Background:Hereditary diffuse gastric cancer (HDGC) with CDH1 germline pathogenic variants carries a high lifetime risk of signet ring cell carcinoma (SRCC). There is limited data to inform decision between endoscopic surveillance and prophylactic total gastrectomy (PTG) in patients with early SRCC, which could have indolent behaviour. We hypothesise patients with few early SRCC lesions can be monitored endoscopically. Therefore, we aimed to identify clinical predictors early SRCC burden and evaluate the natural histoary of early cancer lesions in HDGC. Methods:This is a single centre longitudinal cohort study of CDH1 germline variant carriers recruited at Cambridge University Hospitals (United Kingdom) between 2005 and 2024. We analysed two cohorts: 53 patients who underwent endoscopic evaluation followed by PTG and 93 individuals who received longitudinal surveillance. We excluded patients with advanced cancer at baseline endoscopy. Participants received high-resolution endoscopy with targeted and systematic random biopsies following Cambridge protocol. Multivariable negative binomial regression, logistic regression, and linear mixed-effects models were applied to assess predictors of SRCC burden and temporal dynamics of SRCC detection. Findings:In PTG cohort, 89% individuals had early-stage cancer (pT1aN0M0) and 11% had no evidence of carcinoma (pT0N0M0). The number of SRCC foci ranged from 0 to 273 (median 14, IQR 2-37). The number of positive targeted and random biopsies independently predicted SRCC burden on gastrectomy (P < 0.001), whereas age, CDH1 mutation type and number of affected relatives were not significantly associated. In the surveillance cohort, the number of positive biopsies remained largely stable over time, with no significant temporal increase detected (Incidence rate ratio: 1.026 per six months, 95% CI: 0.985-1.068, P = 0.214). Interpretation:Endoscopic surveillance using systematic biopsies reliably estimates SRCC burden on gastrectomy in HDGC. Individuals with few SRCC lesions showed stable findings during long-term surveillance, supporting the safety of endoscopic monitoring and extended surveillance intervals. Future research should clarify the clinical significance of high SRCC burden. Funding:Medical Research Council and Cancer Research UK.

Definitive treatment for HDGC remains prophylactic total gastrectomy (PTG) but this carries significant nutritional consequences. Patients undergoing PTG do not have invasive cancer or undergo chemotherapy treatment which could confound weight changes. We aimed to study the long-term effect of PTG on weight. Weight changes were defined in patients undergoing PTG at a national referral centre between 2005 and 2025 and changes calculated relative to pre-operative baseline. Weight was measured pre-operatively and serially post-operatively using conventional and self-reported electronic methods. Follow-up included regular review by a multidisciplinary team including a specialist dietician and clinical interventions made as necessary. A total of 59 patients had pre-operative and serial post-operative weight measurements. Post-operative weight loss was universal at 3 months post-operatively but plateaued across all patients between 9 and 12 months at 20% absolute loss from baseline. A weight increase of 5% baseline weight was observed between 2 and 4 years post-op with a further weight plateau up to 10 post-operative years at 15% absolute weight loss across patients. In subgroups, the greatest magnitude of weight loss was seen in pre-operatively obese patients and maintained beyond 5 years. Conversely after initial weight loss, weight was regained in pre-operatively normal weight patients between 2 and 5 years post-operatively to reach pre-operative levels. Conclusions: Despite inevitable weight loss in the first 12 months post-PTG, weight regain is possible several years post-operatively within the context of a specialist multidisciplinary follow-up and nutritional support. Self-reporting using electronic tools provides promise for remote monitoring.

Hereditary diffuse gastric cancer (HDGC) is predominantly due to germline CDH1 variants and confers a high lifetime risk of diffuse gastric cancer (DGC). Prophylactic total gastrectomy (PTG) is thought to prevent DGC but has potential long-term functional, nutritional and quality-of-life (QOL) sequelae. We report the clinical, pathological and long-term weight and QOL outcomes from a prospective cohort of patients with HDGC who underwent PTG. This is a single-centre prospective cohort study (Familial Gastric Cancer Study) of CDH1 pathogenic variant carriers managed at Addenbrooke’s Hospital (2005–2024). Patients with CDH1 pathogenic variants and completed □2 QOL questionnaires were included. Patients who underwent PTG or endoscopic surveillance were included. The clinical, pathological, weight and QOL outcomes for patients undergoing PTG (n=60) are reported. The QOL of patients undergoing endoscopic surveillance only (n=25) and surveillance followed by PTG were also reported. Longitudinal changes in QOL were analysed using linear mixed models with Bonferroni-Holm correction. Median age at PTG was 31 years (IQR 25–41); 75% underwent vagal-sparing PTG. The major complication rate was <2% with no operative mortalities and a median hospital stay of 8 days. Foci of intramucosal signet ring cell (SRC) carcinoma (pT1a) were seen in 88%, pT0 in 10% with a median number of SRC foci of 8. The disease-specific and overall-survivals was 100% with median follow-up of 9.7 years. Weight loss was universal, reaching ∼15% at 3 months and extending to 20% by 24 months. Partial weight regain was seen in those with normal pre-operative BMI between 2–5 years. QOL worsened markedly at 1–3 months but largely returned to baseline by 12–24 months and remained stable at baseline levels beyond 10 years. Younger patients (<35) had better role functioning (p=0.038) and men reported greater persistent appetite loss (p=0.030) following PTG. PTG can be undertaken with a low major complication rate, and is a curative treatment for HDGC. Although substantial early functional and weight effects occur, most QOL domains recover to baseline by 12–24 months and are sustained long-term with regular follow-up within a specialist multidisciplinary service. What are the clinicopathological and long-term impact on weight and health-related quality of life outcomes for patients with hereditary diffuse gastric cancer who undergo prophylactic total gastrectomy? In this study which included 60 patients with HDGC who underwent PTG, there was a lower major complication rate at <2% and the majority of patients at 88.0% had pT1a on gastrectomy specimens. Partial weight regain was seen in those with normal pre-operative BMI between 2 to 5 years and QOL worsened markedly at 1 to 3 months but largely returned to baseline by 12 to 24 months and remained stable at baseline levels beyond 10 years. PTG can be undertaken with a low major complication rate and most QOL domains return to baseline within 24 months and sustained in the long-term within the context of a specialist multidisciplinary service.

