Organ Preservation Strategies Research Articles

What To Do With Suspected Nodal Regrowth on Magnetic Resonance Imaging During Follow-up in an Organ Preservation Approach for Rectal Cancer?

BACKGROUND: For nodal regrowth in patients with rectal cancer following watch-and-wait standardized protocols on diagnostic procedures and subsequent treatment are lacking. OBJECTIVE: Evaluate the diagnosis and treatment of suspected nodal regrowth following an organ preservation approach. SETTINGS: Patients were included from national and institutional watch-and-wait -databases. DESIGN: Thirty-five rectal cancer patients with suspected nodal regrowth on magnetic resonance imaging were retrospectively identified during watch-and-wait follow-up. PATIENTS: Twenty-seven of 35 patients followed watch-and-wait after neoadjuvant (chemo)radiotherapy and 8/35 followed watch-and-wait schedule after local excision for early rectal cancer. MAIN OUTCOME MEASURES: Diagnostic procedures, treatment and histopathological outcome. RESULTS: Median follow-up was 34 months. Median time from end of (chemo)radiotherapy or local excision to first detection of suspected nodal regrowth on magnetic resonance imaging following watch-and-wait was 9 and 10 months. After first detection, 17 of 35 patients underwent immediate treatment without further diagnostics, of whom 7 also had luminal regrowth. In 18 of 35 patients, additional diagnostic procedures were performed. In 4 of 18 patients, positron emission tomography-computed tomography or endorectal ultrasound-guided biopsy was performed and treatment was initiated based on increased nodal regrowth suspicion. In 14 of 18 patients, MRI was repeated after 8-12 weeks: growth of suspected lymph nodes was the most decisive factor to proceed to treatment. In 8 patients, repeated magnetic resonance imaging was combined with positron emission tomography-computed tomography and/or endorectal ultrasound-guided biopsy: in half of them it contributed to treatment initiation. In total, 34/35 patients were treated: 9 received (re-)irradiation and 33 underwent total mesorectal excision. In 27 of 33 patients, nodal regrowth was pathologically confirmed in the total mesorectal excision-resection specimen; 5 of 6 patients without nodal involvement had pathologically confirmed luminal regrowth. LIMITATIONS: Highly selected study population. CONCLUSIONS: During watch-and-wait follow-up of patients with rectal cancer in an organ preservation strategy, magnetic resonance imaging plays an important role in diagnosis of nodal regrowth. Repeated magnetic resonance imaging after an interval can be helpful in making treatment decisions, and the role of positron emission tomography-computed tomography and endorectal ultrasound-guided biopsy appears limited. See Video Abstract.

604. REAL-WORLD MANAGEMENT AND OUTCOMES OF PATIENTS WITH NON METASTATIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA IN THE FREGAT DATABASE

