The impact of preoperative nutritional screening, ERAS protocol, and mini-invasive surgery in surgical oncology: A multi-institutional SEM analysis of patients with digestive cancer.

Background: Mini-invasive surgery (MIS), ERAS, and preoperative nutritional screening are currently used to reduce complications and the length of hospital stay (LOS); however, inter-variable correlations have seldom been explored. This research aimed to define inter-variable correlations in a large series of patients with gastrointestinal cancer and their impact on outcomes. Methods: Patients with consecutive cancer who underwent radical gastrointestinal surgery between 2019 and 2020 were analyzed. Age, BMI, comorbidities, ERAS, nutritional screening, and MIS were evaluated to determine their impact on 30-day complications and LOS. Inter-variable correlations were measured, and a latent variable was computed to define the patients' performance status using nutritional screening and comorbidity. Analyses were conducted using structural equation modeling (SEM). Results: Of the 1,968 eligible patients, 1,648 were analyzed. Univariable analyses documented the benefit of nutritional screening for LOS and MIS and ERAS (≥7 items) for LOS and complications; conversely, being male and comorbidities correlated with complications, while increased age and BMI correlated with worse outcomes. SEM analysis revealed that (a) the latent variable is explained by the use of nutritional screening (p0·004); (b) the variables were correlated (age-comorbidity, ERAS-MIS, and ERAS-nutritional screening, p < 0·001); and (c) their impact on the outcomes was based on direct effects (complications: sex, p0·001), indirect effects (LOS: MIS-ERAS-nutritional screening, p < 0·001; complications: MIS-ERAS, p0·001), and regression-based effects (LOS: ERAS, MIS, p < 0·001, nutritional screening, p0·021; complications: ERAS, MIS, p < 0·001, sex, p0·001). Finally, LOS and complications were correlated (p < 0·001). Conclusion: Enhanced recovery after surgery (ERAS), MIS, and nutritional screening are beneficial in surgical oncology; however, the inter-variable correlation is reliable, underlying the importance of the multidisciplinary approach.

Primary Tumor Resection for Metastatic Colorectal, Gastric and Pancreatic Cancer Patients: In Search of Scientific Evidence to Inform Clinical Practice.

The management of the primary tumor in metastatic colorectal, gastric and pancreatic cancer patients may be challenging. Indeed, primary tumor progression could be associated with severe symptoms, compromising the quality of life and the feasibility of effective systemic therapy, and might result in life-threatening complications. While retrospective series have suggested that surgery on the primary tumor may confer a survival advantage even in asymptomatic patients, randomized trials seem not to definitively support this hypothesis. We discuss the evidence for and against primary tumor resection for patients with metastatic gastrointestinal (colorectal, gastric and pancreatic) cancers treated with systemic therapies and put in context the pros and cons of the onco-surgical approach in the time of precision oncology. We also evaluate current ongoing trials on this topic, anticipating how these will influence both research and everyday practice.

Use of fluorescence imaging and indocyanine green for sentinel node mapping during gastric cancer surgery: Results of an intercontinental Delphi survey.

BACKGROUND: Understanding the extent of tumor spread to local lymph nodes is critical to managing early-stage gastric cancer. Recently, fluorescence imaging with indocyanine green has been used to identify and characterize sentinel lymph nodes during gastric cancer surgery, but no published guidelines exist. We sought to identify areas of consensus among international experts in the use of fluorescence imaging with indocyanine green for mapping sentinel lymph nodes during gastric-cancer surgery. METHODS: In this 2-round, online Delphi survey, 27 international experts voted on 79 statements pertaining to patient preparation and contraindications to fluorescence imaging with indocyanine green during gastric cancer surgery; indications; technical aspects; advantages/disadvantages and limitations; and training and research. Methodological steps were adopted during survey design to minimize bias. RESULTS: Consensus was reached on 61 of 79 statements, including giving single injections of indocyanine green into each of the 4 quadrants peritumorally, administering indocyanine green on the same day as surgery, injecting a total of 1 to 5 mL of 5 mg/mL indocyanine green, injecting endoscopically into submucosa, and repeating indocyanine green injections a second time if sentinel lymph node visualization remains inadequate. Consensus also was reached that fluorescence imaging with indocyanine green is an acceptable single-agent modality for sentinel lymph node identification and that the sentinel lymph node basin method is preferred. However, sentinel lymph node dissection should be limited to T1 gastric cancer and tumors ≤4 cm in diameter, and further research is necessary to optimize the technique and render fluorescence-guided sentinel lymph nodes dissection acceptable for routine clinical use. CONCLUSION: Although considerable consensus was achieved, further research is necessary before this technology should be used in routine practice.

