Palatability attributed to alcohol and alcohol-paired flavors.

The orosensory features of alcoholic drinks are potent relapse triggers because they acquire incentive properties during consumption, including enhanced palatability. Whether mice similarly perceive alcoholic drinks to be more palatable after repeated consumption is complicated by reports showing that alcohol elicits aversive taste reactivity responses and conditions flavor avoidance. Here, by analyzing the microstructure of alcohol consumption, we report a gradual increase in lick bout duration relative to water that is partially maintained by an alcohol-paired flavor in extinction. We interpret lick bout duration to reflect an increase in the palatability alcohol and an alcohol-paired flavor. This finding demonstrates that bout duration is amenable to Pavlovian conditioning and highlights the importance of considering the microstructure of alcohol consumption in preclinical models of alcohol misuse.

Development of a consensus-based delineation guideline for locally recurrent rectal cancer.

BACKGROUND AND PURPOSE: Neoadjuvant chemoradiotherapy (nCRT) is used in locally recurrent rectal cancer (LRRC) to increase chances of a radical surgical resection. Delineation in LRRC is hampered by complex disease presentation and limited clinical exposure. Within the PelvEx II trial, evaluating the benefit of chemotherapy preceding nCRT for LRRC, a delineation guideline was developed by an expert LRRC team. MATERIALS AND METHODS: Eight radiation oncologists, from Dutch and Swedish expert centres, participated in two meetings, delineating GTV and CTV in six cases. Regions at-risk for re-recurrence or irradical resection were identified by eleven expert surgeons and one expert radiologist. Target volumes were evaluated multidisciplinary. Inter-observer variation was analysed. RESULTS: Inter-observer variation in delineation of LRRC appeared large. Multidisciplinary evaluation per case is beneficial in determining target volumes. The following consensus regarding target volumes was reached. GTV should encompass all tumour, including extension into OAR if applicable. If the tumour is in fibrosis, GTV should encompass the entire fibrotic area. Only if tumour can clearly be distinguished from fibrosis, GTV may be reduced, as long as the entire fibrotic area is covered by the CTV. CTV is GTV with a 1 cm margin and should encompass all at-risk regions for irradical resection or re-recurrence. CTV should not be adjusted towards other organs. Multifocal recurrences should be encompassed in one CTV. Elective nodal delineation is only advised in radiotherapy-naïve patients. CONCLUSION: This study provides a first consensus-based delineation guideline for LRRC. Analyses of re-recurrences is needed to understand disease behaviour and to optimize delineation guidelines accordingly.

Selected stage IV rectal cancer patients managed by the watch-and-wait approach after pelvic radiotherapy: a good alternative to total mesorectal excision surgery?

AIM: The aim of this study was to assess the clinical and oncological outcome of a selected group of stage IV rectal cancer patients managed by the watch-and-wait approach following a (near-)complete response of the primary rectal tumour after radiotherapy. METHOD: Patients registered in the Dutch watch-and-wait registry since 2004 were selected when diagnosed with synchronous stage IV rectal cancer. Data on patient characteristics, treatment details, follow-up and survival were collected. The 2-year local regrowth rate, organ-preservation rate, colostomy-free rate, metastatic progression-free rate and 2- and 5-year overall survival were analysed. RESULTS: After a median follow-up period of 35 months, local regrowth was observed in 17 patients (40.5%). Nine patients underwent subsequent total mesorectal excision, resulting in a permanent colostomy in four patients. The 2-year local regrowth rate was 39.9%, the 2-year organ-preservation rate was 77.1%, the 2-year colostomy-free rate was 88.1%, and the 2-year metastatic progression-free rate was 46.7%. The 2- and 5-year overall survival rates were 92.0% and 67.5%. CONCLUSION: The watch-and-wait approach can be considered as an alternative to total mesorectal excision in a selected group of stage IV rectal cancer patients with a (near-)complete response following pelvic radiotherapy. Despite a relatively high regrowth rate, total mesorectal excision and a permanent colostomy can be avoided in the majority of these patients.

Oncological Outcomes and Hospital Costs of the Treatment in Patients With Rectal Cancer: Watch-and-Wait Policy and Standard Surgical Treatment.