Abstract Background International guidelines for locally advanced esophageal squamous cell carcinoma (ESCC) recommend both neoadjuvant chemoradiotherapy (nCRT) followed by planned surgery (P-surg) or definitive chemoradiotherapy (dCRT) with salvage surgery (S-surg). However, the optimal treatment remains unknown, and the ongoing pragmatic NEEDS randomized trial is assessing the efficacy of an organ-preserving strategy after dCRT (Nilsson, Front Oncol 2022). Real-world data on the management of non-metastatic ESCC is limited. This study aims to describe the treatment strategies and prognosis of patients with non-metastatic ESCC in a real-world setting. Methods We conducted a retrospective cohort study of patient treated for non-metastatic ESCC between 2014 and 2022. Data were extracted from the FREGAT database. For the entire population, different treatment strategies were described. We compared patients who received nCRT with those who received dCRT under real-life conditions (“Real-life” population) and according to the NEEDS randomized trial criteria (“NEEDS-like” population). Five-year overall survival (OS) and relapse-free survival (RFS) were compared between nCRT and dCRT patients using a Cox proportional hazard model adjusting for major confounders. In operated patients, the impact of surgery on OS and RFS was assessed using a time-dependent Cox proportional hazard model. Postoperative outcomes were compared between P-surg and S-surg using Fisher’s exact test. Results From 971 patients diagnosed with non-metastatic ESCC, 867 (89.3%) received a curative treatment including dCRT (41.0%), nCRT (28.0%), primary esophagectomy (9.8%), neoadjuvant chemotherapy (3.4%), or endoscopic resection (1.0%). Fifty-nine patients (6,1%) received supportive care or chemotherapy alone. Forty-five patients (4.6%) died during or before treatment. In the “real-life” population (n=659), 269 patients received nCRT and 390 patients received dCRT. A total of 229 patients (93.5%) in nCRT group underwent P-surg and S-surg was performed in 44 patients (11.3%) in dCRT group. After adjustment, dCRT was associated with a significantly poorer 5-year OS and RFS (respectively HR=1.83, 95%CI 1.44-2.33; HR=1.98, 95%CI 1.57-2.49). A complete clinical response (cCR) was observed in 21.6% and 29.5% of the nCRT and dCRT groups, respectively. Among cCR undergoing resection, 35.8% had residual disease on pathological specimen. Time between CRT and surgery was 58 days (IQR44-72) vs. 109 days (IQR71-278) for P-surge and S-Surg respectively. The 90-day mortality, major morbidity (Clavien-Dindo III/IV) and pulmonary complication rates were similar in both groups, except for a higher risk of anastomotic leakage after S-surg (p=0.05). In the “NEEDS-like” population (n=598), findings were consistent and comparable to those observed in the “real-life” population. Conclusion Among non-mestastatic ESCC included in the FREGAT database, 10.6% had a non-curative approach or died prematurely. Most patients underwent dCRT, with S-surg rate of only 11.3%. Neoadjuvant CRT followed by P-surg was associated with the best outcome in terms of OS and RFS in both “rela life” and “Needs-like” populations. In operated patients, postoperative outcomes were similar after nCRT and dCRT, except for a higher incidence of anastomotic leakage after S-surg. This study highlighted the therapeutic strategies used and their results in real-life conditions for non-metastatic ESCC inside the FREGAT database. The treatment option of nCRT followed by P-surg appears to remain the optimal curative treatment regimen.

A Survey of United States Transplant Center Donation After Circulatory Death Kidney Transplant Practices in the Modern Era

IntroductionThe mismatch between the number of patients awaiting kidney transplantation and the supply of donor organs has in part resulted in a rise in kidney transplantation from donors after circulatory death (DCD). Persistently long waiting times have led the transplant community to continue to explore the use of expanded criteria DCD kidneys. In parallel, advances in organ preservation strategies have contributed to an overall increase in DCD organ transplantation and are altering the transplant landscape. Some of these techniques may improve kidney allograft outcomes and affect how DCD kidneys are utilized. We aimed to better understand practices in accepting DCD kidney offers in the modern era. MethodsDirectors of 196 U.S. kidney transplant centers were emailed a link to an online survey over a 5-week period. Results48 (13%) out of the 364 directors responded with all UNOS regions represented. Definitions of warm ischemia time (WIT) used in DCD kidney evaluation varied widely amongst respondents. The maximum total WIT limit varied with 19 (39.6%) less than 60 minutes responses, followed by 16 (33%) less than 90 minutes responses, and 10 (20.8%) less than 120 minutes responses. ConclusionDespite increasing DCD kidney transplantation volumes in the U.S. there are no standardized procurement biopsy practices, OPO pre-operative protocols, or consensus definition or limits of WIT. Agreement upon terminology may facilitate rapid clinical communication, efficiency of organ allocation and utilization, recording of data, research, and improvements in policy.

Hypothermic oxygenated machine perfusion influences the immunogenicity of donor livers in humans.

Hypothermic oxygenated machine perfusion (HOPE) is an organ preservation strategy shown to reduce ischemia-reperfusion-injury (IRI)-related complications following liver transplantation (LT). In animal models HOPE can also decrease alloimmune responses post-transplantation, but this remains to be evaluated in humans. Our study, involving 27 LT patients enrolled in 2 randomised controlled trials comparing static cold storage (SCS) with HOPE (14 HOPE- and 13 SCS-treated), delves into the impact of HOPE on the molecular profile of liver allografts and on the immune responses elicited post-transplantation. Following HOPE treatment, fewer intra-hepatic immune cells were observed in liver perfusates compared to SCS. Analysis of liver tissue transcriptome at reperfusion revealed an effect of HOPE on the reactive oxygen species pathway. Two weeks post-transplantation, HOPE recipients exhibited increased circulating CD4+FOXP3+CD127lo regulatory T cells (Tregs) (p<0.01), which corresponded to a higher frequency of donor specific Tregs (p<0.01) and was followed by reduced alloreactivity index of CD8+ T cells 3 months post-transplant. Our study provides novel mechanistic insight into the capacity of HOPE to influence liver IRI and to modulate effector and regulatory donor-specific T cell responses post-transplantation. These findings, which confirm observations made in animal models, help explain the decreased rejection rates reported in patients receiving HOPE-treated allografts.

Comparative analysis of organ preservation attempt and radical surgery in clinical T2N0 mid to low rectal cancer

PurposeDebate persists regarding the feasibility of adopting an organ-preserving strategy as the treatment modality for clinical T2N0 rectal cancer. This study aimed to compare the outcomes of attempting organ-preserving strategies versus radical surgery in patients with clinical T2N0 mid to low rectal cancer.MethodsPatients diagnosed with clinical T2N0 rectal cancer, with lesions located within 8 cm from the anal verge as determined by pre-treatment magnetic resonance imaging between January 2010 and December 2020 were included.ResultsOf 119 patients, 91 and 28 were categorized into the organ-preserving attempt group and the radical surgery group, respectively. The median follow-up duration was 48.8 months (range, 0–134 months). The organ-preserving attempt group exhibited a reduced incidence of stoma formation (44.0% vs. 75.0%; p = 0.004) and a lower occurrence of grade 3 or higher surgical complications (5.8% vs. 21.4%; p = 0.025). Univariate analyses revealed no significant association between treatment strategy and 3-year local recurrence-free survival (organ-preserving attempt 87.9% vs. radical surgery 96.2%; p = 0.129), or 3-year disease-free survival (79.6% vs. 84.9%; p = 0.429). Multivariate analysis did not identify any independent prognostic factors associated with oncologic outcomes.ConclusionCompared with radical surgery, attempted organ preservation resulted in lower incidences of stoma formation and severe surgical complications, whereas oncological outcomes were comparable. Attempting organ preservation may be a safe alternative to radical surgery for clinical T2N0 mid to low rectal cancer.

‘Folfirinox’ chemotherapy combined with contact x-ray brachytherapy 50 kVp and ‘CAP50’ chemoradiotherapy aiming at organ preservation for selected intermediate distal-middle cT2-T3 rectal cancers: A feasibility study

PurposeThe standard treatment of T2–T3 rectal adenocarcinoma is radical proctectomy by total mesorectal excision often combined with some neoadjuvant treatment. To reduce morbidity of this surgery, organ preservation strategy using various combination of radiotherapy, chemotherapy and local excision is gaining interest. Some randomized trials have proven the feasibility of such approaches. The OPERA trial demonstrated, for T2 T3<5cm diameter low-middle rectum, that a contact X-ray brachytherapy boost of 90Gy in three fractions over 4 weeks was able to achieve a planned organ preservation in 81% of patients at 3years with 97% success for tumour smaller than 3cm treated with contact X-ray brachytherapy boost first. To try to expand organ preservation to larger tumours we set up a feasibility trial in T2–T3 tumours using total neoadjuvant treatment and a contact X-ray brachytherapy boost. Material and methodThe trial was approved by the institutional review board of Nice. Inclusion criteria were operable patients, 75years or less, adenocarcinoma of the low-middle rectum staged T2c-T3N0 larger than 3.5cm and less than 6cm in diameter or T2-T3N1 less than 6cm in diameter. Treatment started in all cases with neoadjuvant chemotherapy associating 5-fluoro-uracile, irinotecan and oxaliplatin (‘folfirinox’ regimen, four to six cycles). In case of good tumour response after four cycles, a contact X-ray brachytherapy boost (delivering 90Gy in three fractions) was given followed by chemoradiotherapy (external beam radiotherapy delivering 50Gy, with concurrent capecitabine). After six cycles if only a partial response (tumour still larger than 3cm) was seen, chemoradiotherapy was given and contact X-ray brachytherapy boost was delivered after that. At the end of this total neoadjuvant treatment a watch and wait strategy was decided in case of clinical complete response or radical proctectomy by total mesorectal excision for partial response. ResultsBetween July 2019 and October 2022, 14 patients were included; median age was 66years (range: 51–77years), there were nine male and five female, two T2 N1 tumours, seven T3N0, and five T3N1, all were M0. Median tumour diameter was 40mm (range: 11–50mm); three tumours had a circumferential extension greater than 50%. Seven patients received four folfirinox cycles and seven had six cycles. Contact X-ray brachytherapy boost was given during folfirinox chemotherapy before chemoradiotherapy in 11 patients (and after in three). The tolerance was good, with no grade 4–5 toxicity. The main grade 3 early toxicity was in relation with the folfirinox regimen. A clinical complete response was seen in 12 patients at the end of the total neoadjuvant treatment (85%). All these patients are alive and have preserved their rectum with a mean follow-up time of 17.8months (range: 6–48months) and a good bowel function (low anterior rectal resection syndrome score below 30). The main contact X-ray brachytherapy boost toxicity was radiation ulceration in three patients that usually healed within 6 months, sometimes necessitating hyperbaric oxygen. ConclusionThe preliminary results of this feasibility study show that early tolerance of these intensive total neoadjuvant treatment is compatible with an acceptable toxicity. The high rate of organ preservation in this intermediate group of T2–T3 tumours is encouraging and is a good argument to start the next randomized TRESOR trial that will aim at achieving a 65% of 3-year survival with organ preservation in this intermediate tumour group.

