Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression.

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1-targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

The use of Versius CMR for pelvic surgery: a multicentric analysis of surgical setup and early outcomes.

INTRODUCTION: Versius CMR is a novel robotic system characterized by an open surgical console and independent bedside units. The system has potentials of flexibility and versatility, and has been used in urological, gynecological, and general surgical procedure. The aim is to depict a comprehensive analysis of the Versius system for pelvic surgery. METHODS: This is a study involving two Institutions, ASST Santi Paolo and Carlo, Milan, and Apuane Hospital, Massa, Italy. All interventions performed in the pelvic area with the Versius were included. Data about indications, intra-, and post-operative course were prospectively collected and analyzed. RESULTS: A total of 171 interventions were performed with the Versius. Forty-two of them involved pelvic procedures. Twenty-two had an oncological indication (localized prostate cancer), the remaining had a non-oncological or functional purpose. The mostly performed pelvic procedure was radical prostatectomy (22) followed by annexectomy (9). No intra-operative complication nor conversion to other approaches occurred. A Clavien II complication and one Clavien IIIb were reported. Malfunctioning/alarms requiring a power cycle of the system occurred in 2 different cases. An adjustment in trocar placement according to patients' height was required in 2 patients undergoing prostatectomy, in which the trocar was moved caudally. In two cases, a pelvic prolapse was repaired concomitant with other gynecological procedures. CONCLUSIONS: Pelvic surgery with the Versius is feasible without major complications; either dissection and reconstructive steps could be accomplished, provided a proper OR setup and trocar placement are pursued. Versius can be easily adopted by surgeons of different disciplines and backgrounds; a further multi-specialty implementation is presumed and long-term oncological and functional outcomes are awaited.

Performance of CT Colonography in Diagnosis of Synchronous Colonic Lesions in Patients With Occlusive Colorectal Cancer.

OBJECTIVE. The purpose of this study was to evaluate the accuracy of CT colonography (CTC) in the diagnosis of synchronous colonic lesions in a cohort of patients with an occlusive colorectal cancer (CRC) causing incomplete colonoscopy. SUBJECTS AND METHODS. Among 109 patients with CRC causing incomplete colonoscopy who underwent CTC with IV contrast enhancement after cathartic purgation, fecal tagging, and colon distention, 70 (mean age, 70 years) for whom reference standards (surgical reports, first surveillance colonoscopy) were available were evaluated. Per-patient and per-lesion sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of CTC in the diagnosis of synchronous colonic lesions measuring 6 mm or larger were assessed. RESULTS. Twenty-seven of the 70 patients (39%) had at least one 6-mm or larger synchronous lesion, and four patients (6%) had a total of five synchronous CRCs. Per-patient sensitivity in diagnosing synchronous CRC was 1.00 (4/4). There were 59 lesions: 20 with a diameter of 10 mm or greater; 30, 6-9 mm; and nine, 5 mm or less. The overall per-patient CTC sensitivity in detecting synchronous lesions 6 mm or larger was 0.93 (25/27); specificity, 0.98 (42/43); PPV, 0.96; and NPV, 0.95. Per-patient sensitivity for the diagnosis of synchronous advanced neoplasia (advanced adenoma and colorectal cancers) was 0.94 (15/16). Per-lesion CTC sensitivity for detecting synchronous lesions 6 mm or larger was 0.88 (37/42); all adenomatous lesions, 0.89 (55/62); and advanced neoplasia, 0.92 (22/24). CONCLUSION. CTC is a highly accurate test for detecting synchronous colonic lesions in patients with occlusive CRC. The prevalence of advanced neoplasia is high (23%).

Long-term outcome of laparoscopic ablation therapies for unresectable hepatocellular carcinoma: a single European center experience of 426 patients.

