Risks of Organ Preservation in Rectal Cancer: Data From Two International Registries on Rectal Cancer.

PURPOSE: Organ preservation has become an attractive alternative to surgery (total mesorectal excision [TME]) among patients with rectal cancer after neoadjuvant therapy who achieve a clinical complete response (cCR). Nearly 30% of these patients will develop local regrowth (LR). Although salvage resection is frequently feasible, there may be an increased risk for development of subsequent distant metastases (DM). The aim of this study is to compare the risk of DM between patients with LR after Watch and Wait (WW) and patients with near-complete pathologic response (nPCR) managed by TME at the time of reassessment of response. METHODS: Data from patients enrolled in the International Watch & Wait Database (IWWD) with cCR managed by WW and subsequent LR were compared with patients managed by TME (with ≤10% cancer cells-nPCR) from the Spanish Rectal Cancer Project (VIKINGO project). The primary end point was DM-free survival at 3 years from decision to WW or TME. The secondary end point was possible risk factors associated with DM. RESULTS: Five hundred and eight patients with LR were compared with 893 patients with near-complete response after TME. Overall, DM rate was significantly higher among LRs (22.8% v 10.2%; P ≤ .001). Independent risk factors for DM included LR (v TME at reassessment; P = .001), ypT3-4 status (P = .016), and ypN+ status (P = .001) at the time of surgery. 3-year DM-free survival was significantly worse for patients with LR (75% v 87%; P = .001). When stratified for pathologic stage, patients with LR did significantly worse through all stages (P ≤ .009). CONCLUSION: Patients with LR appear to have a higher risk for subsequent DM development than patients with nPCR managed by TME at restaging irrespective of final pathology. Leaving the primary undetectable tumor in situ until development of LR may result in worse oncologic outcomes.

Detection and characterization of colorectal cancer by autofluorescence lifetime imaging on surgical specimens.

Colorectal cancer (CRC) ranks among the most prevalent malignancies worldwide, driving a quest for comprehensive characterization methods. We report a characterization of the ex vivo autofluorescence lifetime fingerprint of colorectal tissues obtained from 73 patients that underwent surgical resection. We specifically target the autofluorescence characteristics of collagens, reduced nicotine adenine (phosphate) dinucleotide (NAD(P)H), and flavins employing a fiber-based dual excitation (375 nm and 445 nm) optical imaging system. Autofluorescence-derived parameters obtained from normal tissues, adenomatous lesions, and adenocarcinomas were analyzed considering the underlying clinicopathological features. Our results indicate that differences between tissues are primarily driven by collagen and flavins autofluorescence parameters. We also report changes in the autofluorescence parameters associated with NAD(P)H that we tentatively attribute to intratumoral heterogeneity, potentially associated to the presence of distinct metabolic subpopulations. Changes in autofluorescence signatures of malignant tumors were also observed with lymphatic and venous invasion, differentiation grade, and microsatellite instability. Finally, we characterized the impact of radiative treatment in the autofluorescence fingerprints of rectal tissues and observed a generalized increase in the mean lifetime of radiated adenocarcinomas, which is suggestive of altered metabolism and structural remodeling. Overall, our preliminary findings indicate that multiparametric autofluorescence lifetime measurements have the potential to significantly enhance clinical decision-making in CRC, spanning from initial diagnosis to ongoing management. We believe that our results will provide a foundational framework for future investigations to further understand and combat CRC exploiting autofluorescence measurements.

MHC class II proteins mediate sialic acid independent entry of human and avian H2N2 influenza A viruses.

Influenza A viruses (IAV) pose substantial burden on human and animal health. Avian, swine and human IAV bind sialic acid on host glycans as receptor, whereas some bat IAV require MHC class II complexes for cell entry. It is unknown how this difference evolved and whether dual receptor specificity is possible. Here we show that human H2N2 IAV and related avian H2N2 possess dual receptor specificity in cell lines and primary human airway cultures. Using sialylation-deficient cells, we reveal that entry via MHC class II is independent of sialic acid. We find that MHC class II from humans, pigs, ducks, swans and chickens but not bats can mediate H2 IAV entry and that this is conserved in Eurasian avian H2. Our results demonstrate that IAV can possess dual receptor specificity for sialic acid and MHC class II, and suggest a role for MHC class II-dependent entry in zoonotic IAV infections.