Optimizing Organ-Preservation Strategies Through Chemotherapy-Based Selection in Esophageal Squamous Cell Carcinoma: Results From the CROC Multi-Institutional Phase 2 Clinical Trial

PurposeThis study aimed to assess the viability of definitive chemoradiotherapy (dCRT) as an organ-preservation strategy for remarkable responders who were downstaged to stage IA after receiving induction chemotherapy for resectable esophageal squamous cell carcinoma (ESCC). Methods and MaterialsChemotherapy-naïve patients with resectable ESCC (stage IB–III, UICC, International Cancer Control 7th edition) were eligible for the study. All patients received three cycles of DCF therapy (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and 5-fluorouracil [5-FU] 750 mg/m2 on days 1–5, repeated every three weeks). A remarkable response was defined as a reduction of the tumor to T1, metastatic lymph nodes smaller than 1 cm on the short axis, and downstaging to stage IA after three cycles of DCF therapy. Remarkable responders then underwent dCRT, which included two courses of cisplatin 75 mg/m2 and 5-FU 1000 mg/m2 on days 1–4, repeated every four weeks, along with 50.4 Gy of concurrent radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) in remarkable responders following DCF therapy and subsequent dCRT. Secondary endpoints included 3-year overall survival (OS) and esophagectomy-free survival (EFS). ResultsOf the 92 patients registered, 90 were analyzed. A remarkable response to three courses of DCF therapy was observed in 58.4% of patients. Among these responders, 89.8% achieved a complete response after dCRT. During the median follow-up period of 33 months (range: 1–85 months), the 1-year PFS was 89.8% (95% confidence interval = 77.2%–95.6%, primary endpoint), and the 3-year OS was 83.7%. The 3-year OS and EFS rates in the analysis group were 74.1% and 45.3%, respectively. An 18F-fluorodeoxyglucose-positron emission tomography response after two courses of DCF therapy was significantly associated with OS (p = 0.0049). ConclusionsIn patients with resectable ESCC, dCRT for remarkable responders downstaging to stage IA after induction chemotherapy with three courses of DCF therapy is a feasible treatment option and provides an optimizing organ-preservation strategy of chemotherapy-based selection.

High Rates of Organ Preservation in Rectal Cancer with Papillon Contact X-ray Radiotherapy: Results from a Swiss Cohort.

Rectal cancer typically necessitates a combination of radiotherapy (RT), chemotherapy, and surgery. The associated functional disorders and reduction in quality of life have led to an increasing interest in organ preservation strategies. Response strongly correlates with RT dose, but dose escalation with external beam remains limited even with modern external beam RT techniques because of toxicity of the surrounding tissues. This study reports on the use of Papillon, an endocavitary Radiotherapy device, in the treatment of rectal cancer. The device delivers low energy X-rays, allowing for safe dose escalation and better complete response rate. Between January 2015 and February 2024, 24 rectal cancer patients were treated with the addition of a boost delivered by Papillon to standard RT, with or without chemotherapy, in an upfront organ preservation strategy. After a median follow-up (FU) of 43 months, the organ preservation rate was 96% (23/24), and the local relapse rate was 8% (2/24). None of our patients developed grade 3 or more toxicities. Our results demonstrate that the addition of Papillon contact RT provides a high rate of local remission with sustained long-term organ preservation, offering a promising alternative to traditional surgical approaches in patients with rectal cancer.

Effect of optical diagnosis training on recognition and treatment of submucosal invasive colorectal cancer in community hospitals: a prospective multicenter intervention study.

Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35 %-60 % in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals. In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists. 1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47 %] trained). Median T1 CRC size was 20 mm. Lesions were mainly located in the distal colorectum (66 %). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74 % vs. 62 %; mixed model analysis odds ratio [OR] 2.90, 95 %CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69 % vs. 56 %; OR 1.73, 95 %CI 1.03-2.91). Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies.

Transanal endoscopic microsurgery vs. radical surgery for mid-low rectal cancer in patients with clinical complete or near-complete response after neoadjuvant chemoradiotherapy.

e15616 Background: Following neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision surgery used to be the standard therapy for locally advanced rectal cancer (LARC). However, the radical surgery is associated with high complication rates and impairs patients' quality of life, especially for non-sphincter preservation procedures. For the past two decades, nCRT followed by organ preservation strategies like watch-and-wait (W&amp;W) or local resection offers an alternative for patients being clinically evaluated with complete response or near complete response, however the oncological outcomes of these approaches require further exploration. Methods: We prospectively collected data on 80 patients with T3-4N0M0 or TanyN+M0 mid-low rectal cancer who achieved cCR or near-cCR after nCRT from May 2017 to September 2021 at 5 tertiary centers in China. Patients were divided into the TEM group (group A) or the radical surgery group (group B). Clinicopathological features, operative outcomes, oncological and functional results were analyzed. Results: A total of 76 cases were analyzed, with 38 in each group. Baseline characteristics were comparable between the two groups. Postoperative histology revealed 22 ypT0Nx(57.9%), 5 ypT1Nx(13.2%), 10 ypT2Nx (26.3%), 1 ypT3Nx(2.6%) in group A, and 18 ypT0N0 (47.4%), 5 ypT1N0 (13.2%), 11 ypT2-3N0 (28.9%), 1 ypT0N1 (2.6%), 3 ypT2-3N1 (7.9%) in group B. After a median follow-up of 61 months, 2 patients (5.26%) in group A experienced local recurrence, while none in group B. 8 patients (21.05%) in group A developed distant metastases compared to 5 (13.16%) in group B. There was no statistically significant difference between two groups in 5-year disease-free survival(P = 0.320), or 5-year overall survival (P = 0.425). Patients in group A had significantly faster postoperative recovery and a superior quality of life evaluated by the Wexner and LARS scores compared to group B. Conclusions: For cCR and near-cCR LARC patients after nCRT, organ preservation with TEM may serve as a staging method to evaluate local tumor persisrence. And it provides an alternative therapy for carefully selected patients who have needs to preserve sphincteric function or can’t tolerate radical resection, without significantly compensate long-term oncological outcomes. This strategy could relatively safely enable sphincteric function preservation for these patients with faster postoperative recovery and better quality of life. Clinical trial information: NCT03042000 .

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

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. 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. 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. 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.

PERSPECTIVE: The cold chain delivery of organs for transplantation: from research laboratories and individual enthusiasts to pan-global networks in 50 years

It is some 50 years since the first published reports appeared of ex vivo preservation of organs for transplantation. Over the intervening decades, organ preservation strategies have become one essential component of world-wide clinical transplant services. In the formative years, translational research in organ hypothermic preservation was grappling with the questions about whether static or dynamic storage was preferable, and the practical implications of those choices. Those studies were also informing the newly expanding clinical transplant services. During the middle years, both preservation modalities were practiced by individual group choices. By the 2000???s, the shift in donor demographics demanded a re-evaluation of organ preservation strategies, and now a new era of research and development is promoting adoption of new technologies. In this review we outline many important academic studies which have contributed to this successful history, and give profile to the increasing innovative approaches which are being evaluated for the future.

Considerations for the use of porcine organ donation models in preclinical organ donor intervention research.

Use of animal models in preclinical transplant research is essential to the optimization of human allografts for clinical transplantation. Animal models of organ donation and preservation help to advance and improve technical elements of solid organ recovery and facilitate research of ischemia-reperfusion injury, organ preservation strategies, and future donor-based interventions. Important considerations include cost, public opinion regarding the conduct of animal research, translational value, and relevance of the animal model for clinical practice. We present an overview of two porcine models of organ donation: donation following brain death (DBD) and donation following circulatory death (DCD). The cardiovascular anatomy and physiology of pigs closely resembles those of humans, making this species the most appropriate for pre-clinical research. Pigs are also considered a potential source of organs for human heart and kidney xenotransplantation. It is imperative to minimize animal loss during procedures that are surgically complex. We present our experience with these models and describe in detail the use cases, procedural approach, challenges, alternatives, and limitations of each model.

Clinicopathological factors predict residual lymph node metastasis in locally advanced rectal cancer with ypT0-2 after neoadjuvant chemoradiotherapy

PurposeResidual lymph node metastases (RLNM) remained a great concern in the implementation of organ-preserving strategies and led to poor prognosis in locally advanced rectal cancer (LARC). In this study, we aimed to identify the clinicopathological factors correlated with RLNM in LARC patients with ypT0-2 after neoadjuvant chemoradiotherapy (NCRT).MethodsWe retrospectively analyzed 417 patients histologically diagnosed middle-low LARC after NCRT and total mesorectal excision (TME), whose pathological staging was ypT0-2. All patients received pelvic magnetic resonance imaging (MRI) before NCRT. The radiation doses were 50–50.6 Gy for the planning gross tumor volume and 41.8–45 Gy for the planning target volume, respectively. A nomogram for predicting RLNM was constructed using a binary logistic regression. Nomogram performance was assessed by receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC).ResultsAfter surgery, 191 patients (45.8%) were ypT0, 43 patients (10.3%) were ypT1 and 183 patients (43.9%) were ypT2, and a total of 49 patients (11.8%) were found the presence of RLNM. Multivariable analyses identified MRI-defined mesorectal fascia (MRF)-positive, high-grade histopathology at biopsy, advanced ypT-category, and the presence of perineural invasion (PNI) as the predictive factors. The nomogram, incorporating all these predictors, showed good discrimination and calibration efficacy, with the areas under the ROC curve of 0.690 (95% CI: 0.610–0.771). Both DCA and CIC demonstrated that this nomogram has good clinical usefulness.ConclusionThe nomogram model can predict RLNM in patients with ypT0-2 tumors. It can help select suitable patients for performing organ-preserving strategies after NCRT.

Ex vivo kidney machine perfusion: meta-analysis of randomized clinical trials.

Machine perfusion is an organ preservation strategy used to improve function over simple storage in a cold environment. This article presents an updated systematic review and meta-analysis of machine perfusion in deceased donor kidneys. RCTs from November 2018 to July 2023 comparing machine perfusion versus static cold storage in kidney transplantation were evaluated for systematic review. The primary outcome in meta-analysis was delayed graft function. A total 19 studies were included, and 16 comparing hypothermic machine perfusion with static cold storage were analysed. The risk of delayed graft function was lower with hypothermic machine perfusion (risk ratio (RR) 0.77, 95% c.i. 0.69 to 0.86), even in kidneys after circulatory death (RR 0.78, 0.68 to 0.90) or brain death (RR 0.73, 0.63 to 0.84). Full hypothermic machine perfusion decreased the risk of delayed graft function (RR 0.69, 0.60 to 0.79), whereas partial hypothermic machine perfusion did not (RR 0.92, 0.69 to 1.22). Normothermic machine perfusion or short-term oxygenated hypothermic machine perfusion preservation after static cold storage was equivalent to static cold storage in terms of delayed graft function and 1-year graft survival. Hypothermic machine perfusion reduces delayed graft function risks and normothermic approaches show promise.

