines for the management of mucinous adenocarcinoma of testis. It is essential to rule out mucinous carcinoma of gastrointestinal tract metastasizing to testis before labeling as primary mucinous adenocarcinoma of testis. Surgery remains the mainstay of treatment in metastasis confined to retroperitoneal and inguinal lymph nodes. Further studies are needed to identify optimal chemotherapy regimen for metastatic and adjuvant scenarios.

Establishment and characterization of NCC-PMP2-C1: a novel patient-derived cell line of pseudomyxoma peritonei with signet ring cells.

Pseudomyxoma peritonei (PMP) is a rare phenomenon, characterized by accumulation of mucus in the abdominal cavity due to a mucinous neoplasm. Histologically, PMP is divided into three prognostic classes, namely low-grade mucinous carcinoma peritonei (LGMCP), high-grade mucinous carcinoma peritonei (HGMCP), and high-grade mucinous carcinoma peritonei with signet ring cells (HGMCP-S); HGMCP-S exhibits the worst prognosis. Complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have been established as the standard therapy for PMP. However, 50% of patients with PMP experience a recurrence, and 30-40% are unable to receive the standard treatment due to invasive diseases. Therefore, novel therapies are required for their treatment. Although patient-derived cell lines are important tools for basic and pre-clinical research, PMP cell lines derived from patients with HGMCP-S have never been reported. Thus, we established a novel PMP cell line NCC-PMP2-C1, using surgically resected tumor tissue from a patient with HGMCP-S. NCC-PMP2-C1 cells were maintained for more than five months and passaged 30 times under culture conditions. NCC-PMP2-C1 cells exhibited multiple deletions and somatic mutations, slow growth, histological features, and dissemination of tumor cells in nude mice. Screening for the anti-proliferative effects of anti-cancer drugs on cells revealed that bortezomib, mubritinib, and romidepsin had a significant response against NCC-PMP2-C1 cells. Thus, the NCC-PMP2-C1 cell line is the first PMP cell line harboring signet ring cells and will be a valuable resource for basic and preclinical studies of HGMCP-S.

Signet Ring Cell Colorectal and Appendiceal Cancer: A Small Signet Ring Cell Component Is Also Associated with Poor Outcome.

BACKGROUND: Colorectal signet ring cell (SRC) carcinoma with ≥50% SRCs (SRC ≥ 50) has a poor prognosis, but the prognostic role of SRCs < 50% (SRC < 50) is unclear. The aim of this study was to provide a clinicopathological characterization of SRC colorectal and appendiceal tumours and analyse the importance of the SRC component size. METHODS: All patients in the Swedish Colorectal Cancer Registry diagnosed with colorectal or appendiceal cancer in 2009-2020 at Uppsala University Hospital, Sweden, were included. The SRCs were verified, and the components estimated by a gastrointestinal pathologist. RESULTS: Of the 2229 colorectal cancers, 51 (2.3%) had SRCs, with a median component size of 30% (interquartile range of 12.5-40) and 10 (0.45%) had SRC ≥ 50. The SRC tumours were primarily localized in the right colon (59%) and appendix (16%). No patients with SRCs had stage I disease, and 26 (51%) had stage IV, of whom, 18 (69%) had peritoneal metastases. The SRC tumours were often high grade with perineural and vascular invasion. The 5-year overall survival (OS) rate for patients with SRC ≥ 50 were 20% (95% confidence interval (CI) 6-70), for SRC < 50, 39% (95% CI 24-61); and for non-SRCs, 55% (95% CI 55-60). Among the patients with SRC < 50 and <50% extracellular mucin, the 5-year OS was 34% (95% CI 19-61), while those with ≥50% extracellular mucin had an OS of 50% (95% CI 25-99). The 5-year recurrence-free survival rates were 51% (95% CI 13-83) for patients with SRC tumours, as compared to 83% (95% CI 77-89) and 81% (95% CI 79-84) for mucinous and non-mucinous adenocarcinoma, respectively. CONCLUSIONS: The presence of SRCs was strongly associated with aggressive clinicopathological features, peritoneal metastases, and poor prognosis, also when they make up <50% of a tumour.