BACKGROUND: Radiofrequency ablation (RFA) is widely used as a first-line option in patients with hepatocellular carcinoma (HCC). However, since percutaneous approach of RFA may be, in some cases, unfeasible by the tumor size and its location, laparoscopic ablation therapies (LATs) were used as an alternative. Objective of the present study was to assess the efficacy of laparoscopic ultrasound examination in addition to LATs in the treatment of HCC in patients not eligible for percutaneous RFA or surgical resection. METHODS: Four hundred and twenty-six patients who underwent LATs were analyzed. Laparoscopic approach was offered to patients fulfilling at least one of the following criteria: (a) patients with a single nodule or up to three nodules smaller than 3 cm not suitable for liver transplantation or not eligible for HR because of severe portal hypertension, impaired liver function, or coexistent comorbidities; (b) patients not suitable for percutaneous RFA because of inconvenient tumor location; and (c) short-term recurrence of HCC (<3 months). RESULTS: Technical success was achieved in one session in 396 patients (93 %). One-month mortality and morbidity rates were 0.23 % (1 patient) and 25 % (106 patients), respectively. During a median follow-up of 37.2 months (range 2-193) in the remaining 425 patients, 276 (65 %) developed intra-hepatic recurrence: It appeared as a local tumor progression in 65 cases (15 %). Patients median survival was 39 months (95 % CI 34.8-47.2), while overall survivals at 1, 3, and 5 years were 88, 55, and 34 %, respectively. CONCLUSIONS: In the treatment of HCC, LATs proved to be a safe and effective technique, as they permit to treat with low-morbidity-rate lesions not manageable by percutaneous approach. Moreover, they allow achieving a more accurate staging of the disease in one-fifth of patients, thus better redefining the prognosis of such individuals.

Impact of contrast-enhanced computed tomography colonography on laparoscopic surgical planning of colorectal cancer.

AIM: To evaluate the impact of contrast-enhanced computed tomography colonography (CE-CTC) on laparoscopic surgery planning in patient with stenosing colorectal cancer. MATERIALS AND METHODS: Sixty-nine patients with endoscopically proven colorectal cancer underwent CE-CTC, after incomplete conventional colonoscopy. Two experienced radiologists evaluated site, length, and TNM staging of colorectal cancers on three-dimensional double contrast enema-like views, 2D axial and multiplanar reconstructions. All the patients underwent colorectal resection and surgery bulletin, pathology of surgical specimens, and radiological follow-up at about 8 months were used as reference standard. RESULTS: The detection rate of colorectal cancer was 100 % (75/75); CE-CTC allowed for a diagnosis of a synchronous colorectal cancer in five patients (7 %). CE-CTC correctly judged the site of the lesions in all the cases; clinically significant localization errors at conventional colonoscopy were noted in 3 out of 69 patients (4 %). Additional colonic polyps greater than 6 mm in diameter were found in 21 out of 69 patients (30 %); in two patients (3 %) the surgeon performed an enlarged colectomy to include synchronous polyps proximal to colorectal cancer. Sensitivity, specificity, PPV, NPV, and accuracy were for T1-T2 vs. T3-T4: 96 %, 71 %, 92 %, 87 %, and 91 %, respectively; for N: 94 %, 42 %, 64 %, 86 %, and 70 %; for M: 100 %, 100 %, 83 %, 100 %, and 97 %. There were no complications associated with CE-CTC. CONCLUSION: Information given by CE-CTC concerning colorectal cancer location and synchronous colonic cancers and polyps changed the laparoscopic surgical strategy in almost 14 % of patients.

[Colonic metastasis from primary carcinoma of the lung. Case report]. / Metastasi del colon da tumore primitivo del polmone. Caso clinico.