BACKGROUND: Little is known about the costs of the current treatment strategy in locally advanced rectal cancer, in which patients with a clinical complete response after chemoradiotherapy are treated in a watch-and-wait policy. OBJECTIVE: The aim of this study is to present the oncological outcome and hospital costs of patients with a complete response after chemoradiotherapy (watch-and-wait policy) and patients with an incomplete response after chemoradiotherapy (total mesorectal excision). DESIGN: This was a cohort study. SETTINGS: This study was conducted at an academic and a nonacademic hospital. PATIENTS: Patients with locally advanced rectal cancer received either a watch-and-wait policy or total mesorectal excision depending on their clinical response to chemoradiotherapy. INTERVENTIONS: Watch-and-wait policy and total mesorectal excision were the treatments applied. MAIN OUTCOME MEASURES: The primary outcomes measured were overall, local recurrence-free, and distant metastasis-free survival and hospital costs over a 2-year follow-up period. RESULTS: A total of 292 patients with locally advanced rectal cancer were included. Mean age was 65.1 years, and 64.7% were men. One hundred five patients were included in the watch-and-wait subgroup, and 187 patients were in the total mesorectal excision subgroup. Both subgroups showed good oncological outcomes. Hospital costs consisted of 5 categories: costs of primary surgery, costs of adjuvant chemotherapy, costs of examinations, costs of additional surgery, and costs of treatment of regrowth/metastasis. The mean costs per patient were &OV0556;6713 (watch-and-wait subgroup) and &OV0556;17,108 (total mesorectal excision subgroup) over the first 2 years. LIMITATIONS: This study was limited by the following: costs were only from a hospital perspective, follow-up was 2 years, the study was retrospective in part, and there was no comparative study. CONCLUSIONS: Overall survival was good in both subgroups and comparable to literature. The mean costs per patient differ between the watch-and-wait subgroup (&OV0556;6713) and the total mesorectal excision subgroup (&OV0556;17,108). No comparison between the groups could be made. Based on the results of this study, the current strategy, where patients with a clinical complete response are treated in a watch-and-wait policy, and patients with an incomplete response are treated with total mesorectal excision, is likely to be (cost)saving. See Video Abstract at http://links.lww.com/DCR/B177. RESULTADOS ONCOLÓGICOS Y COSTOS HOSPITALARIOS EN EL TRATAMIENTO DE PACIENTES CON CANCER DE RECTO: ACTITUD DE ESPERA-VIGILANCIA Y TRATAMIENTO QUIRÚRGICO ESTANDARD: Se sabe poco sobre el costo del tratamiento actual en casos de cancer de recto localmente avanzado, cuando se aplica una política de vigilancia y espera en aquellos pacientes que presentan una respuesta clínica completa después de radio-quimioterapia.El propósito final del presente estudio es dar a conocer el resultado oncológico y los costos hospitalarios de los pacientes que presentan una respuesta clínica completa después de radio-quimioterapia (actitud de vigilancia-espera) y los pacientes con una respuesta incompleta después luego de radio-quimioterapia (excisión total del mesorrecto-ETM).Estudio de cohortes.Hospitales académicos y no académicos.Todos aquellos pacientes tratados por un cáncer de recto localmente avanzado y que fueron seguidos con una política de vigilancia y espera o la ETM, en función de la respuesta clínica a la radio-quimioterapia.Políticas de vigilancia-espera, excisión total del mesorrecto.Sobrevida global libre de recurrencia local, metástasis a distancia, sobrevida libre de enfermedad y costos hospitalarios durante un período de seguimiento de dos años.Se incluyeron 292 pacientes diagnosticados de cancer de recto localmente avanzado. La edad media fue de 65,1 años, 64,7% eran de sexo masculino. Se incluyeron 105 pacientes en el subgrupo de vigilancia-espera, y 187 en el subgrupo de excisión total del mesorrecto. Ambos subgrupos mostraron optimos resultados oncológicos. Los costos hospitalarios se dividieron en cinco categorías: costos de cirugía primaria; costos de quimioterapia adyuvante; costos de exámenes; costos de cirugía adicional; y costos del tratamiento de rebrote / metástasis. Los costos medios por paciente fueron de &OV0556; 6.713 (subgrupo de espera-vigilancia) y &OV0556; 17.108 (subgrupo de excisión total del mesorrecto) durante los primeros dos años.Analisis de costos desde una perspectiva hospitalaria durante un seguimiento de dos años, estudio parcialmente retrospectivo, no comparativo.La sobrevida general fue optima en ambos subgrupos y comparable con la literatura. El costo promedio por paciente difiere entre el subgrupo de vigilancia y espera (&OV0556; 6.713) con el subgrupo de la ETM(&OV0556; 17.108). No se pudieron comparar definitivamente ambos grupos. Basados en los resultados del presente estudio, es probable que la estrategia actual, en la que los pacientes con respuesta clínica completa sean tratados con una política de vigilancia y espera, presenten muy probablemente un cierto ahorro en el costo con relación a los pacientes con una respuesta incompleta tratados con excisión total del mesorrecto. Consulte Video Resumen en http://links.lww.com/DCR/B177. (Traducción-Dr. Xavier Delgadillo).