ICG-Guided Lymphadenectomy during Surgery for Colon and Rectal Cancer-Interim Analysis of the GREENLIGHT Trial.

Lymphadenectomy is crucial for an optimal oncologic resection of colon and rectal cancers. However, without a direct visualization, an aberrant route of lymph node (LN) diffusion might remain unresected. Indocyanine-green (ICG) lymphatic mapping permits a real-time LNs visualization. We designed the GREENLIGHT trial to explore in 100 patients undergoing robotic colorectal resection the clinical significance of a D3 ICG-guided lymphadenectomy. The primary endpoint was the number of patients in whom ICG changed the extent of lymphadenectomy. We report herein the interim analysis on the first 70 patients. After endoscopic ICG injection 24 h (n = 49) or 72 h (n = 21) ahead, 19, 20, and 31 patients underwent right colectomy, left colectomy, and anterior rectal resection. The extent of lymphadenectomy changed in 35 (50%) patients, mostly (29 (41.4%)) for the identification of LNs (median two) outside the standard draining basin. Identification of such LNs was less frequent in rectal tumors that had undergone chemoradiotherapy (26.3%) (p > 0.05). A non-significant correlation between time-to-ICG injection and identification of aberrant LNs was observed (48.9% at 24 h vs. 23.8% at 72 h). The presence of LN metastases did not affect a proper fluorescent mapping. These data indicate that ICG lymphatic mapping provides relevant information in 50% of patients, thus increasing the accuracy of potentially curative resections.

Personalized therapeutic strategies in HER2-driven gastric cancer.

BACKGROUND: Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. METHODS: We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. RESULTS: Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. CONCLUSION: These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.

Robotic taTME using the da Vinci SP: technical notes in a cadaveric model.

Transanal total mesorectal excision (taTME) is an emerging albeit complex technique to treat rectal cancer. The aim of this proof-of-concept preclinical study was to determine the technical feasibility of robotic taTME using the da Vinci SP (dVSP). Two fresh cadavers, one female (case 1) and one male (case 2), were used. Focus was given only to the transanal phase of the taTME. Two different clinical scenarios were simulated: in case 1, the tumor was hypothesized to be at 1 cm above the anorectal junction; in case 2, at > 4 cm. The GelPOINT Path was used as the transanal access platform through which the 2.5 cm single port robotic trocar and a 10 mm sleeve were inserted. A complete taTME was performed in both cases with a sleeve mucosectomy initiated at the level of the dentate line in case 1. In case 2, the purse-string was created and tightened robotically. At the completion of the procedure, the quality of the mesorectal dissection was verified showing an intact mesorectal fascia in both cases. Operation times were 124 and 106 min with a ~ 15 min of non-console time for robot positioning and docking. Robotic taTME with the dVSP is technically feasible and might overcome the limits of the traditional laparoscopic approach.

Fluorescence-guided D3 lymphadenectomy in robotic right colectomy with complete mesocolic excision.

BACKGROUND: In robotic right hemicolectomy for cancer, appropriate lymphadenectomy is essential. Visualization of draining lymph nodes and blood flow with near-infrared (NIR) fluorescence DaVinci® imaging system is a recent development. We present the technique of robotic right colectomy with complete mesocolic excision (CME) and D3 lymphadenectomy using Indocyanine Green (ICG) endoscopic submucosal injection to intraoperatively identify tumour lymphatic basin. METHODS: The day before surgery, in patients scheduled for robotic right colectomy an endoscopic submucosal injection of 3 mg of ICG solution around the tumor is realized. Robotic right hemicolectomy is performed with suprapubic trocars layout and "bottom to up dissection", realizing a CME with central vessel ligation and D3 lymphadenectomy. Site of primary tumor and lymphatic basin are visible with the FireflyTM camera modality. RESULTS: From July 2016 to July 2020, 85 patients received a robotic right colectomy with CME and D3 lymphadenectomy. In 50 patients, ICG submucosal injection was performed: visualisation of the site of primary tumour and of LN in the D3 area was possible in all cases; in 17/50 patients (34%), LN out from anatomical lymphatic basin were identified. No side effects were observed. CONCLUSIONS: In this series, submucosal ICG injection showed to be feasible and safe. The accuracy in identification of D3 lymphatic basin was high, thus permitting an image-guided radical lymphadenectomy. Fluorescent technology represents an interesting innovation to ameliorate surgery of colon cancer.