Lung cancer is the most common cause of cancer-related death in both men and women in Western countries. About one-half of patients with lung cancer have metastatic disease at the time of initial diagnosis. Metastasis to the gastrointestinal tract from primary lung cancer has rarely been described. The most common metastatic site is the small bowel whereas large bowel secondary lesions are very rare. The majority of patients are referred to a surgeon only after the intestinal secondary lesion becomes symptomatic posing a threat to the patient's life. Although the outcome is still unfavourable, the development of chemotherapy and of surgical techniques allows aggressive treatment when facing a single intestinal metastasis from lung cancer. We report on a case of a patient who came to our observation for a neoplastic stenosis of the descending colon with a single liver secondarism. Histology proved both lesions to be metastases of primitive adenocarcinoma of the lung.

Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ.

Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues.

Liver transplantation for spontaneous intrapartum rupture of a hepatic adenoma.

BACKGROUND: Hepatocellular adenomas can rupture during pregnancy with high fetal and maternal associated mortality. CASE: A primipara underwent an emergency cesarean delivery at 37 weeks of gestation for abruptio placentae. A few hours later she developed hemorrhagic shock, and laparotomy revealed the rupture of the right lobe of the liver. Bleeding was controlled with perihepatic gauze packing and she was transferred to a transplant center for emergency orthotopic liver transplantation. Histologic examination revealed the presence of an intrahepatic hematoma caused by the rupture of a 12-cm hepatocellular adenoma. At 48 months after transplantation she and her infant were both in good condition. CONCLUSION: Emergency orthotopic liver transplantations performed for acute rupture of an hepatocellular adenoma represents a valid therapy provided that bleeding can be controlled long enough to locate a suitable donor.

Risk Factors for Prolonged Postoperative Ileus in Adult Patients Undergoing Elective Colorectal Surgery: An Observational Cohort Study.

PURPOSE: Prolonged Postoperative Ileus (PPOI) after abdominal surgery may affect unfavourably the patient recovery. The aim of this study was to estimate the incidence of PPOI in patients elective for colorectal resection and investigate perioperative variables associated with PPOI. METHODS: A consecutive series of 428 patients undergoing colorectal resection (median age 72, range 24-92, years; men/women ratio 1.14) were analyzed. Data were extracted retrospectively throughout a five-year period from an electronic prospectively maintained database. PPOI was defined as the need for postoperative insertion of a nasogastric tube in a patient experiencing nausea and two episodes of vomiting and further showing absence of adequate bowel function (absence of flatus/stool) with lack of bowel sounds and abdominal distension. RESULTS: Incidence of PPOI was 7% [95% confidence interval (95%CI), 4.8-9.9%]. Mean hospital stay was 8 days longer in patients with PPOI. Male gender, cancer, cardiac and respiratory co-morbidity, rectal resection, open/converted access, duration of operation, stoma formation and body mass index were associated with PPOI at univariate analysis (0.001< P< 0.048). PPOI was independently associated with male gender [adjusted odds ratio (OR), 4.2; 95%CI, 1.5-11.5], stoma formation (OR, 2.8; 95%CI, 1.2-6.8) and obesity (OR of obese vs. normal weight patients, 3.8, 95%CI, 1.2-12.0). CONCLUSION: After colorectal resection, PPOI leads to a prolonged hospital stay and slower patient's recovery. An international standardized definition of PPOI is strongly needed to make comparable results from researches and to reliably identify patients with increased risk, also to improve the therapeutic preventive policies in these patients.

Enhanced recovery pathway in elderly patients undergoing colorectal surgery: is there an effect of increasing ages? Results from the perioperative Italian Society Registry.

Previous studies reported that enhanced recovery pathway (ERP) is safe in elderly who did not require a specifically tailored protocol. In previous studies, elderly have been considered as a homogeneous cohort and the cut-off value to identify them was different. The aim of the present study is to assess the compliance to ERP and its impact on postoperative outcome in three subgroups of elderly patients with increasing ages. Prospectively collected data entered in an electronic Italian registry specifically designed for ERP were reviewed. 315 elderly patients undergoing elective colorectal resection were divided into three groups. Group 1: 71-75 years (n = 105), Group 2: 76-80 years (n = 117), Group 3: over 80 years (n = 93). Primary endpoints of the study were adherence to ERP and time to readiness for discharge (TRD). Compliance to ERP was similar in the three groups. No difference among groups was found for mortality, overall morbidity, major complications, reoperation rate and readmission rate. Median TRD and length of hospital stay (LOS) were progressively longer with increasing age (p = 0.018 and p = 0.078, respectively). Increasing age did not impact on adherence to ERP and postoperative morbidity, but delayed both TRD and LOS.