The association of parental methylenetetrahydrofolate reductase polymorphisms (MTHFR 677C > T and 1298A > C) and fetal loss: a case-control study in South Australia.

Objective: To determine the association between parental MTHFR 677C > T (RS1801133) and 1298A > C (RS1801131), and fetal loss (FL).Design: Case-control study.Setting: Department of Obstetrics and Gynecology, Lyell McEwin Hospital (LMH), and the Women's and Children's Hospital (WCH) in Adelaide, Australia.Patients: A total of 222 couples with FL and 988 couples with uncomplicated pregnancies.Measurements: The main outcomes were FL and hyperhomocysteinemia (HHcy). All couples were tested for MTHFR 677C > T and 1298A > C. Fasting homocysteine was measured in the women with FL.Results: The main finding was a significant difference between the FL group and controls in couples with ≥4 abnormal alleles compared to <4 [p=.0232, OR 1.9 (95% CI 1.1-3.3)]. None of the couples with FL had zero abnormal alleles (both parents 677CC/1298 AA). However, this was also rare amongst the controls. Maternal carriage of both 677C > T and the 1298A > C polymorphisms was similar between the FL group and controls. The prevalence of paternal 677TT/1298AA and 677CC/1298AC was significantly higher in the FL group compared with controls. HHcy was significantly more common in the FL group compared with controls.Conclusion: The presence of parental MTHFR 677C > T and 1298A > C is associated with FL. The association between maternal MTHFR genotypes with FL is less pronounced than in previously published articles investigating first trimester miscarriages. Maternal HHcy is a significant risk factor for FL.

Long-term imaging characteristics of clinical complete responders during watch-and-wait for rectal cancer-an evaluation of over 1500 MRIs.

OBJECTIVES: Rectal cancer patients with a clinical complete response after chemoradiotherapy (CRT) may be followed with a 'watch-and-wait' (W&W) approach as an alternative to surgery. MRI plays an important role in the follow-up of these patients, but basic knowledge on what to expect from the morphology of the irradiated tumour bed during follow-up is lacking, which can hamper image interpretation. The objective was to establish the spectrum of non-suspicious findings during long-term (> 2 years) follow-up in patients with a sustained clinical complete response undergoing W&W. METHODS: A total of 1509 T2W MRIs of 164 sustained complete responders undergoing W&W were retrospectively evaluated. Morphology of the tumour bed was evaluated (2 independent readers) on the restaging MRI and on the various follow-up MRIs and classified as (a) no fibrosis, (b) minimal fibrosis, (c) full thickness fibrosis, or (d) irregular fibrosis. Any changes occurring during follow-up were documented. RESULTS: A total of 104 patients (63%) showed minimal fibrosis, 38 (23%) full thickness fibrosis, 8 (5%) irregular fibrosis, and 14 (9%) no fibrosis. In 93% of patients, the morphology remained completely stable during follow-up; in 7%, a minor increase/decrease in fibrosis was observed. Interobserver agreement was excellent (κ 0.90). CONCLUSIONS: Typically, the morphology as established at restaging remains completely unchanged. The majority of patients show fibrosis with the predominant pattern being a minimal fibrosis confined to the rectal wall. Complete absence of fibrosis occurs in only 1/10 cases. Once validated in independent cohorts, these findings may serve as a reference for radiologists involved in the clinical follow-up of W&W patients. KEY POINTS: • In rectal cancer patients with a sustained complete response after chemoradiation, the rectal wall morphology as established on restaging MRI typically remains unchanged during long-term MRI follow-up. • The vast majority of complete responders show fibrosis with the predominant pattern being a minimal fibrotic remnant that remains confined to the rectal wall; complete absence of fibrosis occurs in only 10% of the cases. • Once validated in independent cohorts, the findings of this study may serve as a reference for radiologists involved in the clinical follow-up of rectal cancer patients undergoing watch-and-wait.