Zebrafish Avatar-test forecasts clinical response to chemotherapy in patients with colorectal cancer.

Cancer patients often undergo rounds of trial-and-error to find the most effective treatment because there is no test in the clinical practice for predicting therapy response. Here, we conduct a clinical study to validate the zebrafish patient-derived xenograft model (zAvatar) as a fast predictive platform for personalized treatment in colorectal cancer. zAvatars are generated with patient tumor cells, treated exactly with the same therapy as their corresponding patient and analyzed at single-cell resolution. By individually comparing the clinical responses of 55 patients with their zAvatar-test, we develop a decision tree model integrating tumor stage, zAvatar-apoptosis, and zAvatar-metastatic potential. This model accurately forecasts patient progression with 91% accuracy. Importantly, patients with a sensitive zAvatar-test exhibit longer progression-free survival compared to those with a resistant test. We propose the zAvatar-test as a rapid approach to guide clinical decisions, optimizing treatment options and improving the survival of cancer patients.

International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy.

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.

Local Regrowth and the Risk of Distant Metastases Among Patients Undergoing Watch-and-Wait for Rectal Cancer: What Is the Best Control Group? Multicenter Retrospective Study.

BACKGROUND: A proportion of rectal cancer patients who achieve a clinical complete response may develop local regrowth. Although salvage appears to provide appropriate local control, the risk of distant metastases is less known. OBJECTIVE: To compare the risk of distant metastases between patients who achieve a clinical complete response (watch-and-wait strategy) and subsequent local regrowth and patients managed by surgery after chemoradiation. DESIGN: Retrospective multicenter cohort study. SETTINGS: This study used data of patients from 3 institutions who were treated between 1993 and 2019. PATIENTS: Patients with initial clinical complete response (after neoadjuvant therapy) followed by local regrowth and patients with near-complete pathological response (≤10%) after straightforward surgery after chemoradiation were included. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify risk factors for distant metastases. Kaplan-Meier curves were created (log-rank test) to compare survival outcomes. Analyses were performed using time zero as last day of radiation therapy or as date of salvage resection in the local regrowth group. RESULTS: Twenty-one of 79 patients with local regrowth developed distant metastases, whereas only 10 of 74 after upfront total mesorectal excision following neoadjuvant chemoradiation therapy ( p = 0.04). Local regrowth and final pathology (ypT3-4) were the only independent risk factors associated with distant metastases. When using date of salvage resection as time zero, distant metastases-free survival rates were significantly inferior for patients with local regrowth (70% vs 86%; p = 0.01). LIMITATIONS: Small number of patients, many neoadjuvant therapies, and selection bias. CONCLUSIONS: Patients undergoing watch-and-wait strategy who develop local regrowth are at higher risk for development of distant metastases compared to patients with near-complete pathological response managed by upfront surgery after chemoradiation. See Video Abstract. NUEVO CRECIMIENTO LOCAL Y EL RIESGO DE METSTASIS A DISTANCIA ENTRE PACIENTES SOMETIDOS A OBSERVACIN Y ESPERA POR CNCER DE RECTO CUL ES EL MEJOR GRUPO DE CONTROL ESTUDIO RETROSPECTIVO MUTICNTRICO: ANTECEDENTES:Una proporción de pacientes que logran una respuesta clínica completa pueden desarrollar un nuevo crecimiento local. Si bien el rescate parece proporcionar un control local apropiado, el riesgo de metástasis a distancia es menos conocido.OBJETIVO:Comparar el riesgo de metástasis a distancia entre los pacientes que logran una respuesta clínica completa (estrategia de observación y espera) y el nuevo crecimiento local posterior con los pacientes tratados con cirugía después de la quimiorradiación.DISEÑO:Estudio de cohorte multicéntrico retrospectivo.CONFIGURACIÓN:Este estudio utilizó datos de pacientes de 3 instituciones que fueron tratados entre 1993 y 2019.PACIENTES:Pacientes con respuesta clínica completa inicial (después de la terapia neoadyuvante) seguida de crecimiento local nuevo y pacientes con respuesta patológica casi completa (≤10 %) después de cirugía directa después de quimiorradiación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó un análisis univariante/multivariante para identificar los factores de riesgo de metástasis a distancia. Se crearon curvas de Kaplan-Meier (prueba de rango logarítmico) para comparar los resultados de supervivencia. El análisis se realizó utilizando el tiempo cero como último día de radioterapia (1) o como fecha de resección de rescate (2) en el grupo de recrecimiento local.RESULTADOS:Veintiuno de 79 pacientes con recrecimiento local desarrollaron metástasis a distancia, mientras que solo 10 de 74 después de una cirugía sencilla (p = 0,04). El recrecimiento local y la patología final (ypT3-4) fueron los únicos factores de riesgo independientes asociados con las metástasis a distancia. Cuando se utilizó la fecha de la resección de rescate como tiempo cero, las tasas de supervivencia sin metástasis a distancia fueron significativamente inferiores para los pacientes con recrecimiento local (70 frente a 86 %; p = 0,01).LIMITACIONES:Pequeño número de pacientes, muchas terapias neoadyuvantes, sesgo de selección.CONCLUSIONES:Los pacientes sometidos a observación y espera que desarrollan un nuevo crecimiento local tienen un mayor riesgo de desarrollar metástasis a distancia en comparación con los pacientes con una respuesta patológica casi completa manejados con cirugía por adelantado después de la quimiorradiación. (Traducción-Dr. Xavier Delgadillo ).

