Manipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?

The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved immunotherapies, which have transformed the outlook for patients with other advanced solid tumours. Accumulating evidence relates this resistance to its hallmark immunosuppressive milieu, which instils progressive dysfunction among tumour-infiltrating effector T cells. This milieu is established at the inception of neoplasia by immunosuppressive cellular populations, including regulatory T cells (Tregs), which accumulate in parallel with the progression to malignant PDAC. Thus, the therapeutic manipulation of Tregs has captured significant scientific and commercial attention, bolstered by the discovery that an abundance of tumour-infiltrating Tregs correlates with a poor prognosis in PDAC patients. Herein, we propose a mechanism for the resistance of PDAC to anti-PD-1 and CTLA-4 immunotherapies and re-assess the rationale for pursuing Treg-targeted therapies in light of recent studies that profiled the immune landscape of patient-derived tumour samples. We evaluate strategies that are emerging to limit Treg-mediated immunosuppression for the treatment of PDAC, and signpost early-stage trials that provide preliminary evidence of clinical activity. In this context, we find a compelling argument for investment in the ongoing development of Treg-targeted immunotherapies for PDAC.

Current Management of T1 Colon Cancer in Denmark: A Nationwide Cohort Study.

OBJECTIVE: To describe the management of T1 colon cancer in a retrospective study of a national cancer registry. BACKGROUND: There is increasing interest in the potential of local excision (LE) as an organ-preserving treatment for early colon cancer. However, accurate identification of patients who may have lymph node metastases (LNM) and require further surgery is a major challenge. METHODS: Patients diagnosed with T1 colon cancer in Denmark from 2016 to 2020 were included and divided according to treatment: polypectomy (referred to as LE), upfront colectomy and completion colectomy. Primary outcome was the proportion of patients diagnosed by LE. Secondary outcomes included the rate of LNM, the association of histopathological risk factors with LNM, and overall survival. RESULTS: 1,749 patients were included, and 1,022 patients (58.4%) underwent initial LE. The rate of R1 margins after initial LE was 31.0%. Colectomy was performed in 1,160 patients (upfront in 727, completion in 433), of whom 58.3% had pT1 cancer. The rate of LNM was 11.5%. Rates of LNM were similar in patients undergoing upfront or completion colectomy (10.2% vs 12.4%, P=0.392), and in patients with any single histopathological risk factor compared to those with none (8.9% vs 10.6%, P=0.565). Although overall survival was significantly shorter in patients undergoing LE alone, no association between survival and treatment strategy was found on multivariable analysis. CONCLUSIONS: LE is the most common mode of diagnosis in patients with T1 colon cancer and does not negatively impact survival and postoperative outcomes. Current strategies to stratify patients to completion surgery appear insufficient, and more robust predictors are needed.

The Role of Scientific Research in Human Papillomavirus Vaccine Discussions on Twitter: Social Network Analysis.

BACKGROUND: Attitudes toward the human papillomavirus (HPV) vaccine and accuracy of information shared about this topic in web-based settings vary widely. As real-time, global exposure to web-based discourse about HPV immunization shapes the attitudes of people toward vaccination, the spread of misinformation and misrepresentation of scientific knowledge contribute to vaccine hesitancy. OBJECTIVE: In this study, we aimed to better understand the type and quality of scientific research shared on Twitter (recently rebranded as X) by vaccine-hesitant and vaccine-confident communities. METHODS: To analyze the use of scientific research on social media, we collected tweets and retweets using a list of keywords associated with HPV and HPV vaccines using the Academic Research Product Track application programming interface from January 2019 to May 2021. From this data set, we identified tweets referring to or sharing scientific literature through a Boolean search for any tweets with embedded links, hashtags, or keywords associated with scientific papers. First, we used social network analysis to build a retweet or reply network to identify the clusters of users belonging to either the vaccine-confident or vaccine-hesitant communities. Second, we thematically assessed all shared papers based on typology of evidence. Finally, we compared the quality of research evidence and bibliometrics between the shared papers in the vaccine-confident and vaccine-hesitant communities. RESULTS: We extracted 250 unique scientific papers (including peer-reviewed papers, preprints, and gray literature) from approximately 1 million English-language tweets. Social network maps were generated for the vaccine-confident and vaccine-hesitant communities sharing scientific research on Twitter. Vaccine-hesitant communities share fewer scientific papers; yet, these are more broadly disseminated despite being published in less prestigious journals compared to those shared by the vaccine-confident community. CONCLUSIONS: Vaccine-hesitant communities have adopted communication tools traditionally wielded by health promotion communities. Vaccine-confident communities would benefit from a more cohesive communication strategy to communicate their messages more widely and effectively.

