Gianpietro Zanchettin

Interval Between Neoadjuvant Chemoradiotherapy and Surgery for Squamous Cell Carcinoma of the Thoracic Esophagus Does Delayed Surgery Have an Impact on Outcome

Objective:Aim of this study was to evaluate whether delayed surgery after neoadjuvant chemoradiotherapy (CRT) affects postoperative outcomes in patients with locally advanced squamous cell carcinoma (SCC) of the thoracic esophagus. Background:Esophagectomy is usually recommended within 4 to 6 weeks after completion of neoadjuvant CRT. However, the optimal timing of surgery is not clearly defined. Methods:A total of 129 consecutive patients with locally advanced esophageal cancer, treated between 1998 and 2007, were retrospectively analyzed using prospectively collected data. Patients were divided into 3 groups on the basis of timing to surgery: group 1, ⩽30 days (n = 17); group 2, 31 to 60 days (n = 83); and group 3, 61 to 90 days (n = 29). Subsequently, only 2—numerically more consistent—groups were studied, using the median value of timing intervals as a cutoff level: group A, ⩽46 days (n = 66); and group B, >46 days (n = 63). Results:Groups were comparable in terms of patient and tumor characteristics, type of neoadjuvant regimen, toxicity, postoperative morbidity and mortality rates, tumor downstaging, and pathologic complete responses. The overall 5-year actuarial survival rate was 0% in group 1, 43.1% in group 2, and 35.9% in group 3 (P = 0.13). After R0 resection (n = 106), the 5-year actuarial survival rate was 0%, 51%, and 47.3%, respectively (P = 0.18). Tumor recurrence after R0 resection seemed to be inversely related, even if not significantly (P = 0.17), to the time interval between chemoradiation and surgery: 50% in group 1, 40.6% in group 2, and 21.7% in group 3. When considering only 2 groups, the overall 5-year survival was 33.1% in group A and 42.7% in group B (P = 0.64); after R0 resection, the 5-year survival was 37.8% and 56.3%, respectively (P = 0.18). The rate of tumor recurrence was significantly lower in group B (25%) than in group A (48.3%) (P = 0.02). Conclusion:Delayed surgery after neoadjuvant chemoradiation does not compromise the outcomes of patients with locally advanced SCC of the esophagus. Delaying surgery up to 90 days offers relevant advantages in the clinical management of the patients, can reduce tumor recurrences, and may improve prognosis after complete R0 resection surgery.

Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia.Cachexia is a metabolic syndrome leading to muscle and adipose tissue loss in majority of cancer patients. Here the authors show that, in a mouse model, BET inhibitor JQ1 counteracts muscle and adipose tissue wasting tempering cachexia and prolonging survival through a mechanism unrelated to tumour growth.

Endoscopic Tumor Length Should Be Reincluded in the Esophageal Cancer Staging System: Analyses of 662 Consecutive Patients

Esophageal cancer represents the 6th cause of cancer mortality in the World. New treatments led to outcome improvements, but patient selection and prognostic stratification is a critical aspect to gain maximum benefit from therapies. Today, patients are stratified into 9 prognostic groups, according to a staging system developed by the American Joint Committee on Cancer. Recently, trying to better select patients with curing possibilities several authors are reconsidering tumor length as a valuable prognostic parameter. Specifically, endoscopic tumor length can be easily measured with an esophageal endoscopy and, if its utility in esophageal cancer staging is demonstrated, it may represent a simple method to identify high risk patients and an easy-to-obtain variable in prognostic stratification. In this study we retrospectively analyzed 662 patients treated for esophageal cancer, stratified according to cancer histology and current staging system, to assess the possible role of endoscopic tumor length. We found a significant correlation between endoscopic tumor length, current staging parameters and 5-year survival, proving that endoscopic tumor length may be used as a simple risk stratification tool. Our results suggest a possible indication for preoperative therapy in early stage squamocellular carcinoma patients without lymph nodes involvement, who are currently treated with surgery alone.

Cervical Esophageal Cancer Treatment Strategies: A Cohort Study Appraising the Debated Role of Surgery