Impact of radiotherapy on anorectal function in patients with rectal cancer following a watch and wait programme.

BACKGROUND AND PURPOSE: To assess the long-term anorectal function in rectal cancer patients following a watch-and-wait policy after chemoradiotherapy and to investigate the dose-volume effects of radiotherapy on the anorectal function. METHODS AND MATERIALS: Thirty-three patients with primary rectal cancer who were treated with chemoradiotherapy and a watch-and-wait policy with minimum follow-up of 2  years were included. We assessed the anorectal function using anorectal manometry and patient reported outcomes (Vaizey and LARS score). Dose-volume histograms were calculated for the rectum and anal sphincter complex, and associations between the dose-volume parameters and anorectal function were assessed. RESULTS: Dmean to the rectum and anal sphincter complex was 50.5 Gy and 44.7 Gy, respectively. After a median follow-up of 38 (range 23-116) months, 33.3% of the patients reported major LARS. Mean LARS score was 23.4 ±â€¯11.3 and mean Vaizey score was 4.3 ±â€¯4.1. The most frequent complaints were clustering of defaecation and faecal urgency. Trends towards a higher Vaizey and LARS score after higher anal sphincter complex dose were observed, although these associations were not statistically significant. CONCLUSIONS: This is the first study to investigate the late dose-volume effects of radiotherapy specifically on the anorectal function in rectal cancer patients. One-third of the patients had major LARS and the most frequent reported complaints were clustering and faecal urgency. Additionally, we observed trends towards worse long-term anorectal function after higher anal sphincter complex radiotherapy dose. However, this should be evaluated on a larger scale. Future efforts to minimise the dose to the sphincters could possibly reduce the impact of radiotherapy on the anorectal function.

Organ Preservation in Rectal Cancer After Chemoradiation: Should We Extend the Observation Period in Patients with a Clinical Near-Complete Response?

BACKGROUND: To assess whether extending the observation period in patients with a near clinical complete response (near cCR) after chemoradiation (CRT) leads to an impaired oncological outcome. METHODS: Patients who had a clinical complete response (cCR) 8-10 weeks after CRT restaging with magnetic resonance imaging and endoscopy were offered a watch-and-wait strategy (W&W1), while patients with a near cCR were offered to undergo local excision or a second restaging 6-12 weeks later. Patients who achieved a cCR at the second restaging were also offered a watch-and-wait strategy (W&W2). RESULTS: Overall, 102 patients with a cCR at the first restaging immediately entered the W&W1, while the remaining 68 patients had a near cCR: 19 patients underwent transanal endoscopic microsurgery and 49 patients opted for a second restaging. Additionally, 44/49 (90%) patients showed a cCR at the second restaging and entered the W&W2. Patients in the W&W1 group had a 2-year local regrowth-free rate (LRFR) of 84% and 2-year overall survival (OS) of 99%, while patients in the W&W2 group had a 2-year LRFR of 73% and OS of 98% (p > 0.05). Multivariable Cox regression analyses showed that late inclusion was not a significant predictive factor for higher risk of LR or lower non-regrowth disease-free survival. CONCLUSIONS: Overall, 90% of patients with a near cCR 8-10 weeks after CRT will proceed to a cCR 6-12 weeks later; therefore, it seems logical to extend the observation period rather than to proceed to surgery. Although there is a non-significant increase in local regrowth rate in these patients, it does not seem to impact the oncological outcome.

Quality of Life in Rectal Cancer Patients After Chemoradiation: Watch-and-Wait Policy Versus Standard Resection - A Matched-Controlled Study.