Natural history of a randomized trial comparing distal spleno-renal shunt with endoscopic sclerotherapy in the prevention of variceal rebleeding: a lesson from the past.

AIM: To compare endoscopic sclerotherapy (ES) with distal splenorenal shunt (DSRS) in the prevention of recurrent variceal bleeding in cirrhotic patients during a long-term follow-up period. METHODS: In 1984 we started a prospective, controlled study of patients with liver cirrhosis. Long-term follow-up presents a natural history of liver cirrhosis complicated by advanced portal hypertension. In this study the effects of 2 types of treatment, DSRS or ES, were evaluated. The study population included 80 patients with cirrhosis and portal hypertension referred to our department from October 1984 to March 1991. These patients were drawn from a pool of 282 patients who underwent either elective surgery or ES during the same period of time. Patients were assigned to one of the 2 groups according to a random number table: 40 to DSRS and 40 to ES using polidocanol. RESULTS: During the postoperative period, no DSRS patient died, while one ES patient died of uncontrolled hemorrhage. One DSRS patient had mild recurrent variceal hemorrhage despite an angiographically patent DSRS and another patient suffered duodenal ulcer rebleeding. Eight ES patients suffered at least one episode of gastrointestinal bleeding: 4 from varices and 4 from esophageal ulcerations. Eight ES patients developed transitory dysphagia. Long-term follow-up was completed in all patients except for 5 cases (2 DSRS and 3 ES patients). Five-year survival rates for shunt (73%) and ES (56%) groups were statistically different: in this follow-up period and in subsequent follow-ups this difference decreased and ceased to be of statistical relevance. The primary cause of death became hepatocellular carcinoma (HCC). Four DSRS patients rebled due to duodenal ulcer, while eleven ES patients had recurrent bleeding from esophago-gastric sources (seven from varices, three from hypertensive gastropathy, one from esophageal ulcerations) and two from unknown sources. Nine DSRS and 2 ES patients developed a chronic encephalopathy; 13 DSRS and 5 ES patients suffered at least one episode of acute encephalopathy. Five ES patients had esophageal stenoses, which were successfully dilated. CONCLUSION: In a subgroup of patients with good liver function, DSRS with a correct portal-azygos disconnection more effectively prevents variceal rebleeding than ES. However, this positive effect did not influence the long-term survival because other factors (e.g. HCC) were more important in deciding the fate of the cirrhotic patients with portal hypertension.

[Laparoscopic management of oesophageal epiphrenic diverticulum: a case report]. / Trattamento laparoscopico di diverticolo esofageo epifrenico: presentazione di un caso.

Epiphrenic diverticuli are rare pulsion "pseudodiverticuli" of the distal oesophagus that are commonly associated with oesophageal motility disorders. Surgical treatment is usually reserved for patients with symptoms. Traditionally, patients are treated with diverticulectomy, myotomy and fundoplication via a left thoracotomy. The aim of this study was to describe the laparoscopic technique and review the international literature on this minimally invasive approach. We report the case of a 66-year-old woman with a 1-year history of retrosternal pain, regurgitation and weight loss caused by an oesophageal epiphrenic diverticulum. The patient underwent barium oesophagography and oesophagogastroduodenoscopy. The oesophageal diverticulum measured 5 cm. We treated the condition with a laparoscopic oesophageal diverticulectomy, Heller myotomy and Dor fundoplication with intraoperative endoscopy. The operative time was 210 minutes. The postoperative course was complicated by a suspected leakage from the staple line, which was not subsequently confirmed. The patient is now totally asymptomatic after 3 months. Laparoscopy offers good access to the distal oesophagus and the inferior mediastinum. Resection of the diverticulum, treatment of the motor disorder and prevention of postoperative reflux can be obtained with this approach. It should be considered as an alternative to the traditional transthoracic approach and may eventually become the standard technique.