Colectomía derecha robótica con escisión completa del mesocolon y linfadenectomía D3 mediante abordaje suprapúbico «bottom-to-up»: aspectos técnicos clave / Robotic right colectomy with Complete Mesocolic Excision (CME) and D3 lymphadenectomy with a suprapubic bottom-to-up approach: technical key points

No disponible

Atypical haemolytic-uraemic syndrome in patient with metastatic colorectal cancer treated with fluorouracil and oxaliplatin: a case report and a review of literature.

Background. Thrombotic microangiopathies (TMA) are relatively rare but severe disorders characterised by non-immune haemolytic anaemia, thrombocytopaenia and organ failure. In patients with metastatic cancer, sporadic forms of TMA can be triggered by chemotherapeutic agents or can occur as complication of malignancy itself or of infections. Case report. Hereby, we report a case of a patient diagnosed with metastatic colorectal cancer who experienced an atypical haemolytic-uraemic syndrome (aHUS) during chemotherapy treatment with FOLFOX6 scheme. The use of eculizumab led to prompt recovery of laboratory parameters that was maintained despite treatment discontinuation due to appearance of pneumonia infectious. Additionally, genetic analyses revealed the presence in heterozygosis of CFH gene polymorphisms associated with aHUS. Conclusion. This case emphasises the importance of considering TMA as a possible diagnosis in patients with cancer presenting with haemolytic non-immune mediate anaemia and thrombocytopaenia associated with worsening of renal function. Prompt diagnosis is crucial for the requirement of its specific treatment that can impact on long-term outcome and prognosis.

A Comprehensive PDX Gastric Cancer Collection Captures Cancer Cell-Intrinsic Transcriptional MSI Traits.

Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell-intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell-intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis. SIGNIFICANCE: This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.

Correction to: Robotic Versus Laparoscopic Right Colectomy with Complete Mesocolic Excision for the Treatment of Colon Cancer: Perioperative Outcomes and 5-Year Survival in a Consecutive Series of 202 Patients.

Dario Ribero's affiliation is corrected as reflected here.

Double indocyanine green technique of robotic right colectomy: Introduction of a new technique.

In robotic right hemicolectomy for colorectal cancer (CRC), appropriate lymphadenectomy and anastomotic leak prevention are critical. Visualisation of lymph nodes and blood flow with near-infrared (NIR) fluorescence DaVinci® imaging system is a recent development. Herein, we present an improved robotic modified complete mesocolic excision (mCME) technique using indocyanine green (ICG) fluorescence. Before surgery, ICG is injected into the submucosa around the tumour with endoscopy for intraoperative detection of lymph nodes. Robotic mCME with central vascular ligation is performed, supplemented in most of the cases with selective extended lymphadenectomy. Intestinal blood flow before anastomosis is evaluated by administering ICG intravenously and NIR visualisation. Visualisation of the lymph nodes with ICG facilitates standard mCME lymphadenectomy and enables extended lymphadenectomy. Blood flow of the intestinal walls of the anastomotic site can be assessed and determines the extent of intestinal resection. Robotic double ICG technique for robotic right hemicolectomy enables improved lymphadenectomy and warrants the extent of intestinal resection; thus, becoming a strong candidate for gold standard in robotic resections of the right colon for CRC.

Robotic Versus Laparoscopic Right Colectomy with Complete Mesocolic Excision for the Treatment of Colon Cancer: Perioperative Outcomes and 5-Year Survival in a Consecutive Series of 202 Patients.

BACKGROUND: During the past decade, the concept of complete mesocolic excision (CME) has emerged as a possible strategy to minimize recurrence for right colon cancers. The purpose of this study was to compare robotic versus laparoscopic CME in performing right colectomy for cancer. METHODS: Pertinent data of all patients who underwent robotic or laparoscopic right colectomy with CME using a Pfannenstiel incision and intracorporeal anastomosis performed between October 2005 and November 2015 were entered in a prospectively maintained database. RESULTS: A total of 202 patients underwent robotic (n = 101) or laparoscopic (n = 101) right colectomy within the study period. Patient characteristics were equivalent between groups. The robotic group showed a statistically significant reduction in conversion rate (0% vs. 6.9%, p = 0.01) but a longer operative time (279 min vs. 236 min, p < 0.001) compared with the laparoscopic group. There were no other differences in perioperative clinical or pathological outcomes. Five-years overall survival was 77 versus 73 months for the robotic versus laparoscopic groups (p = 0.64). The disease-free survival (DFS) rates were 85% and 83% for the robotic versus laparoscopic groups (p = 0.58). Among UICC stage III patients, there was a slight but not significant difference in 5-year DFS for the robotic group (81 vs. 68 months; p = 0.122). CONCLUSIONS: Both approaches for right colectomy with CME were safe and feasible and resulted in excellent survival. Robotic assistance was beneficial for performing intracorporeal anastomosis and dissection as evidenced by the lower conversion rates. Further robotic experience may shorten the operative time.