BACKGROUND: Fifteen to twenty percent of patients with locally advanced rectal cancer have a clinical complete response after chemoradiation therapy. These patients can be offered nonoperative organ-preserving treatment, the so-called watch-and-wait policy. The main goal of this watch-and-wait policy is an anticipated improved quality of life and functional outcome in comparison with a total mesorectal excision, while maintaining a good oncological outcome. OBJECTIVE: The aim of this study was to compare the quality of life of watch-and-wait patients with a matched-controlled group of patients who underwent chemoradiation and surgery (total mesorectal excision group). DESIGN: This was a matched controlled study. SETTINGS: This study was conducted at multiple centers. PATIENTS: The study population consisted of 2 groups: 41 patients after a watch-and-wait policy and 41 matched patients after chemoradiation and surgery. Patients were matched on sex, age, tumor stage, and tumor height. All patients were disease free at the moment of recruitment after a minimal follow-up of 2 years. MAIN OUTCOME MEASURES: Quality of life was measured by validated questionnaires covering general quality of life (Short Form 36, European Organization for Research and Treatment of Cancer QLQ-C30), disease-specific total mesorectal excision (European Organization for Research and Treatment of Cancer QLQ-CR38), defecation problems (Vaizey and low anterior resection syndrome scores), sexual problems (International Index of Erectile Function and Female Sexual Function Index), and urinary dysfunction (International Prostate Symptom Score). RESULTS: The watch-and-wait group showed better physical and cognitive function, better physical and emotional roles, and better global health status compared with the total mesorectal excision group. The watch-and-wait patients showed fewer problems with defecation and sexual and urinary tract function. LIMITATIONS: This study only focused on watch-and-wait patients who achieved a sustained complete response for 2 years. In addition, this is a study with a limited number of patients and with quality-of-life measurements on nonpredefined and variable intervals after surgery. CONCLUSIONS: After a successful watch-and-wait approach, the quality of life was better than after chemoradiation and surgery on several domains. However, chemoradiation therapy on its own is not without long-term side effects, because one-third of the watch-and-wait patients experienced major low anterior resection syndrome symptoms, compared with 66.7% of the patients in the total mesorectal excision group. See Video Abstract at http://links.lww.com/DCR/A395.

MRI surveillance for the detection of local recurrence in rectal cancer after transanal endoscopic microsurgery.

OBJECTIVES: To evaluate diagnostic performance of follow-up MRI for detection of local recurrence of rectal cancer after transanal endoscopic microsurgery (TEM). METHODS: Between January 2006 and February 2014, 81 patients who underwent TEM were included. Two expert readers (R1 and R2), independently evaluated T2-weighted (T2W) MRI and diffusion-weighted (DWI) MRI for the detection of local recurrence, retrospectively, and recorded confidence on a five-point scale. Diagnostic performance of follow-up MRI was assessed using ROC-curve analysis and kappa statistics for the reproducibility between readers. RESULTS: 293 MRIs were performed, 203 included DWI. 18 (22%) patients developed a local recurrence: luminal 11, nodal two and both five. Areas under the curve (AUCs) for local recurrence detection were 0.72 (R1) and 0.80 (R2) for T2W-MRI. For DWI, AUCs were 0.70 (R1) and 0.89 (R2). For nodal recurrence AUCs were 0.72 (R1) and 0.80 (R2) for T2W-MRI. Reproducibility was good for T2W-MRI (κ0.68 for luminal and κ0.71 for nodal recurrence) and moderate for DWI (κ0.57). AUCs and reproducibility for recurrence detection increased during follow-up. CONCLUSIONS: Follow-up with MRI after TEM for rectal cancer is feasible. Postoperative changes can be confusing at the first postoperative MRI, but during follow-up diagnostic performance and reproducibility increase. KEY POINTS: • Follow-up with MRI is feasible for follow-up after TEM for rectal cancer. • DWI-MRI is a useful addition to detect recurrences after TEM. • Postoperative changes can be confusing and can lead to underestimation of recurrence. • Appearance of intermediate signal at T2W-MRI is suspicious for recurrence. • Nodal staging remains challenging.