Retrospective study evaluating dental side effects of radiotherapy in patients treated for head and neck cancer

IntroductionHead and neck cancer squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with around 600,000 new diagnosis each year. Nowadays, in locally advanced disease, radiotherapy (RT) play an important role, this with or without chemotherapy in organ preservation strategies. More specific for early stage localized disease, RT (or surgery) seems to give similar results on locoregional control (LRC) and choice is made according to the organ preservation issue. Despite the fact that technical improvements have been made to optimize the radiation dose delivery and minimize the normal tissue toxicity, RT is associated with potential early and late toxicities. Osteoradionecrosis of the jaw (ORNJ), especially seen after teeth extraction, is one of the associated toxicities and can significantly impair the patient's quality of life. Because of the fear of developing ORNJ, one is very reluctant to extract or place a dental implant post-radiotherapy, especially in high irradiation dose zones (>40 Gy). Hence, it is important to define teeth at risk of future extraction before initiating RT and to handle those in high-risk irradiation zones. In order to optimise extractions, we created a predictive model of the expected irradiation dose, and thus the need for extraction, to the teeth bearing bones. The aim of this study is to validate our model and to define the potential relationship between the radiation dose received by each tooth and the dental complications observed. Material and methodsBetween March 2012 and March 2018, patients with HNSCC treated by intensity modulated RT were retrospectively analysed. The mean irradiation dose for each tooth was generated on the administered treatment plan by contouring each tooth separately on each dosimetric scan section using dedicated software (Eclipse, Varian). In order to validate our predictive model, we compared the actual generated/administered teeth irradiation doses with the irradiation doses predicted by our model. ResultsOur predictive model was accurate in 69.6% of the cases. In 12.5% of cases the predicted dose was higher than the calculated dose and lower in 17,8% of the cases. A correct- or over-estimation (is the latter being clinically less worrying than an underestimated dose) was achieved in 82% of cases. For the 18% of cases underfitting, the mean margin of error was 5.7 Gy. No statistically significant association was found between the development of caries and doses to the teeth, doses to the parotid glands or dental hygiene. However, a significant association between dental irradiation at more than 40 Gy and the occurrence of dental fractures (p = 0.0002) were demonstrated. ConclusionsOur predictive model seems to be 82% accurate for dose prediction, hence might be helpful for optimizing/minimizing prophylactic extractions. Indeed, following our model, professionals could decide not to extract damaged teeth in areas not at risk of ORNJ, lowering morbidity during and after RT. Contrary to the literature, no relationship was found between the occurrence of dental caries and parotid irradiation and the patient's oral hygiene. However, for the first time, a highly significant correlation between the occurrence of dental fracture and dental irradiation at more than 40 Gy was observed.

Exploiting BRAF mutations in the therapeutic approach towards oral and maxillofacial tumors

Oral and maxillofacial tumors pose a significant clinical challenge due to their tendency to recur, despite advancements in surgical removal techniques. The jaw's intricate structure further complicates treatments and affects patient quality of life. Consequently, emphasis has shifted towards pharmacological interventions, to potentially reduce invasive surgical procedures. One promising approach targets BRAF mutations, specifically the common V600E mutation. BRAF, a critical protein kinase, regulates cell growth and differentiation via the RAS-RAF-MEK-ERK-MAP kinase pathway. A specific nucleotide change at position 1799, swapping Thymine (T) for Adenine (A), results in the V600E mutation, causing unchecked cell growth. This mutation is common in certain oral and maxillofacial tumors like ameloblastoma. A recent neoadjuvant therapy targeting BRAF, involving the use of dabrafenib and trametinib, has showcased a promising, safe, and effective strategy for organ preservation in the treatment of mandibular ameloblastoma. This convergence of molecular insights and targeted therapies holds the key to managing BRAF-mutated oral and maxillofacial tumors effectively, promising improved patient outcomes.

Multi-omics staging of locally advanced rectal cancer predicts treatment response: a pilot study

Treatment response assessment of rectal cancer patients is a critical component of personalized cancer care and it allows to identify suitable candidates for organ-preserving strategies. This pilot study employed a novel multi-omics approach combining MRI-based radiomic features and untargeted metabolomics to infer treatment response at staging. The metabolic signature highlighted how tumor cell viability is predictively down-regulated, while the response to oxidative stress was up-regulated in responder patients, showing significantly reduced oxoproline values at baseline compared to non-responder patients (p-value < 10–4). Tumors with a high degree of texture homogeneity, as assessed by radiomics, were more likely to achieve a major pathological response (p-value < 10–3). A machine learning classifier was implemented to summarize the multi-omics information and discriminate responders and non-responders. Combining all available radiomic and metabolomic features, the classifier delivered an AUC of 0.864 (± 0.083, p-value < 10–3) with a best-point sensitivity of 90.9% and a specificity of 81.8%. Our results suggest that a multi-omics approach, integrating radiomics and metabolomic data, can enhance the predictive value of standard MRI and could help to avoid unnecessary surgical treatments and their associated long-term complications.

MR radiomics predicts pathological complete response of esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: a multicenter study

BackgroundMore than 40% of patients with resectable esophageal squamous cell cancer (ESCC) achieve pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT), who have favorable prognosis and may benefit from an organ-preservation strategy. Our study aims to develop and validate a machine learning model based on MR radiomics to accurately predict the pCR of ESCC patients after nCRT.MethodsIn this retrospective multicenter study, eligible patients with ESCC who underwent baseline MR (T2-weighted imaging) and nCRT plus surgery were enrolled between September 2014 and September 2022 at institution 1 (training set) and between December 2017 and August 2021 at institution 2 (testing set). Models were constructed using machine learning algorithms based on clinical factors and MR radiomics to predict pCR after nCRT. The area under the curve (AUC) and cutoff analysis were used to evaluate model performance.ResultsA total of 155 patients were enrolled in this study, 82 in the training set and 73 in the testing set. The radiomics model was constructed based on two radiomics features, achieving AUCs of 0.968 (95%CI 0.933–0.992) in the training set and 0.885 (95%CI 0.800-0.958) in the testing set. The cutoff analysis resulted in an accuracy of 82.2% (95%CI 72.6-90.4%), a sensitivity of 75.0% (95%CI 58.3-91.7%), and a specificity of 85.7% (95%CI 75.5-96.0%) in the testing set.ConclusionA machine learning model based on MR radiomics was developed and validated to accurately predict pCR after nCRT in patients with ESCC.

Organ-preservation in rectal cancer: What is at risk when offering watch and wait for a clinical complete response? Data from 2 international registries in rectal cancer.

7 Background: Organ-preservation has become an attractive alternative to total mesorectal excision (TME) among patients with rectal cancer following neoadjuvant therapy. Patients who achieve a clinical complete response (cCR) are currently offered watch-and-wait (WW) without immediate resection. Nearly 30% of these patients will develop local regrowth usually within 3 years from initial decision to WW. While salvage resection is frequently feasible, keeping the primary tumor in situ (despite clinically undetectable) may contribute to the risk for development of subsequent distant metastases (DM). The aim of the present study is to compare the risk of DM between patients with local regrowth (LR) after WW (undetectable residual disease) and patients with near-complete pathological response managed by TME at time of reassessment of response. Methods: Data from patients with rectal cancer following neoadjuvant therapy entered a prospective international database (IWWD) with cCR managed by WW and subsequent LR were compared to patients managed by TME from a prospectively maintained national registry (VIKINGO project). Near-complete response was defined at the presence of ≤10% residual cancer cells in the resected specimen. Primary endpoint was DM-free survival at 3 years from decision to WW or TME. Cox-logistic regression was performed to search for predictors of DM development. Kaplan-Meier curves were used to compare DM-free survival between groups based on statistically significant features found at multivariate analysis (p≤0.05) using log-rank test. Results: 508 patients with LR were compared to 893 patients with near-complete response after TME. Overall, DM rate was significantly higher among local regrowths (22.8% vs. 10.2%,; p≤0.001). Independent risk factors for DM included LR (versus TME at reassessment; p=0.001), ypT3-4 status (p=0.016) and ypN+ status (p=0.001) at the time of surgery. 3yr-DM-free survival was significantly worse for patients with local regrowth (75% vs. 87%; p=0.001). When stratified for pathological stage, patients with local regrowth did significantly worse through all stages ypT1-2N0 (p&lt;0.001); ypT3-4N0 (p=0.009) and ypTanyN+ (p&lt;0.001). Conclusions: Development of LR following WW is a significant and independent risk factor for subsequent DM. Final pathological stage is also a risk factor for subsequent DM. Patients with local regrowth have a higher risk for subsequent DM development than patients managed by TME at restaging irrespective of final ypT and ypN status. Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes. Future studies incorporating organ-preservation strategies should focus on the subsequent risk of DM among patients who eventually develop local regrowth as one of clinically relevant primary endpoints.