Clinical Features of Gastric Signet Ring Cell Cancer: Results from a Systematic Review and Meta-Analysis.

BACKGROUND: Conflicting results about the prognostic relevance of signet ring cell histology in gastric cancer have been reported. We aimed to perform a meta-analysis focusing on the clinicopathological features and prognosis of this subgroup of cancer compared with other histologies. METHODS: A systematic literature search in the PubMed database was conducted, including all publications up to 1 October 2021. A meta-analysis comparing the results of the studies was performed. RESULTS: A total of 2062 studies referring to gastric cancer with signet ring cell histology were identified, of which 262 studies reported on its relationship with clinical information. Of these, 74 were suitable to be included in the meta-analysis. A slightly lower risk of developing nodal metastases in signet ring cell tumours compared to other histotypes was found (especially to undifferentiated/poorly differentiated/mucinous and mixed histotypes); the lower risk was more evident in early and slightly increased in advanced gastric cancer. Survival tended to be better in early stage signet ring cell cancer compared to other histotypes; no differences were shown in advanced stages, and survival was poorer in metastatic patients. In the subgroup analysis, survival in signet ring cell cancer was slightly worse compared to non-signet ring cell cancer and differentiated/well-to-moderately differentiated adenocarcinoma. CONCLUSIONS: Most of the conflicting results in signet ring cell gastric cancer literature could be derived from the lack of standardisation in their classification and the comparison with the different subtypes of gastric cancer. There is a critical need to strive for a standardised classification system for gastric cancer, fostering clarity and coherence in the forthcoming research and clinical applications.

Thrombotic microangiopathy and disseminated intravascular coagulation in a patient with carcinomatosis of the bone marrow due to gastric adenocarcinoma: Case report.

Carcinomatosis of the bone marrow is a rare clinical condition characterized by diffuse tumor infiltration of the bone marrow accompanied by hematological abnormalities, including thrombotic microangiopathy (TMA) and disseminated intravascular coagulation (DIC). In patients with gastric carcinoma, this association is infrequent. Below we present a case of a 19-year-old female patient with no known pathological history who presented with upper digestive tract bleeding. Upon examination, anemia and thrombocytopenia were documented, with schistocytes in the peripheral blood smear and prolonged coagulation times. Endoscopic studies indicated a lesion in the Borrmann IV gastric body, and the bone marrow biopsy showed the presence of signet ring cells. Because there was no possibility of systemic therapy, the patient died during hospitalization. This case contributes to the medical literature by describing an unusual presentation of a very frequent pathology.

Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient.

High-grade mucinous colorectal cancer (HGM CRC) is particularly aggressive, prone to metastasis and treatment resistance, frequently accompanied by "signet ring" cancer cells. A sizeable fraction of HGM CRCs (20-40%) arises in the context of the Lynch Syndrome, an autosomal hereditary syndrome that predisposes to microsatellite instable (MSI) CRC. Development of patient-derived preclinical models for this challenging subtype of colorectal cancer represents an unmet need in oncology. We describe here successful propagation of preclinical models from a case of early-onset, MSI-positive metastatic colorectal cancer in a male Lynch syndrome patient, refractory to standard care (FOLFOX6, FOLFIRI-Panitumumab) and, surprisingly, also to immunotherapy. Surgical material from a debulking operation was implanted in NOD/SCID mice, successfully yielding one patient-derived xenograft (PDX). PDX explants were subsequently used to generate 2D and 3D cell cultures. Histologically, all models resembled the tumor of origin, displaying a high-grade mucinous phenotype with signet ring cells. For preclinical exploration of alternative treatments, in light of recent findings, we considered inhibition of the proteasome by bortezomib and of the related NEDD8 pathway by pevonedistat. Indeed, sensitivity to bortezomib was observed in mucinous adenocarcinoma of the lung, and we previously found that HGM CRC is preferentially sensitive to pevonedistat in models with low or absent expression of cadherin 17 (CDH17), a differentiation marker. We therefore performed IHC on the tumor and models, and observed no CDH17 expression, suggesting sensitivity to pevonedistat. Both bortezomib and pevonedistat showed strong activity on 2D cells at 72 hours and on 3D organoids at 7 days, thus providing valid options for in vivo testing. Accordingly, three PDX cohorts were treated for four weeks, respectively with vehicle, bortezomib and pevonedistat. Both drugs significantly reduced tumor growth, as compared to the vehicle group. Interestingly, while bortezomib was more effective in vitro, pevonedistat was more effective in vivo. Drug efficacy was further substantiated by a reduction of cellularity and of Ki67-positive cells in the treated tumors. These results highlight proteasome and NEDD8 inhibition as potentially effective therapeutic approaches against Lynch syndrome-associated HGM CRC, also when the disease is refractory to all available treatment options.