BackgroundFew studies have examined optimal treatment specifically for cervical esophageal carcinoma. This study evaluated the outcome of three common treatment strategies with a focus on the debated role of surgery.MethodsAll patients with cervical esophageal cancer treated at a single center were identified and their outcomes analyzed in terms of morbidity, mortality, and recurrence according to the treatment they received, i.e. surgery alone, definitive platinum-based chemoradiation (CRT), or CRT followed by surgery.ResultsThe study population included 148 patients with cervical esophageal cancer from a prospective database of 3445 patients. Primary surgery was the treatment of choice for 56 (37.83%) patients, definitive CRT was the treatment of choice for 52 (35.13%) patients, and CRT followed by surgery was the treatment of choice for 40 (27.02%) patients. CRT-treated patients obtained 36.96% complete clinical response, with overall morbidity and mortality rates of 36.95 and 2.17%, respectively. Surgical complete resection was achieved in 71.88% of surgically treated cases, with morbidity and mortality rates of 52.17 and 6.25%, respectively. No significant survival difference existed among the three treatments, but patients who underwent surgery alone had a significantly lower stage of disease (p = 0.031). Compared with patients with complete response after CRT, surgery did not confer any significant survival benefit, and overall 5-year survival was lower than definitive CRT alone. In contrast, surgery improved survival significantly in patients with non-complete response after definitive CRT (p = 0.023).ConclusionsDefinitive platinum-based CRT should be the treatment of choice for cervical esophageal cancer. Surgery has a role for patients with non-complete response as it adds significant survival benefit, with acceptable morbidity and mortality.

Cancer de l’œsophage cervical et hypopharynx : fist-line radiochimiothérapie devrait être le traitement de choix

Introduction Pour les tumeurs de l’hypopharynx et de l’œsophage cervical, une premiere ligne radiochimio est de plus en plus utilisee, la chirurgie etant reservee aux tumeursrecurrentes ou qui ne repondent pas. Methodes Nous rapportons une etude retrospective sur 190 patients avec un carcinome epidermoide de l’hypopharynx et de l’œsophage cervical, traites dans notre Service de 1992 a 2012. Le stade clinique etait T3–4 dans 164 (86,3 %) patients, et N + dans 129 (67,9 %). 26 patients (14 %) ont eu une chirurgie premiere, et 164 (86 %) ont ete traites avec une radiochimio premiere. Resultats Pour la chirurgie premiere la mortalite postoperatoire etait de 15,4 % (4 sur 26) et la survie a 3 et 5 de 23 % et 19 %. Dans le groupe radiochimio premiere (164 patients) la reponse clinique etait : complete (CR) chez 58 patients (41 %), et partielle (PR) chez 40 patients (28 %). La mortalite postop. apres traitement radiochimio etait de 4 %. Le taux de survie a 3 ans et 5 ans des patients avec un CR clinique etait de 57 % et 41 %, et pour les patients avec une PR clinique, il a ete de 39 % et 33 %. Discussion Les patients ayant subi une chirurgie primaire avaient un plus mauvais pronostic que les patients qui ont eu une premiere ligne radiochimio malgre le fait qu’ils avaient des tumeurs de stade precoce. Conclusion La radiochimio premiere devrait etre le traitement de choix pour le cancer de l’hypopharynx et de l’œsophage cervical, et la chirurgie premiere seulement pour les tumeurs que ne repondent pas.

Su1793 Subclinical Myopathy and Colorectal Cancer: Identification and Role of New Muscle Damage and Regeneration Biomarkers

Background Skeletal muscle is the major reservoir of body proteins and it can be affected in conditions associated to altered protein turnover and metabolism such as cancer. Although severe wasting is seen primarily in patients with advanced malignancy, some of them present degree of wasting at the onset of disease. Autophagy has been recently described to play a relevant role in muscle wasting. Materials and Methods We performed morphometric studies and immunohistochemical analyses on intraoperative rectus abdominis muscle biopsies from 50 consecutive weight stable colorectal patients and 25 weight-stable patients operated for non-inflammatory benign diseases with no clinical signs of myopathies. Biochemical and molecular analyses have been performed in order to evaluate protein profile, the presence of autophagy induction and their correlation with clinical outcome. Results In cancer patients, we observed a subclinical myopathy characterized by an abnormal distribution of myonuclei relocated from the periphery inside the myofiber. The percentage of myofibers with abnormally located myonuclei was significantly higher in patients compared to controls. Analyses on serum samples showed that, in the absence of systemic inflammation, in the prevalence of cancer patients the levels of albumin and prealbumin were below the normal range and the mean value was significantly lower compared to that detected in controls. Molecular analyses showed an accumulation of p62, a typical marker of autophagy induction, significantly higher in cancer patients compared to controls. We found an inverse correlation between the number of abnormally nucleated myofibers and the presence of lymph node metastasis. Cancer relapse was correlated with low serum levels of prealbumin and high levels of p62 in myofibers of cancer patients. Conclusions Colorectal cancer patients have a subclinical myopathy characterized by myofibers with internally located myonuclei. In the absence of inflammation, cancer patients show low levels of prealbumin and albumin as markers of altered protein turnover and persistent high levels of p62 in myofibers as expression of autophagy induction with an impairment in physiological autophagic flux. Up to now our data indicate that skeletal muscle fibers show nuclear abnormalities that seems to be associated to a better prognosis, while the presence of an altered protein turnover at an early stage of disease, with an impairment in the physiological autophagic flux, that could be predictive of cancer relapse and onset of cancer cachexia.