The role of multimodal treatment in patients with advanced lung neuroendocrine tumors.

Lung neuroendocrine tumors (NETs) comprise typical (TC) and atypical carcinoids (AC). They represent the well differentiated (WD) or low/intermediate grade forms of lung neuroendocrine neoplasms (NENs). Unlike the lung poorly differentiated NENs, that are usually treated with chemotherapy, lung NETs can be managed with several different therapies, making a multidisciplinary interaction a key point. We critically discussed the multimodal clinical management of patients with advanced lung NETs. Provided that no therapeutic algorithm has been validate so far, each clinical case should be discussed within a NEN-dedicated multidisciplinary team. Among the systemic therapies available for metastatic lung NETs everolimus is the only approved drug, on the basis of the results of the phase III RADIANT-4 trial. Another phase III trial, the SPINET, is ongoing comparing lanreotide with placebo. Peptide receptor radionuclide therapy and chemotherapy were not studied within phase III trials for lung NETs, and they have been reported to be active within retrospective or phase II prospective studies. Temozolomide and oxaliplatin are two interesting chemotherapeutic agents in lung NETs. While some European Institutions were certificated as Centers of Excellence for gastroenteropancreatic NENs by the European Neuroendocrine Tumor Society (ENETS), an equivalent ENETS certification for lung NENs does not exist yet. Ideally a lung NEN-dedicated multidisciplinary tumor board should include NEN-dedicated medical oncologists, thoracic medical oncologist, thoracic surgeons, pathologists, interventional radiologists, endocrinologists, radiotherapists, interventional pneumologists, nuclear physician.

Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

Blocking Surgically Induced Lysyl Oxidase Activity Reduces the Risk of Lung Metastases.

Surgery remains the most successful curative treatment for cancer. However, some patients with early-stage disease who undergo surgery eventually succumb to distant metastasis. Here, we show that in response to surgery, the lungs become more vulnerable to metastasis due to extracellular matrix remodeling. Mice that undergo surgery or that are preconditioned with plasma from donor mice that underwent surgery succumb to lung metastases earlier than controls. Increased lysyl oxidase (LOX) activity and expression, fibrillary collagen crosslinking, and focal adhesion signaling contribute to this effect, with the hypoxic surgical site serving as the source of LOX. Furthermore, the lungs of recipient mice injected with plasma from post-surgical colorectal cancer patients are more prone to metastatic seeding than mice injected with baseline plasma. Downregulation of LOX activity or levels reduces lung metastasis after surgery and increases survival, highlighting the potential of LOX inhibition in reducing the risk of metastasis following surgery.

Current Status on Cholangiocarcinoma and Gallbladder Cancer.

BACKGROUND: Cholangiocarcinomas (CC) as well as gallbladder cancers are relatively rare and intractable diseases. Clinical, pathological, and epidemiological studies on these tumors have been under investigation. The current status and/or topics on biliary tract cancers have been reported in the East West Association of Liver Tumor (EWALT), held in Milano, Italy in 2015. SUMMARY: All the authors, herein, specifcally reported the current status and leading-edge findings on biliary tract cancers as the following sequence: epidemiology of CC, surgical therapy for intrahepatic CC, surgical therapy for perihilar CC, surgical therapy for gallblad der cancer, chemotherapy for biliary tract cancers, and new histological features in CC. KEY MESSAGE: The present review article will update the knowledge on biliary tract cancers, en hancing the quality of daily clinical practice. However, many features about these cancers remain unknown; further studies are required to establish disease-specific optimal treatment strategies.

Notes of robotic surgical technique: four ways to mobilize splenic flexure.

Splenic flexure mobilization is a challenging surgical procedure, but is it necessary to safely perform left colon and rectal resections. This paper is a technical focus detailing the four ways to mobilize splenic flexure in robotic surgery. The medial approach involves an extensive dissection of the medial plane separating descending mesocolon form Toldt fascia; the sovramesocolic approach starts with gastrocolic ligament section; the lateral approach starts with coloparietal detachment and the "one inch-one inch" approach starts with section of transverse mesocolon.