The Risk of Distant Metastases in Patients With Clinical Complete Response Managed by Watch and Wait After Neoadjuvant Therapy for Rectal Cancer: The Influence of Local Regrowth in the International Watch and Wait Database.

BACKGROUND: Nearly 30% of patients with rectal cancer develop local regrowth after initial clinical complete response managed by watch and wait. These patients might be at higher risk for distant metastases. OBJECTIVE: This study aimed to investigate risk factors for distant metastases using time-dependent analyses. DESIGN: Data from an international watch and wait database were retrospectively reviewed. Cox regression analysis was used to determine risk factors for worse distant metastases-free survival. Conditional survival modeling was used to investigate the impact of risk factors on the development of distant metastases. SETTING: Retrospective, multicenter database. PATIENTS: A total of 793 patients (47 institutions) with rectal cancer and clinical complete response to neoadjuvant treatment from the International Watch & Wait Database were included. MAIN OUTCOME MEASURES: Distant metastases-free survival. RESULTS: Of the 793 patients managed with watch and wait (median follow-up 55.2 mo)' 85 patients (10.7%) had distant metastases. Fifty-one of 85 patients (60%) had local regrowth at any time. Local regrowth was an independent factor associated with worse distant metastases-free survival in the multivariable model. Using conditional estimates, patients with local regrowth without distant metastases for 5 years (from decision to watch and wait) remained at higher risk for development of distant metastases for 1 subsequent year compared to patients without local regrowth (5-year conditional distant metastases-free survival 94.9% vs 98.4%). LIMITATIONS: Lack of information on adjuvant chemotherapy, salvage surgery for local regrowth, and heterogeneity of individual surveillance/follow-up strategies used may have affected results. CONCLUSIONS: In patients with clinical complete response managed by watch and wait, development of local regrowth at any time is a risk factor for distant metastases. The risk of distant metastases remains higher for 5 years after development of local regrowth. See Video Abstract at http://links.lww.com/DCR/C53. EL RIESGO DE METSTASIS A DISTANCIA EN PACIENTES CON RESPUESTA CLNICA COMPLETA MANEJADA POR WATCH AND WAIT DESPUS DE LA TERAPIA NEOADYUVANTE PARA EL CNCER DE RECTO LA INFLUENCIA DEL NUEVO CRECIMIENTO LOCAL EN LA BASE DE DATOS INTERNACIONAL WATCH AND WAIT: ANTECEDENTES:Casi el 30 % de los pacientes con cáncer de recto desarrollan un nuevo crecimiento local después de la respuesta clínica completa inicial manejada por watch and wait. Estos pacientes podrían tener un mayor riesgo de metástasis a distancia.OBJETIVO:Investigar los factores de riesgo de metástasis a distancia mediante análisis dependientes del tiempo.DISEÑO:Se revisó retrospectivamente los datos de la base de datos internacional de Watch and Wait. Se utilizó el análisis de regresión de Cox para determinar los factores de riesgo de peor sobrevida libre de metástasis a distancia. Se utilizó un modelo de sobrevida condicional para investigar el impacto de los factores de riesgo en el desarrollo de metástasis a distancia. El tiempo transcurrido hasta el evento se calculó utilizando la fecha de decisión para watch and wait y la fecha del nuevo crecimiento local para el diagnóstico de metástasis a distancia.ESCENARIOBase de datos multicéntrica retrospectiva.PACIENTES:Se incluyeron un total de 793 pacientes (47 instituciones) con cáncer de recto y respuesta clínica completa al tratamiento neoadyuvante de la base de datos internacional de Watch and Wait.PRINCIPALES MEDIDAS DE RESULTADO:Desarrollo de metástasis a distancia.RESULTADOS:De los 793 pacientes tratados con watch and wait (mediana de seguimiento de 55,2 meses), 85 (10,7%) tenían metástasis a distancia. 51 de 85 (60%) tuvieron recrecimiento local en algún momento. El recrecimiento local fue un factor independiente asociado a una peor supervivencia libre de metástasis a distancia en el modelo multivariable. Además, al usar estimaciones condicionales, los pacientes con recrecimiento local sin metástasis a distancia durante 5 años (desde la decisión de watch and wait) permanecieron en mayor riesgo de desarrollar metástasis a distancia durante un año subsiguiente en comparación con los pacientes sin recrecimiento local (sobrevida libre de metástasis a distancia a 5 años: recrecimiento local 94,9% frente a no recrecimiento local 98,4%).LIMITACIONES:La falta de información relacionada con el uso de quimioterapia adyuvante, las características específicas de la cirugía de rescate para el nuevo crecimient o local y la heterogeneidad de las estrategias individuales de vigilancia/seguimiento utilizadas pueden haber afectado los resultados observados.CONCLUSIONES:En pacientes con respuesta clínica completa manejados por Watch and Wait, el desarrollo de recrecimiento local en cualquier momento es un factor de riesgo para metástasis a distancia. El riesgo de metástasis a distancia sigue siendo mayor durante 5 años después del desarrollo de un nuevo crecimiento local. Consulte Video Resumen en http://links.lww.com/DCR/C53. (Traducción-Dr. Felipe Bellolio).