Current treatment of pT1 rectal cancers in Denmark: A retrospective national cohort study.

AIM: Organ preservation strategies for patients with rectal cancer are increasingly common. In appropriately selected patients, local excision (LE) of pT1 cancers can reduce morbidity without compromising cancer-related outcomes. However, determining the need for completion surgery after LE can be challenging, and it is unknown if prior LE compromises subsequent total mesorectal excision (TME). The aim of this study is to describe the current management of patients with pT1 rectal cancers. METHOD: This is a retrospective national cohort study of the Danish Colorectal Cancer Group database, including patients with newly diagnosed pT1 cancers between 2016 and 2020. Patients were stratified according to treatment into LE alone, completion TME after LE or upfront TME. The treatment and outcomes of these groups were compared. RESULTS: A total of 1056 patients were included. Initial LE was performed in 715 patients (67.7%), of whom 194 underwent completion TME (27.1%). The remaining 341 patients underwent upfront TME (32.3%). Patients undergoing LE alone were more likely to be male with low rectal cancers and greater comorbidity. No differences in specimen quality or perioperative outcomes were noted between patients undergoing completion or upfront TME. Eighty-five patients (15.9%) had lymph node metastases (LNM). Pathological risk factors poorly discriminated between patients with and without LNM, with similar rates seen in patients with zero (14.1%), one (12.0%) or two (14.4%) risk factors. CONCLUSION: LE is a key component of the treatment of pT1 rectal cancer and does not appear to affect the outcomes of completion TME. Patient selection for completion TME remains a major challenge, with current stratification methods appearing to be inadequate.

Neoadjuvant treatment of colorectal cancer: comprehensive review.

BACKGROUND: Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery. METHODS: A narrative review of the most recent relevant literature was conducted. RESULTS: Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients. CONCLUSION: Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments.

Prevention of Equinus Deformity after External Fixation for Open Tibia Fractures: A Comparison between Plaster of Paris Backslab and Passive Ankle Physiotherapy.

Background: Ankle equinus deformity is a common complication of prolonged external fixator use in tibia fractures with an incidence of 15%-16%. It affects gait and may lead to foot, leg, and back problems. Treatment of equinus deformity increases the cost of treatment of open tibia fractures and increases the time spent off work. Several preventive modalities have been suggested in literature with variable success, but no standard protocol exists. Objectives: The aim of this study was to determine the most appropriate method of preventing equinus deformity of the ankle joint during the management of open tibia fractures with unilateral uniplanar external fixators by comparing plaster of paris (POP) backslab application with passive ankle physiotherapy using strips of car tyre inner tubing. Materials and Methods: The study was a prospective randomised study involving patients with open tibia fractures who were managed with external fixators at the Korle Bu Teaching Hospital between April 2020 and February 2021. Patients were randomised into two groups; one group had below knee POP backslab and the other group did passive ankle physiotherapy using a strip of car tyre inner tubing. The passive ankle range of motion was measured at the beginning and after 6 weeks using a goniometer. Results: Fifty-six participants were recruited with 29 in the POP backslab group and 27 in the ankle physiotherapy group. The median age was 35.0 years. Male-to-female ratio was 4.6:1. Motor vehicle crash contributed to over 90% with 42.9% being motorbike riders. Initial and final mean ankle measurements for the POP backslab group were 6.79° and 10.14° for dorsiflexion and 29.93° and 34.52° for plantarflexion, respectively. The ankle physiotherapy group had initial and final dorsiflexion of 7.19° and 12.85° and plantarflexion of 30.44° and 34.52°, respectively. The ankle physiotherapy group had a better range of motion (47.37°) than the POP group (40.66°) with a P value of 0.008. One participant (3.7%) from the ankle physiotherapy group had equinus deformity compared with seven (24%) from the POP backslab group, a difference which gives a P value of 0.029. Conclusions: Passive ankle physiotherapy with car tyre inner tube is a better and cheaper modality of preventing ankle equinus deformity and maintaining ankle range of motion.

A network model of legal relations.