Abstract Background Hereditary diffuse gastric cancer (HDGC) syndrome is commonly linked to CDH1 germline pathogenic variants (PV) and carries a high lifetime risk of diffuse gastric cancer (DGC). Definitive treatment remains prophylactic total gastrectomy (PTG). However, endoscopic surveillance can be offered to inform decision-making around surgery, although the optimal time for treatment escalation remains unclear. This study aims to establish whether histopathological assessment of endoscopic biopsies can predict burden of early signet ring cell (SRC) carcinoma on PTG specimens. Methods We performed a retrospective review of prospectively collected data on endoscopic and surgical histopathologic results from CDH1 PV carriers who underwent PTG at Addenbrooke’s Hospital between January 2006 and May 2023. Targeted and systematic Cambridge protocol biopsies were performed. Patients with confirmed DGC (stage 2 or higher) at baseline endoscopy were excluded. Pearson correlation was performed to assess the relationship between number of SRC foci on endoscopy and surgical specimens. Results 46 patients underwent PTG with median of 3 pre-operative surveillance endoscopies over 22 months. Final stage was pT1aN0M0 in 41 patients and pT0N0M0 in 5 patients. The number of SRC foci on PTG specimens ranged from 0 to 273. There was a strong correlation between number of SRC foci on gastrectomy specimens and from targeted and random biopsies when evaluated separately and together for last 2 and all endoscopies. The strongest correlation was seen with total number of SRC foci on random biopsies for last 2 endoscopies (r=0.738, p-value<0.001). Random biopsies outperformed targeted biopsies in prediction of early SRC burden. Conclusions Endoscopic surveillance with systematic targeted and random biopsies by expert endoscopists within a dedicated specialist service provides useful information to estimate the burden of early SRCC. Low number of SRC foci at last two endoscopies indicate scarce gastric neoplastic involvement.

Hereditary diffuse gastric cancer (HDGC) associated with CDH1 germline pathogenic variants (GPV), carries a high lifetime risk of signet ring cell carcinoma (SRCC). Currently, there is uncertainty regarding to whom and when to recommend prophylactic total gastrectomy (PTG). We hypothesise a small number of early SRCC lesions correlates with low risk of progression to clinical gastric cancer. This study aimed to identify predictors of early SRCC burden and provide evidence to inform best surveillance intervals. We analyzed data from 53 CDH1 -GPV carriers who underwent PTG prospectively recruited between Aug 2004 and Aug 2024 (PTG dataset) and a separate cohort of 94 CDH1 CDH1 -GPV carriers with ≥2 surveillance endoscopies (endoscopy dataset). Targeted biopsies (TB) and systematic random biopsies (RB) were obtained using the Cambridge protocol. Multivariable negative binomial regression was used to assess the association of clinical (age, family history, CDH1 variant type) and endoscopic factors (mean number of positive TB and RB per endoscopy) with SRCC burden in PTG specimens. A logistic regression model with significant predictors was trained to classify patients into low and high SRCC burden. Temporal trends in biopsy findings were analyzed using linear mixed-effects models, and pathological outcomes at 6-, 12- and 24-month intervals were compared in endoscopy dataset. Of the 53 patients, 89% had early-stage cancer (pT1aN0M0) and 11% had no cancer (pT0N0M0). The number of SRCC foci ranged from 0 to 273 (median 33, IQR 2–37). The number of positive targeted ( P = 0.003) and random biopsies ( P < 0.001) during endoscopy surveillance were independent predictors of SRCC burden in the PTG specimen, whereas age, CDH1 mutation type (truncating vs. non-truncating), number of 1st and 2nd degree relatives (SDRs) were not significantly associated. In the endoscopy surveillance cohort, the number of positive biopsies remained largely stable over time, showing fluctuations rather than consistent progression; no significant temporal increase in biopsy positivity was detected over time ( P = 0.177) with stable number of SRCC foci at follow-up. Extending surveillance intervals from 6 to 12 or 24 months did not significantly alter progression detection rates. Endoscopic surveillance using targeted and random biopsies by experienced endoscopists provides a reliable estimate of SRCC burden in HDGC. Our findings suggest that extending surveillance intervals in patients with low early SRCC burden is clinically safe.

Hereditary diffuse gastric cancer is predominantly attributed to germline mutation in the CDH1 gene and is associated with a 30-fold increased risk of advanced gastric cancer by the age of 30. Definitive treatment remains PTG but this significantly impacts short-term health-related quality of life (QOL). It is not established if QOL is impaired in the long-term and this study aimed to evaluate this prospectively. Prospectively consenting patients undergoing PTG at a national referral centre were included in the familial gastric cancer study between 2005 and 2025. Self-reported QOL data were collected using the validated EORTC QLQ-C30 and QLQ-STO22 questionnaires pre-operatively and at serial post-operative timepoints. Both pre-operative and post-operative QOL data were available for 30 patients with follow-up data greater than 5 years in 70%. Symptoms were prevalent in the first 3 months post-op but most recovered by 24 months. Symptoms of diarrhoea, fatigue, appetite loss, reflux and eating difficulties, however, persisted at a level above baseline. Despite these chronic symptoms, physical, social, cognitive and emotional functional domains recovered by 12 months post-operatively and remained stable at baseline levels up to 10 years and beyond. Anxiety symptoms also improved below baseline in long-term follow-up. A high prevalence of post-operative symptoms is noted early post-PTG yet many recover to baseline by 2 years. Despite some ongoing symptoms, most patients recover functional levels to baseline by 12 months and this is preserved at >10 years post-op within the context of regular multidisciplinary specialist follow-up.

Patients with HDGC carry up to a 42% lifetime risk of diffuse gastric cancer. Definitive treatment remains prophylactic total gastrectomy (PTG) but this carries a risk of major complications with mortality reported. We describe the clinicopathological outcomes following PTG at a national referral centre. Retrospective review was performed of prospectively collected clinicopathological data for consecutive patients undergoing PTG between 2005 and 2025. Only patients having prophylactic surgery (no invasive disease) were included. Standard surgery consisted of an open posterior vagal-sparing total gastrectomy with D1 lymphadenectomy. D0/D2 lymphadenectomy and/or truncal vagotomy were undertaken in selected cases. Sixty patients underwent PTG with a median age of 31 [IQR 25-41]. All PTG were open with 73% undergoing D1 lymphadenectomy and 77% vagal-sparing procedures. The median lymph node yield was 12 nodes [7-20]. The major complication rate (Clavien-Dindo ≥III) was 1.6% with a single late anastomotic leak at the jejuno-jejunal anastomosis. Post-operative length of stay was a median of 8 days [7-9]. The final pathological stage was pT1aN0M0 in 87%, pT0N0M0 in 11% with 1 focus in 1 case demonstrating submucosal invasion (pT1bN0M0, 1.6% of patients, 1/1697 lesions across all cases). No lymph node metastases were observed, and complete gastric mucosal resection was achieved for all. The 5-year estimated overall, and disease-specific survivals were 100% at median follow-up of >6 years. PTG remains a robust and effective treatment for patients with HDGC with excellent outcomes achievable in a specialist centre.

Importance: Hereditary diffuse gastric cancer (HDGC) is predominantly due to germline CDH1 variants and confers a high lifetime risk of diffuse gastric cancer (DGC). Prophylactic total gastrectomy (PTG) is thought to prevent DGC but has potential long–term functional, nutritional and quality–of–life (QOL) sequelae. Objective: We report the clinical, pathological and long–term weight and QOL outcomes from a prospective cohort of patients with HDGC who underwent PTG. Design and Setting: This is a single–centre prospective cohort study (Familial Gastric Cancer Study) of CDH1 pathogenic variant carriers managed at Addenbrooke′s Hospital (2005–2024). Participants: All patients who had CDH1 pathogenic variants and completed at least 2 QOL questionnaires were included. Intervention: All patients who underwent PTG or endoscopic surveillance were included. Main Outcomes and Measures: The clinical, pathological, weight and QOL outcomes for patients undergoing PTG (n=60) are reported. The QOL of patients undergoing endoscopic surveillance only (n=25) and surveillance followed by PTG were also reported. Longitudinal changes in QOL were analysed using linear mixed models with Bonferroni–Holm correction. Results: Median age at PTG was 31 years (IQR 25 to 41); 75% underwent vagal-sparing PTG. The major complication rate was <2% with no operative mortalities and a median hospital stay of 8 days. Foci of intramucosal signet ring cell (SRC) carcinoma (pT1a) were seen in 88%, pT0 in 10% with a median number of SRC foci of 8. The disease–specific and overall–survivals was 100% with a median follow–up of 9.7 years. Weight loss was universal, reaching ~15% at 3 months and extending to 20% by 24 months. Partial weight regain was, however, seen in those with normal pre–operative BMI between 2–5 years. QOL worsened markedly at 1–3 months but largely returned to baseline by 12–24 months and remained stable at baseline levels beyond 10 years. Younger patients (<35) had better role functioning (p=0.038) and men reported greater persistent appetite loss (p=0.030) following PTG. Conclusions and Relevance: PTG can be undertaken with a low major complication rate, and is a curative treatment for HDGC. Although substantial early functional and weight effects occur, most QOL domains recover to baseline by 12–24 months and are sustained long-term with regular follow-up within a specialist multidisciplinary service. Keywords: Hereditary diffuse gastric cancer; prophylactic total gastrectomy; quality of life; weight outcomes ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Lim HJ is a PhD student on the Research Training Fellowship funded by National Medical Research Council, Singapore. Di Pietro M is funded by the UK Medical Research Council and received additional funds from the Cancer Research UK Cambridge Centre (grant number CTRQQR-2021\100012). O′Neill JR acknowledges the support of the Cancer Research UK Cambridge Centre Thoracic Cancer programme (CTRQQR-2021\100012). This work was supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Anglia and Oxford Medical Research gave ethical approval for this work with reference number 97/5/32 and any amendments approved by the Cambridgeshire Research Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent.

Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome associated with early onset diffuse gastric cancer. Definitive treatment is prophylactic total gastrectomy (PTG) associated with significant morbidity. Studies published from January 2000 to December 2022 reporting clinical, histopathological or health-related quality of life outcomes in HDGC patients undergoing PTG were identified. The study quality was assessed by the “Newcastle–Ottawa scale”. Of the 257 articles screened, 21 were selected. A total of 353 patients were examined in 15 studies that reported surgical outcomes. The median age was 42 years old. The median major complication and mortality rates were 19.2% and 0.3%, respectively. The most common complications were wound infection at 4.8% followed by anastomotic leak and pulmonary complications at 4.5% each. Following PTG, 88.6% of patients had early lesions amongst 414 patients. The mean/median number of signet ring cell carcinoma foci in the gastrectomy specimens was from 2 to 78. All cases were stage 1 with no lymph node involvement. There was a wide range of psychosocial effects following PTG closely related to the physical symptoms. It is imperative for patients to receive comprehensive preoperative counselling to make an informed decision and be followed up under the care of a multidisciplinary team.

Sarcomas are rare and heterogenous tumours that constitute fewer than 1% of adult solid cancers.1 Owing to their aggressive behaviour, relative rarity and occurrence at multiple anatomical sites, sarcomas can be challenging to treat.2

Introduction Peritoneal carcinomatosis (PC) is a late-stage manifestation of abdominopelvic malignancies. Our team recently demonstrated the prognostic relevance of key paracrine factors in the PC fluid microenvironment that can be inferred via a point-of-care biomarker panel. This study aimed to evaluate the receptivity of patients and their caregivers in utilising this biomarker panel regarding their prognosis and surgical management plan. Methods 30 pairs of patients and their caregivers were interviewed through a 15-minute questionnaire created specifically for our local population to determine their receptivity towards the panel. Results 83.3% of respondents were receptive to a panel with a 90% accuracy rate, with 51.6% of respondents stating that the results may influence their initial decisions to undergo palliative surgery. 70% of patients and 93.3% of caregivers gave a score of 3 or more on a scale of 5 when asked about the importance of learning about the panel results, based on the confidence it would provide them to pursue palliative surgery. This was understandable as 95% of respondents will undergo a medium to high-risk surgery and preferred additional assurance to stand by their decisions. 83.3% of respondents were adverse towards taking a chance with surgery despite the possibility of receiving poor panel results (poor overall survival outcome), with 61.6% of respondents affirming their wish to be well-informed regardless of the outcome. Cost and emotional stress could prevent the panel's use. 40% were keen to pay ≤S$300 while 48.3% preferred not to pay. 23% resonated that they may be predisposed to emotional issues should they know too much, even if it enlists better decision-making and care management. Conclusion Our study suggests a synchronous care plan with sound translational research such that PC patients' and caregivers' expectations and needs are appropriately addressed prior to the implementation of molecular prognostic testing in the context of palliative surgery.

Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide, often presenting with regional spread to the peritoneum. Peritoneal carcinomatosis (PC) has a significantly poorer prognosis compared to metastasis to the other regions of the body. Immunotherapy makes use of the memory and specificity of the adaptive immune system to achieve long lasting effective anti-tumor response. Tumor associated macrophages (TAMs) in the tumor microenvironment have been implicated in tumorigenesis by creating an anti-inflammatory environment suitable for the growth of cancer cells. Thus, our group sought to identify factors associated with immunomodulation in colorectal PC. Methods: We interrogated publicly available colorectal cancer single cell database (n=5) to identify putative immune markers associated with macrophage activation in cancers. Validation was performed using V-set and immunoglobulin containing domain 4 (VSIG4) immunohistochemistry (IHC) staining on tumor microarrays (TMAs) of colorectal primary tumors (n=210). VSIG4 protein expression was assessed in cell-free ascites (n=39) derived from PC. Results: Using publicly available single cell database, we shortlisted the top 100 genes from the expression data of CD136-positive TAMs cluster. Among these macrophage-associated genes, two putative markers, VSIG4 and NR1H3, were involved in the regulation of macrophage activation. NR1H3, also known as liver X receptor-alpha (LXR-α), is particularly associated with cholesterol metabolism and thus was excluded from our exploration of TAMs activity. Interestingly, our target of choice, VSIG4, is a membrane protein expressed by M2 macrophages, which is associated with the activation of anti-inflammatory macrophage subtype and the downregulation of pro-inflammatory macrophages. IHC staining of CRC TMA demonstrated that low VSIG4 expression in stroma of primary CRC is associated with poor prognosis (p=0.018). Moreover, enzyme-linked immunosorbent assay (ELISA) of the ascites from colorectal PC patients showed varying amounts of VSIG4, suggesting a possible biological role of VSIG4 amongst patients with upregulated VSIG4 levels in ascites. Taken together, our studies suggest that VSIG4 plays a possible immunomodulatory role in colorectal PC and warrants further studies to assess its potential role as a therapeutic target in PC. Conclusion: In view of its potential as a target for immunotherapy, further studies should be conducted to understand the role of VSIG4 in the progression of colorectal PC. Citation Format: Yik Yan Chong, Sasinthiran Thiagarajan, Qiu Xuan Tan, Hui Jun Lim, Joey Wee-Shan Tan, Josephine Hendrikson, Gillian Ng, Ying Liu, Clara Yieh Lin Chong, Chin Jin Seo, Jolene Si Min Wong, Claramae Shulyn Chia, Nicholas Brian Shannon, Chin-Ann Johnny Ong. The immunomodulatory role of paracrine signaling factor VSIG4 in peritoneal cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5132.

Abstract Background Hereditary diffuse gastric cancer (HDGC) is predominantly attributed to CDH1 [E-Cadherin] germline mutation and carries a cumulative lifetime risk of diffuse gastric cancer (DGC) of up to 70%. Definitive treatment remains prophylactic total gastrectomy (PTG) with an attendant risk of morbidity and reduced quality of life. Endoscopic surveillance following the Cambridge protocol is an alternative for selected patients, however, the impact on disease stage and long-term gastric cancer prognosis is not established. This study aims to evaluate clinical and histopathological outcomes following PTG in patients with germline CDH1 mutations with or without prior surveillance at a national HDGC referral centre. Methods Retrospective review was performed of clinicopathological outcomes for germline CDH1 mutation carriers who underwent PTG at Addenbrooke’s Hospital between January 2006 and May 2023. Indication for surgery of clinical stage 1 tumours was guided by patient preference, multiple visible lesions and increasing number of signet ring cell (SRC) foci. Endoscopic surveillance was offered to cases with no concerning endoscopic lesion and low number of SRC foci. Patients with confirmed DGC (≥stage 2) at diagnosis were excluded. Standard PTG procedure was open TG with D1 lymphadenectomy and preservation of posterior vagus with D2 lymphadenectomy and truncal vagotomy in selected cases. Results 48 patients underwent open PTG with D1 (93.8%) or D2 (6.2%) lymphadenectomy. PTG was deferred in 18 patients (37.5%) with median of 3 pre-operative surveillance endoscopies over 22 months (5 to 61 months). Median post-operative length of stay was 7 days (6 to 12). Major morbidity was observed in 1 case (2.1%) with no post-operative mortalities. Final stage was pT1aN0M0 in 43 patients (89.6%) and pT0N0M0 in 5 patients (10.4%). No lymph node metastases were observed and complete gastric mucosal resection was achieved for all. The 5-year estimated overall and disease-specific survival were 100% with median follow-up of 7 years. Conclusions PTG remains a robust and effective treatment for patients with pathogenic germline CDH1 mutations who are appropriate surgical candidates. There was no increase in final stage following surveillance in a dedicated specialist service and this remains a safe alternative in selected cases. For patients choosing to proceed with PTG following comprehensive pre-operative counselling, this can be undertaken with low morbidity in a specialist centre. Further long-term data are needed to determine the impact of surgery and endoscopic surveillance on survival, functional outcomes and quality of life.

INTRODUCTION Hookwires are commonly deployed under imaging guidance to localise non-palpable breast lesions for excision. However, the use of hookwires has some disadvantages, including patient discomfort, wire migration, damage to surrounding anatomical structures, surgery scheduling inconveniences and limited access to axillary nodes. Novel, alternative, non-radioactive wireless localisation devices using technologies such as radiofrequency identification, magnetic seed and radar have been developed to address these shortcomings.[1,2] While these devices have seen increasing usage in America and Europe, they were introduced to Asia only recently. One of these wireless techniques, the Savi Scout® (SS) surgical guidance system (Cianna Medical, Merit Medical Systems, Inc., South Jordan, UT, USA), was made available in Asia in 2019, and Singapore was the first Asian country to utilise it for breast and axillary localisations. Savi Scout employs radar technology, and it received the United States Food and Drug Administration clearance in 2014. The SS consists of a reflector implant, a needle introducer and an external check console. The reflector is a 12-mm metallic implant [Figure 1] consisting of thin nitinol antennae protruding from either end of a central transistor body. It is inserted percutaneously into the soft tissue via a single-use, preloaded, 16-gauge needle introducer and is deployed by uncovering the overlying sheath at the distal end of the introducer. This passive reflector delivery mechanism prevents damage to the thin antennae. The introducer is unsheathed by first unlocking the release button to either left or right and then retracting it along a sliding track [Figure 1]. Once the reflector is deployed, it cannot be repositioned. A handheld probe connected to the check console is used to locate the deployed reflector by transmitting a radio wave signal (radar), which is received and reflected back by the reflector. The signal capture and reflection mechanism of the reflector is multidirectional and is used to guide direction and distance to the target up to a depth of 6 cm. Unlike hookwires, SS does not have any components protruding from the skin. In addition, there is no placement expiry after deployment and it can be deployed at any time before surgery day, which provides flexibility in procedural scheduling.Figure 1: Photograph shows the parts and functions of the Savi Scout® needle introducer system and the 12-mm-long reflector (inset).Studies from America and Europe have evaluated SS to be a safe and convenient localisation technique for the breast and axilla.[3-8] However, to the best of our knowledge, there have been no published reports evaluating its performance in Asian women, and it is unclear if dense breast tissue, which is more prevalent in Asian women, may affect SS deployment and signal detection. We described our experience in the initial use of SS in Singapore women with the aims of providing an assessment on its performance in Asian women and finding ways to optimise its use. METHODS This was an institutional, review board-approved retrospective review of patients who underwent imaging-guided SS localisations at multiple centres in Singapore from July 2019 to June 2021. Performance was evaluated by 13 users, six of whom were breast imaging-dedicated radiologists and seven were breast surgeons. The ease of reflector deployment, time taken to deploy the reflector, postdeployment signal detection, incidence of reflector damage, incidence of reflector malpositioning, incidence of reflector migration, radiological visibility of the reflector, ease of intraoperative localisation, surgical retrieval rate, complication rate and overall user satisfaction were evaluated. Malpositioning was defined as the centre of reflector sited more than 10 mm from the epicentre of the lesion at deployment. Reflector migration referred to displacement of more than 10 mm from its original deployment site. Deployment time was the duration interval between introducer entry and exit of the skin. Assessments were graded on a 4-point scale of none, low/mild, moderate and high/severe categories, where appropriate. Statistical tests were performed with the online software GraphPad QuickCalcs (https://www.graphpad.com/quickcalcs/). Continuous variables were compared using the Student’s t-test. Comparisons of categorical variables were performed with Fisher’s exact test. The differences were considered statistically significant at P < 0.05. RESULTS Forty-four reflectors were deployed for 31 breast lesions and 13 axillary nodes in 40 female patients. Planned deployments had to be cancelled for five other women with a history of nickel allergy. Thirty-eight (86.4%) reflectors were deployed under ultrasound guidance, while six (13.6%) were performed under mammogram guidance. Four (9.1%) breast placements were inserted before commencement of neoadjuvant chemotherapy, with a mean placement duration of 184 days. There were ten (22.7%) placements in metastatic nodes that were inserted before neoadjuvant chemotherapy for subsequent targeted axillary dissection (TAD), with a mean placement period of 148 days. Twenty-one (47.7%) reflectors were inserted on the same day as surgery and another nine (20.5%) were non-same day deployments within 2 weeks of surgery. All users expressed overall satisfaction with SS use and there were no major complications. On specific technical aspects of deployment, there was no significant resistance when advancing the introducer in dense breast tissue. The introducer’s release button was highlighted to be mechanically stiff in 12 (27.3%) instances, with four (9.1%) encountering mild resistance and eight (18.2%) encountering significant resistance. Mean deployment times were 3 min and 9 s and 1 min and 53 s (P = 0.037) for insertions performed under ultrasound and mammogram guidance, respectively. There were no cases of reflector damage, malpositioning or migration [Tables 1 and 2].Table 1: Deployment outcomes by lesion and deployment types.Table 2: Surgical technical performance of deployments (N=44).On the surgical technical aspect, five of seven breast surgeons (71.4%) felt that SS provided greater flexibility in incision placement. Intraoperatively, the reflector was easily and accurately located with the use of the check console, apart from a few cases that encountered signal detection difficulty. Specimen radiographs confirmed that the reflectors were all fully retrieved with no evidence of damage. Failed signal detection on immediate postdeployment was encountered in three (6.8%) cases. In two of these cases, the reflector was inserted into a metastatic axillary node before commencement of neoadjuvant chemotherapy for the purpose of TAD. In both instances, core needle biopsy of the nodes was performed just before reflector deployment and postbiopsy haematomas were the likely cause of signal impedance. Signal was detected for both reflectors during a signal check a week later. At surgery 5 months later, signal was detected intraoperatively for one of the cases, but was absent in the other (2.3%). In this case of the absent intraoperative signal, the targeted node and the reflector were successfully retrieved after surgical exploration with the aid of intraoperative ultrasound. Subsequent investigations showed no malfunction of the reflector and check console, with no definite cause found for the signal failure. The third case of signal failure was related to a mammogram-guided deployment on surgery day, targeting a postbiopsy clip. There was a residual moderate-sized, postbiopsy haematoma next to the clip, which was likely impeding the signal. The clip was subsequently localised with a hookwire as an additional measure, but there was intermittent signal detected intraoperatively, which was sufficient to guide excision without difficulty. There was also one (2.3%) case of intermittent signal in a case of ultrasound-guided deployment adjacent to a moderate-sized, post-core needle biopsy haematoma. There was mild difficulty locating the reflector intraoperatively, but excision was successful. Signal loss triggered by diathermy contact was encountered in two cases (4.5%) that involved wide local excision for breast cancer. In both instances, the reflector tip was visible in the dissection plane at the time of signal loss, and the reflectors and tumours were excised with clear margins. The reflector was well visualised on ultrasound in 30 out of 31 cases (96.8%) and poorly visualised in one case (3.2%). The reflector was distinctively visualised on all postdeployment mammograms that were performed (30/30) [Figure 2]. In the six cases that had breast magnetic resonance imaging (MRI), the reflector was well seen in all of them and was best visualised in the T1-weighted, non-subtracted, postcontrast sequences with fat saturation. The reflector was seen as a small blooming artefact on MRI.Figure 2: Radiological appearance of reflectors (arrows) in a patient. (a) Mammogram shows the reflectors inserted before neoadjuvant chemotherapy embedded within the breast tumour and metastatic axillary node. (b) Sonogram shows the echogenic linear reflector within the enlarged node.DISCUSSION Our multicentre early experience demonstrated the utility of SS in a variety of clinical settings with good outcomes in Asian women. There was no signal inhibition in dense breast tissue and the introducer was able to advance into dense breasts without difficulty. Unlike hookwires, the small reflector posed little risk of injuring adjacent structures and was a useful alternative to hookwires for difficult-to-access sites such as lesions close to the chest wall or axillary nodes close to vital anatomical structures. Flexibility in scheduling deployments was a welcomed benefit. The implant also had the advantage of causing minimal MRI artefacts, which did not significantly obscure MRI assessment. There were, however, a few drawbacks encountered. Rare instances of intermittent or absent reflector signal were documented, mostly related to signal impedance by an adjacent haematoma, which is well documented as a cause of signal failure.[6,7] To reduce the risk of signal failure, the reflector is best placed superficial to the haematoma if present. True reflector malfunction is extremely rare, but it has been documented before.[3,6,8] We recommend performing a signal check just before surgery, so that alternative means of localisation can still be arranged before surgery in the rare event of signal failure. Another intraoperative pitfall was reflector deactivation after electrocautery contact. To avoid this, there is a need to carry out dissections with greater care when nearing the reflector and use the check console to guide proximity distance from the reflector frequently. Even with reflector deactivation, we did not feel it was a significant problem because it would indicate that the targeted site has been reached and the reflector together with the lesion will be identified in the dissection plane by then. In our series, the two cases of reflector deactivation did not adversely affect surgical outcomes. In the event that the reflector cannot be detected and located during surgery, it can be localised with the aid of intraoperative imaging. Being easily seen on sonography and X-ray examinations, the reflector may be located with the help of intraoperative ultrasound or fluoroscopy, as in one of our cases. The introducer’s delivery mechanism was slightly cumbersome. The needle tip had to be advanced a further 6 mm, so that the reflector would be centred well upon deployment. For ultrasound deployments, the proceduralist may take a few adjustments to achieve this optimal needle position, whereas this additional advancement can be precalibrated into the mammogram machine settings, removing the need for manual adjustments in mammogram-guided localisations. This was reflected in the longer procedural times for ultrasound-guided deployments compared to mammogram-guided ones. Notably, there was unexpected difficulty in retracting the introducer’s release button during reflector deployment. A few cases required extreme effort to fully retract the button and the procedure took longer to complete. It was not an isolated batch problem and there were also no such reports in other studies for reference. To troubleshoot this, our users found it easier to retract after switching the button to the opposite sliding track. The needle position may also unintentionally shift during the physical struggle to retract the release button, especially when performing under ultrasound guidance. We suggest checking the needle position when the release button is retracted halfway. If there is a need to reposition, the release button may be reversed to resheath and protect the reflector before proceeding to reposition the needle. We found that the reflector was not damaged with this manoeuvre. On the surgical technical aspect, most of the breast surgeons felt that SS allowed greater flexibility in incision placement. The accurate localisation facilitated a more targeted resection, which can help reduce excessive tissue resection, and skin incisions could be confidently placed directly over the lesion or cosmetically placed far from the lesion. Finally, SS use was limited by nickel allergy and cost considerations. The nitinol antennae contain small amount of nickel and, out of caution, we did not proceed with SS insertion for a few women who had nickel allergy.[4,5] Nickel allergy, however, is fairly prevalent and clinicians should routinely ask patients about this, so that they can plan in advance for alternative localisation methods, if necessary. Cost-wise locally, the reflector can be up to nine times more expensive than a hookwire. A significant capital outlay would also be necessary for procurement of the console. Unlike the findings from several American and European studies, many local clinicians felt that SS was too expensive for routine localisations despite its perceived benefits, which largely explained the low usage during the study period. However, we found that the most cost-effective utility in our local setting was the upfront deployment of SS in patients undergoing neoadjuvant chemotherapy before a planned breast conservation surgery or TAD. This group of patients will fully benefit from the dual functionality of SS acting as both a tumour clip and a localisation guide for subsequent surgical excision, eliminating the need for another localisation on surgery day, which will save procedural costs. One of the limitations of this paper is not evaluating the patients’ experience. However, none of the patients explicitly expressed dissatisfaction or discomfort with the reflector deployed in them. Cosmetic outcomes were also not evaluated. These are important points that can be explored in future. In summary, SS worked well in Asian women with some clinical benefits, but users need to be aware of its limitations. We have suggested ways on how to troubleshoot and optimise its use, and we hope our early experience will help other institutions in Asia to implement SS or other wireless localisation devices in their clinical practice and to navigate potential challenges. Acknowledgement We would like to thank Dr Permeen Akhtar bt Mohamed Yusoff from Research Office, Singapore General Hospital, Singapore, for assistance in editing and formatting of the manuscript. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

BACKGROUND:Stenting as a bridge to curative surgery (SBTS) for obstructing colon cancer (OCC) has been associated with possibly worse oncological outcomes.AIM:To evaluate the recurrence patterns, survival outcomes, and colorectal cancer (CRC)-specific death in patients undergoing SBTS for OCC.METHODS:Data from 62 patients undergoing SBTS at a single tertiary centre over ten years between 2007 and 2016 were retrospectively examined. Primary outcomes were recurrence patterns, overall survival (OS), cancer-specific survival (CSS), and CRC-specific death. OS and CSS were estimated using the Kaplan-Meier curves. Competing risk analysis with cumulative incidence function (CIF) was used to estimate CRC-specific mortality with other cause-specific death as a competing event. Fine-Gray regressions were performed to determine prognostic factors of CRC-specific death. Univariate and multivariate subdistribution hazard ratios and their corresponding Wald test P values were calculated.RESULTS:28 patients (45.2%) developed metastases after a median period of 16 mo. Among the 18 patients with single-site metastases: Four had lung-only metastases (14.3%), four had liver-only metastases (14.3%), and 10 had peritoneum-only metastases (35.7%), while 10 patients had two or more sites of metastatic disease (35.7%). The peritoneum was the most prevalent (60.7%) site of metastatic involvement (17/28). The median follow-up duration was 46 mo. 26 (41.9%) of the 62 patients died, of which 16 (61.5%) were CRC-specific deaths and 10 (38.5%) were deaths owing to other causes. The 1-, 3-, and 5-year OS probabilities were 88%, 74%, and 59%; 1-, 3-, and 5-year CSS probabilities were 97%, 83%, and 67%. The highest CIF for CRC-specific death at 60 mo was liver-only recurrence (0.69). Liver-only recurrence, peritoneum-only recurrence, and two or more recurrence sites were predictive of CRC-specific death.CONCLUSION:The peritoneum was the most common metastatic site among patients undergoing SBTS. Liver-only recurrence, peritoneum-only recurrence, and two or more recurrence sites were predictors of CRC-specific death.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germline CDH1 mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context of CDH1 pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examining CDH1 germline variants, second-hit mechanisms of CDH1 , pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncating CDH1 variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit of CDH1 most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear β-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach in CDH1 -deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.

Surgery is the mainstay of curative treatment for breast cancer with mastectomy offering the lowest risk of local recurrence. Post-mastectomy reconstruction options include autologous flaps and/or implants. Autologous flaps are commonly harvested from various areas, including rectus abdominis muscle, latissimus dorsi muscle, gracilis muscle and gluteal areas. While good cosmetic outcomes are often achieved, donor site morbidity and long patient downtime remain an issue. The intercostal perforator flaps have fewer of these problems but it often does not have sufficient volume for full reconstruction after mastectomy. Intercostal perforator flaps were developed for volume replacement after breast-conserving surgery. These perforator flaps are not used for full autologous reconstruction after mastectomy as the volume from a single perforator flap is often inadequate. Hence, the authors describe the first report of a novel approach of combining the anterior intercostal artery perforator (AICAP) flap and lateral intercostal artery perforator (LICAP) flap, the stacked intercostal artery perforator (STICAP) flaps, for full autologous reconstruction following an areolar-sparing mastectomy. Our patient is a 76-year-old lady diagnosed with a left breast 6 o'clock retro-areolar invasive ductal carcinoma measuring 2.8 cm x 1.6 cm x 2.3 cm. The patient underwent a left breast areolar-sparing mastectomy and axillary sampling followed by immediate STICAP (AICAP and LICAP) flaps reconstruction which achieved an excellent aesthetic appearance and high level of patient satisfaction.