Synchronous primary gastric and renal tumors: a case report.

Synchronous multiple primary cancers of the stomach and kidney are very rare, only 45 cases of synchronous multiple primary cancers of the stomach and kidney had been reported in the literature up until 2020. Thus far, no particular risk factors have been identified. We present a case of synchronous multiple primary cancers of the stomach and kidney in a 67-year-old female presenting with a 3-month history of vomiting and abdominal pain. The diagnosis of gastric adenocarcinoma with signet ring cells was confirmed through upper endoscopy with biopsies, while CT-guided biopsies of the renal tumor confirmed the diagnosis of primary kidney neoplasm.

Having more than one cancer at the same time is known as multiple primary malignancies. Having cancers in both the stomach and kidney at the same time is even rarer, with only 45 cases reported in literature. The exact causes of such cancers occurring together are not yet known. We present a 67-year-old woman who was diagnosed with synchronous multiple primary cancers of the stomach and kidney. She presented with vomiting and abdominal pain. The diagnosis of gastric cancer was confirmed through upper endoscopy with biopsies, while biopsies of the renal tumor confirmed the diagnosis of primary kidney cancer.

Correlation between PSOGI pathological classification and survival outcomes of patients with pseudomyxoma peritonei treated using cytoreductive surgery and HIPEC: national referral centre experience and literature review.

Objectives: The Peritoneal Surface Oncology Group International (PSOGI) consensus subdivided pseudomyxoma peritonei (PMP) into four groups according to histopathological features. The aim of this paper is to report survival outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) from a national referral centre and to correlate the PSOGI classification with survival. Methods: A retrospective study of a prospectively maintained database was performed. Consecutive patients treated with CRS + HIPEC for PMP of appendiceal origin were included (September-2013 to December-2021). Pathological features of the peritoneal disease were used to classify patients into the four groups proposed by PSOGI. Survival analysis was performed to evaluate the correlation of pathology on overall survival (OS) and disease-free survival (DFS). Results: Overall, 104 patients were identified; 29.6 % were reclassified as acellular mucin (AM), 43.9 % as low-grade mucinous carcinoma peritonei (LGMCP), 22.4 % as high-grade MCP (HGMCP) and 4.1 % as HGMCP with signet ring cells (HGMCP-SRC). Median PCI and rate of optimal cytoreduction were 19 and 82.7 %, respectively. Median OS and DFS were not reached, 5-year OS and DFS were 88.6(SD 0.04) % and 61.6(SD 0.06) %, respectively. Log-Rank test revealed significant differences in terms of OS and DFS across the different histological subgroups (p<0.001 in both cases). However, histology did not retain its significance in the multivariate analysis for OS or DFS (p=0.932 and p=0.872, respectively). Conclusions: Survival outcomes after CRS + HIPEC for PMP are excellent. The PSOGI pathological classification correlates with OS and DFS, but differences were not significant at multivariate analysis when adjusted for other prognostic factors.