Contrast-enhanced computed tomography colonography in preoperative distinction between T1-T2 and T3-T4 staging of colon cancer.

RATIONALE AND OBJECTIVES: To predict the T stage of nonrectal colon cancer using contrast-enhanced computed tomography colonography. MATERIALS AND METHODS: Sixty-one patients with 67 nonrectal colon cancers consecutively underwent contrast-enhanced computed tomography colonography after an incomplete colonoscopy. Two readers evaluated wall deformity and perilesional fat abnormality on three-dimensional double contrast enema-like views and multiplanar reconstructions. Pathology was used as the standard of reference. McNemar, Fisher, and Cohen κ statistics were used. RESULTS: At pathologic examination, we found the following stages: T1 (n = 5), T2 (n = 10), T3 (n = 41), T4a (n = 6), and T4b (n = 5). Intraobserver and interobserver reproducibilities were almost perfect for wall deformity (κ = 1.00 and κ = 0.88, respectively), substantial for perilesional fat abnormality (κ = 0.79 and κ = 0.74, respectively). Using the results of the more experienced reader, accuracy of wall deformity ≥50% (apple-core) alone for T ≥ 3 was 62 of 67 (0.93, 95% confidence interval [CI] 0.83-0.97) and that of perilesional fat abnormality alone was 37 of 67 (0.55, 95% CI 0.43-0.67) (P < .001). Predictive value for ≥ T3 of the association wall deformity ≥50% with perilesional fat abnormality was 22 of 22 (1.00, 95% CI 0.85-1.00), higher, but not significantly, than that of wall deformity ≥50% with normal perilesional fat 29 of 33 (0.88, 95% CI 0.72-0.97) (P = .148, Fisher exact test). CONCLUSIONS: The presence of apple-core wall deformity, regardless of perilesional fat abnormality, is highly predictive of stage T3 or higher.

Technical quality of CT colonography in relation with diverticular disease.

OBJECTIVE: The aim of the study is to explore how the technical quality of the examination was affected by diverticular disease. MATERIALS AND METHODS: We retrospectively evaluated a consecutive series of 78 subjects who underwent CTC for screening (n=58) or staging (n=20) colorectal cancer, 38 of them (49%) after an incomplete optical colonoscopy. Patients were administered a mild laxative and a iodinated contrast material for fecal tagging. We scored both the bowel preparation and the overall colon distension as poor, good, or optimal and measured the mean sigmoid colon diameter. We counted the number of diverticula and classified patients as having or not a severe diverticular disease (SDD). The number of the prompts of computer aided diagnosis (CAD) per patient was also considered. Mann-Whitney U and χ(2) tests were performed. RESULTS: No CTC complications occurred. The bowel cleansing was poor in 8 (10%) patients, good in 29 (37%) and optimal in 41 (53%); colon distension was poor in 7 (9%) patients, good in 38 (49%), and optimal in 33 (42%). Fifty-four (69%) showed diverticula and 30 (38%) had an SDD. Bowel cleansing and distension were not significantly impaired by neither diverticula (p>0.590) nor the SDD (p>0.110). Mean sigmoid colon diameter was reduced in presence of diverticula (28 mm versus 23 mm, p=0.009) or SDD (26 mm versus 22 mm, p=0.016). The mean number of CAD prompts per patient was not significantly increased by the presence of SDD (p=0.829). CONCLUSIONS: Bowel cleansing and distension at CTC were not influenced by the presence of diverticular disease.