Zebrafish Avatars of rectal cancer patients validate the radiosensitive effect of metformin.

Neoadjuvant chemoradiation (nCRT) followed by surgery represents the standard of care in patients with locally advanced rectal cancer. Increasing radiotherapy (RT) doses and chemotherapy cycles with 5FU have been associated with increased rates of complete response, however these strategies imply significant toxicity. In the last years, epidemiologic findings have demonstrated that metformin is associated with significantly higher rates of pathological complete response to nCRT. Also, pre-clinical studies using cell lines provide evidence for the radiosensitive effect of metformin. However, no studies have been performed using rectal cancer patient samples to test this radiosensitive effect of metformin and compared it to the standard 5FU. Here, we designed an experimental study to compare both radiosensitizers in the zebrafish xenograft model (zAvatar), using rectal cancer surgical specimens and diagnostic biopsies. Patient zAvatars confirmed that metformin has indeed a powerful in vivo radiosensitizer effect, similar to 5FU. Our work confirms that metformin constitutes a promising less toxic alternative to the standard 5FU, which could be game changing in elderly/frail patients to optimize tumor regression.

When the Locus Coeruleus Speaks Up in Sleep: Recent Insights, Emerging Perspectives.

For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain's principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC's roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders.

Potential benefits of structured lipids in bulk compound chocolate: Insights on bioavailability and effect on serum lipids.

The bioavailability impact of serum lipids in compound chocolate products based on structured lipids was studied. Compound chocolate products containing fat with and without structured lipids were digested in vitro under simulated gastrointestinal lipolysis conditions and were studied in vivo in healthy C57BL/6J mice. The in vitro digestion results show that products containing structured lipids, milk compound chocolate filling and white compound coating, significantly reduced the release rate of Free Fatty Acids (FFA) and improved the caloric reduction between 12.49% and 13.71% compared to products without structured lipids, suggesting that FFA were not absorbed. Animal feeding studies revealed no adverse effects on the compound products intake; in fact, these products reduced total cholesterol, LDL-c, VLDL-c and triacylglycerols. The present work shows the relevance of developing functional compound chocolate as providing a potential healthy initiative through the biological effect of the bioactive ingredients incorporated.