From at least the early twentieth century, legal scholars have recognized that rights and other legal relations inhere between individual legal actors, forming a vast and complex social network. Yet, no legal scholar has used the mathematical machinery of network theory to formalize these relationships. Here, we propose the first such approach by modelling a rudimentary, static set of real property relations using network theory. Then, we apply our toy model to measure the level of modularity-essentially, the community structure-among aggregations of these real property relations and associated actors. In so doing, we show that even for a very basic set of relations and actors, law may employ modular structures to manage complexity. Property, torts, contracts, intellectual property, and other areas of the law arguably reduce information costs in similar, quantifiable ways by chopping up the world of interactions between parties into manageable modules that are semi-autonomous. We also posit that our network science approach to jurisprudential issues can be adapted to quantify many other important aspects of legal systems. This article is part of the theme issue 'A complexity science approach to law and governance'.

Leaf Spot Disease Development and Its Effect on Yield of Essential Oil-Producing Hemp Cultivars in Kentucky.

Leaf spot diseases are common on field hemp, causing defoliation, and blighting. The most prevalent leaf spot diseases of hemp in Kentucky are Bipolaris leaf spot (Bipolaris gigantea), Cercospora leaf spot (Cercospora flagellaris), and Septoria leaf spot (Septoria cannabis). In this study, disease progression, cultivar susceptibility, and yield loss were examined using cultivars from four relatedness groups at two locations and in two growing seasons. Septoria leaf spot was the first leaf spot disease to be observed in the field, followed by Bipolaris leaf spot. Both diseases reduced canopy density. Cercospora leaf spot developed in the late reproductive stages as harvest approached. A wide range of susceptibility was documented, suggesting genetic variability across cultivars. Trump group cultivars were the most susceptible, while Otto II group cultivars were the least susceptible. Most importantly, leaf spot diseases had minimal influence on floral biomass and no effect on CBD yield, suggesting that, regardless of disease severity, leaf spot diseases may seldom warrant management. While the importance of foliar disease and corresponding yield loss can shift over time, variation in disease progress among leaf spot diseases and susceptibility of hemp cultivars documented in this study suggest potential disease management through cultural practices such as cultivar and planting date selections.

Habu snakes (Protobothrops flavoviridis) show variation in thoracic aortic vasoreactivity between adjacent Japanese islands.

Habu snakes (Protobothrops flavoviridis) are pit vipers found in the geographically adjacent but ecologically divergent islands of Tokunoshima and Amami-Oshima in southwestern Japan. Abiotic factors can cause variation in animal populations between the two islands, and Habu snakes may show such intraspecific physiological variation. We therefore evaluated the vasoreactivity in aortas isolated from the Habu of both islands. Tokunoshima Habu showed significantly greater contractile responses to angiotensin (Ang) II, acetylcholine (ACh) and noradrenaline, and significantly higher affinities (pEC50) for Ang II and ACh, than Amami-Oshima Habu. ACh caused contractions in aortas from both populations, a finding previously unreported in snakes. Our findings indicate that vasoreactivity may differ between Tokunoshima and Amami-Oshima Habu.

Characterization of Vasoreactivity in a Semi-Arboreal Snake, the Tokara Habu (Protobothrops tokarensis).

Vasoreactivity is relatively well documented in terrestrial snakes but has previously been investigated in only one semi-arboreal snake species. Consequently, the extent to which vasoreactivity is common across snake taxa or varies by habitat is unclear. The Tokara habu (Protobothrops tokarensis) is a semi-arboreal snake endemic to only two small adjacent Japanese islands, and hence a useful species for further investigation of vasoreactivity. We evaluated responses to known vasoactive substances in thoracic aortas isolated from Tokara habu. Under resting tension, noradrenaline and angiotensin II induced concentration-dependent contraction, but acetylcholine, serotonin (5-hydroxytriptamine; 5-HT), and isoproterenol induced relaxation followed by contraction. Histamine and rattlesnake bradykinin had no effect. Experiments with receptor-specific antagonists suggest that M1 and M3 receptors are involved in the acetylcholine-induced response; 5-HT1, 5-HT2, and 5-HT7 receptors in the serotonin-induced response; and ß1 and ß2 adrenoceptors in isoproterenol-induced relaxation. This is the first report on such response patterns in snakes (including serotonin- and isoproterenol-induced relaxation). Nitric oxide may be involved in acetylcholine-induced relaxation but not in the responses to serotonin or isoproterenol. In contrast to the uniform vasoreactivity observed in terrestrial snakes, the vasoreactivity of semi-arboreal snakes may be governed by diverse regulatory mechanisms.

How Psychiatrists' Beliefs on Free Will Influence Their Clinical Practice.

BACKROUND: Literature suggests that most people believe in free will and that this belief is associated with more prosocial behavior. However, with the advent of neuroscience, free will seems to have been progressively excluded from psychiatry. This paper is a narrative literature review of the ways in which mental health professionals' premises and beliefs in free will influence their clinical practice. METHODS: The Scopus database was searched for papers concerning free will and psychiatric practice, 24 papers were included. This review looks at explicit links made by authors between free will and clinical practice as well as logical threads linking a premise of free will to clinical implications. RESULTS: The results suggest that belief in free will leads to trying to strengthen free will in patients. It also appears to be associated with using meaning in psychotherapy, with self-blame in patients, and with ethical questions such as involuntary psychiatric care and assisted suicide requests. Some authors believe the concept of free will should be discarded to make place for concepts such as autonomy, agency, decision-making capacity and self-control. CONCLUSION: While definitional ambiguity and paucity of data are limiting, the results indicate that mental health professionals' beliefs concerning free will can influence their clinical practice. Concepts such as autonomy and agency can sometimes hide psychiatrists' underlying beliefs. Increasing mental health professionals' awareness of their beliefs could be beneficial for psychiatric care.

How to Improve Collaboration Between General Practitioners and Clinical Psychologists for Their Patients' Common Mental Health Problems in Primary Care Context?

BACKGROUND: Mental health problems have become a major topic of public health these last years, particularly since the pandemic of COVID-19. Primary care givers are confronted with high rates of common mental health problems (CMHPs) in population. This questions healthcare organization and specifically collaboration between general practitioners (GPs) and clinical psychologists (CPs). In this paper we aim to review recent literature to identify factors that facilitate or hinder collaboration between GPs and CPs when caring for their patients' CMHPs. METHODS: A non-systematic qualitative literature review was performed, using the PRISMA method. We restricted the review to papers published between 2010 and 2023. RESULTS: We identified 52 papers and after filtering, only 6 were included in the synthesis. Six main themes were identified: barriers to interprofessional collaboration, lack of mutual trust, mutual dissatisfaction with information exchanged, the paradox of professional secrecy, the necessity of a paradigm shift, and conceptual frameworks of collaboration. These themes were discussed to improve collaboration between GPs and CPs. CONCLUSION: This work provides some recommendations to support the development of interprofessional collaboration between GPs and CPs in primary care.

One-year outcomes following operative or non-operative management of adhesional small bowel obstruction.

BACKGROUND: A trial of initial non-operative management is recommended in stable patients with adhesional small bowel obstruction. However, recent retrospective studies have suggested that early operative management may be of benefit in reducing subsequent recurrences. This study aimed to compare recurrence rates and survival in patients with adhesional small bowel obstruction treated operatively or non-operatively. METHODS: This was a prospective cohort study conducted at six acute hospitals in Denmark, including consecutive patients admitted with adhesional small bowel obstruction over a 4-month interval. Patients were stratified into two groups according to their treatment (operative versus non-operative) and followed up for 1 year after their index admission. Primary outcomes were recurrence of small bowel obstruction and overall survival within 1 year of index admission. RESULTS: A total of 201 patients were included, 118 (58.7 per cent) of whom were treated operatively during their index admission. Patients undergoing operative treatment had significantly better 1-year recurrence-free survival compared with patients managed non-operatively (operative 92.5 per cent versus non-operative 66.6 per cent, P <0.001). However, when the length of index admission was taken into account, patients treated non-operatively spent significantly less time admitted to hospital in the first year (median 3 days non-operative versus 6 days operative, P <0.001). On multivariable analysis, operative treatment was associated with decreased risks of recurrence (HR 0.22 (95 per cent c.i. 0.10-0.48), P <0.001) but an increased all-cause mortality rate (HR 2.48 (95 per cent c.i. 1.13-5.46), P = 0.024). CONCLUSION: Operative treatment of adhesional small bowel obstruction is associated with reduced risks of recurrence but increased risk of death in the first year after admission. REGISTRATION NUMBER: NCT04750811 (http://www.clinicaltrials.gov).prior (registration date: 11 February 2021).

Reduced Nitric Oxide Synthase Involvement in Aigamo Duck Basilar Arterial Relaxation.

The basilar arterial endothelium mediates blood vessel relaxation partly through the release of nitric oxide (NO). Apoptosis of cerebrovascular endothelial cells is linked to a high mortality rate in chickens infected with the highly pathogenic avian influenza virus, but interestingly, ducks exhibit a greater resistance to this virus. In this study, we examined the responsiveness of duck basilar arteries (BAs) to various vasoactive substances, including 5-hydroxytryptamine (5-HT), histamine (His), angiotensin (Ang) II, noradrenaline (NA), acetylcholine (ACh), and avian bradykinin ornithokinin (OK), aiming to characterize the receptor subtypes involved and the role of endothelial NO in vitro. Our findings suggest that arterial contraction is mediated with 5-HT1 and H1 receptors, while relaxation is induced with ß3-adrenergic and M3 receptors. Additionally, OK elicited a biphasic response in duck BAs, and Ang II had no effect. Endothelial NO appears to be crucial in relaxation mediated with M3 and OK receptors but not ß3-adrenergic receptors in the duck BA. The reduced endothelial NO involvement in the receptor-mediated relaxation response in duck BAs represents a clear difference from the corresponding response reported in chicken BAs. This physiological difference may explain the differences in lethality between ducks and chickens when vascular endothelial cells are infected with the virus.

Impact of adjuvant chemotherapy on long-term overall survival in patients with high-risk stage II colon cancer: a nationwide cohort study.

BACKGROUND: This study aimed to investigate the impact of adjuvant chemotherapy on long-term survival in unselected patients with high-risk stage II colon cancer including an analysis of each high-risk feature. MATERIALS AND METHODS: Data from the Danish Colorectal Cancer Group, the National Patient Registry and the Danish Pathology Registry from 2014 to 2018 were merged. Patients surviving > 90 days were included. High-risk features were defined as emergency presentation, including self-expanding metal stents (SEMS)/loop-ostomy as a bridge to resection, grade B or C anastomotic leakage, pT4 tumors, lymph node yield < 12 or signet cell carcinoma. Eligibility criteria for chemotherapy were age < 75 years, proficient MMR gene expression, and performance status ≤ 2. The primary outcome was 5-year overall survival. Secondary outcomes included the proportion of eligible patients allocated for adjuvant chemotherapy and the time to first administration. RESULTS: In total 939 of 3937 patients with stage II colon cancer had high-risk features, of whom 408 were eligible for chemotherapy. 201 (49.3%) patients received adjuvant chemotherapy, with a median time to first administration of 35 days after surgery. The crude 5-year overall survival was 84.9% in patients receiving adjuvant chemotherapy compared with 66.3% in patients not receiving chemotherapy, p < 0.001. This association corresponded to an absolute risk difference of 14%. CONCLUSION: 5-year overall survival was significantly higher in patients with high-risk stage II colon cancer treated with adjuvant chemotherapy compared with no chemotherapy. Adjuvant treatment was given to less than half of the patients who were eligible for it.

Inter-hospital variation in management of patients with small bowel obstruction in Denmark.

INTRODUCTION: Inter-hospital variation in the management of small bowel obstruction (SBO) has been described in other countries, but the extent to which similar variations exist in Denmark remains unknown. This study aimed to compare the management of SBO between hospitals in Denmark and identify potential areas for improvement METHODS. This was a multicentre prospective study performed at six emergency hospitals. Patients aged ≥ 18 years with a diagnosis of SBO were eligible for inclusion. The primary study endpoints were the proportion of patients undergoing operative versus non-operative management, laparoscopic surgery versus open surgery and the success rate of non-operative management. RESULTS: A total of 316 patients were included. No differences were noted in diagnostic pathways or operative versus non-operative management. However, variations were noted in compliance with peri-operative care bundles, ranging from 63.2% to 95.8%. The surgical approach also varied, with the use of laparoscopic surgery ranging from 20.7% to 71.0% (p less-than 0.001). Variations were also noted in duration of surgery (63-124 minutes, p less-than 0.001), time to re-introduction of normal diet and length of hospital stay (3-8.5 days, p less-than 0.001). No differences were observed in 30-day or 90-day mortality rates. CONCLUSION: The management of SBO in Denmark is relatively standardised. Future efforts should focus on improving adherence to multidisciplinary peri-operative protocols, optimising patient selection for laparoscopic surgery and standardising nutritional therapy. FUNDING: None. TRIAL REGISTRATION: NCT04750811.

Current practice in assessment and management of malnutrition in surgical oncology practice - An ESSO-EYSAC snapshot analysis.

INTRODUCTION: Malnutrition is common in patients suffering from malignant diseases and has a major impact on patient outcomes. Prevention and early detection are crucial for effective treatment. This study aimed to investigate current international practice in the assessment and management of malnutrition in surgical oncology departments. MATERIAL AND METHODS: The survey was designed by European Society of Surgical Oncology (ESSO) and ESSO Young Surgeons and Alumni Club (EYSAC) Research Academy as an online questionnaire with 41 questions addressing three main areas: participant demographics, malnutrition assessment, and perioperative nutritional standards. The survey was distributed from October to November 2021 via emails, social media and the ESSO website to surgical networks focussing on surgical oncologists. Results were collected and analysed by an independent team. RESULTS: A total of 156 participants from 39 different countries answered the survey, reflecting a response rate of 1.4%. Surgeons reported treating a mean of 22.4 patients per month. 38% of all patients treated in surgical oncology departments were routinely screened for malnutrition. 52% of patients were perceived as being at risk for malnutrition. The most used screening tool was the "Malnutrition Universal Screening Tool" (MUST). 68% of participants agreed that the surgeon is responsible for assessing preoperative nutritional status. 49% of patients were routinely seen by dieticians. In cases of severe malnutrition, 56% considered postponing the operation. CONCLUSIONS: The reported rate of malnutrition screening by surgical oncologists is lower than expected (38%). This indicates a need for improved awareness of malnutrition in surgical oncology, and nutritional screening.

Transvaginal resection of gastrointestinal stromal tumor in the rectum.

A gastrointestinal stromal tumour (GIST) can occur anywhere in the gastrointestinal tract, though rectal GIST is rare. The primary treatment of GIST is surgical resection. Neoadjuvant imatinib treatment may cause tumor reduction and allow local resection. This is a case report of a 70-year-old woman with a high level of comorbidity who was diagnosed with a low rectal GIST. She was successfully treated with imatinib followed by complete GIST resection using a transvaginal technique.

Challenges presented by complete response to immune checkpoint blockade in patients with dMMR colorectal cancer: A case report.

INTRODUCTION: Early clinical trials have demonstrated remarkable responses to immune checkpoint blockade (ICB) in patients with colorectal cancers with deficient mismatch repair (dMMR) mechanisms. The precise role immunotherapy will play in the treatment of these patients is undefined, with these agents likely to produce new challenges as well as opportunities. PRESENTATION OF CASE: A 74-year-old patient was diagnosed with a locally advanced dMMR adenocarcinoma in the transverse colon with clinical suspicion of peritoneal metastases (cT4N2M1). The burden of disease was assessed as incurable, and a referral was made for palliative oncological treatment. After 5 months of treatment with pembrolizumab, a complete radiological response in the primary tumour was seen although there was still radiological suspicion of peritoneal and lymph node metastases. The patient underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy but unfortunately died 6 weeks later due to complications. Final histology of the surgical specimen showed no evidence of residual disease (ypT0N0M0). DISCUSSION: This case highlights the opportunities and challenges presented by the efficacy of ICB in dMMR colorectal cancer. These agents were able to cure a patient who had disseminated disease presumed to be incurable at the time of diagnosis. However, due to current limitations in determining the degree of response to ICB, this result could only be confirmed after major surgery, which ultimately led to the patient's death. CONCLUSION: ICB can lead to dramatic responses in patients with dMMR colorectal cancers. Major challenges remain in differentiating complete and partial responders and determining the indications for conventional surgery.

Relationship between Regional Distribution of Centenarians and Drinking Water Hardness in the Amami Islands, Kagoshima Prefecture, Japan.

People who drink naturally hardened water may experience longevity-enhancing effects. In this study, we investigated water hardness and longevity from both geological and epidemiological perspectives in Japan's Amami islands, where drinking water is drawn from coralline or non-coralline bedrock. We investigated drinking water hardness, limestone bedrock occupancy, and the centenarian rate (number per 10,000 population) by municipality across four adjacent islands (Amami-Oshima (non-coralline), Tokunoshima, Okinoerabu, and Yoron (predominantly coralline)). Limestone was strongly correlated with water hardness (r = 0.99; p < 0.01), occupying more than 80% of the bedrock where the water was the hardest (Tokunoshima's Isen municipality: 86.5%; Yoron: 82.9%) and being scarcely detectable in Amami-Oshima (0.0 to 0.2%), where the water was the least hard. The centenarian rate was also strongly correlated with water hardness (r = 0.84, p < 0.01), with the highest figures in Yoron (29.7) and Isen (29.2), and the lowest in Amami-Oshima (0.0 to 12.2). Therefore, we hypothesize a potentially beneficial effect of hard water on longevity when that water is drawn from coralline limestone. Water hardness is determined by the water content of calcium and magnesium and may plausibly influence life expectancy through a preventative effect against cardiovascular disease. Our findings are of interest to current debates about future global access to drinking water and its quality.