Noradrenergic circuit control of non-REM sleep substates.

To understand what makes sleep vulnerable in disease, it is useful to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-rapid-eye-movement sleep (NREMS). However, sensory vigilance persists in NREMS in animals and humans, suggesting that wake promotion could remain functional. Here, we demonstrate that consolidated mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the ∼50-s timescale in the thalamus. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while noradrenaline (NA) levels declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart-rate variations, both of which are correlates of sensory arousability. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock, or entrain sleep-spindle clustering and heart-rate variations, suggesting that both fore- and hindbrain-projecting LC neurons show coordinated infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic, but not cortical, circuits was required for sleep-spindle clustering and involved NA release into primary sensory and reticular thalamic nuclei that activated both α1- and ß-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC constitutes a vigilance-promoting mechanism that renders mammalian NREMS vulnerable to disruption on the close-to-minute timescale through sustaining thalamocortical and autonomic sensory arousability. VIDEO ABSTRACT.

Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity.

The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very­low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR­B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid­lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.

Elective minimally invasive surgery for sigmoid diverticulitis: operative outcomes of patients with complicated versus uncomplicated disease.

AIM: The aim of this work was to compare the results of elective minimally invasive surgery between patients with complicated sigmoid diverticulitis and those with uncomplicated disease. METHOD: An institutional review board-approved database was searched for all consecutive patients who underwent elective minimally invasive surgery, including laparoscopic, hand-assisted and robotic sigmoidectomy, for diverticulitis between 2010 and 2017; they were classified according to the modified Hinchey classification as having complicated (abscess, fistula, stricture, obstruction, bleeding or previous perforation) versus uncomplicated disease. Data recorded included baseline demographics, indications for surgery, operative details and complications. RESULTS: Three hundred and twenty-five patients underwent elective sigmoidectomy for complicated (n = 105) and uncomplicated (n = 220) diverticulitis. Surgical indications for complicated disease were abscess (n = 74), stricture (n = 14), fistula (n = 28) and bleeding (n = 7). The two groups were statistically comparable for age, gender, body mass index and American Society of Anesthesiologists score. Patients with complicated disease had higher rates of concomitant loop ileostomy creation (9.5% vs. 0.9%, p < 0.001) and synchronous resections (9.5% vs. 2.7%, p = 0.01), higher volumes of blood loss (177 ± 140 vs. 125 ± 92 ml, p < 0.001), longer length of stay (5.6 ± 3 vs. 4.8 ± 2 days, p = 0.04) and longer operating time (218.2 ± 59 vs. 185.8 ± 63 min, p < 0.001). There were no significant differences in anastomotic leakage (3% vs. 1%, p = 0.3), conversion to laparotomy (4.8% vs. 2.3%, p = 0.3) or overall complications (36% vs. 25.9%, p = 0.06) for complicated versus uncomplicated disease, respectively. CONCLUSION: Minimally invasive surgery for complicated diverticulitis resulted in higher rates of construction of proximal ileostomy and synchronous resections and longer operating times and length of hospital stay. Otherwise, it has outcomes that are not significantly different from the results recorded in patients with uncomplicated disease.

Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study.

BACKGROUND: Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy. METHODS: We did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged ≥18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25, 1991, and Dec 31, 2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1, 3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years. FINDINGS: We identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55·2 months (IQR 36·0-75·6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8-90·9), for 3 years was 97·3% (95·2-98·6), and for 5 years was 98·6% (97·6-100·0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3-95·9), for 3 years was 97·8% (96·6-99·3), and for 5 years was 96·6% (94·0-98·9). INTERPRETATION: These results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. FUNDING: European Registration of Cancer Care, financed by the European Society of Surgical Oncology, the Champalimaud Foundation Lisbon, the Bas Mulder Award, granted by the Alpe d'HuZes Foundation and the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre.