Molecular profiling and patient selection for the multimodal approaches for patients with resectable colorectal liver metastases.

Colorectal cancer represents the third most common cancer and about 20% are diagnosed with synchronous metastatic disease. From a historical point of view, surgery remains the mainstream treatment for resectable colorectal liver metastases (CRLM). Furthermore, disease outcomes are improving due significant advances in systemic treatments and diagnostic methods. However, the optimal timing for neoadjuvant chemotherapy or upfront surgery for CRLM has not yet been established and remains an open question. Thus, patient selection combining image workouts, time of recurrence, positive lymph nodes, and molecular biomarkers can improve the decision-making process. Nevertheless, molecular profiling is rising as a promising field to be incorporated in the multimodal approach and guide patient selection and sequencing of treatment. Tumor biomakers, genetic profiling, and circulating tumor DNA have been used to offer as much personalized treatment as possible, based on the precision oncology concept of tailored care rather than a guideline-based therapy. This review article discusses the role of molecular pathology and biomarkers as prognostic and predictor factors in the diagnosis and treatment of resectable CRLM.

Treatment of patients with multiple brain metastases by isolated radiosurgery: Toxicity and survival.

BACKGROUND: Radiosurgery for multiple brain metastases has been more reported recently without using whole-brain radiotherapy. Nevertheless, the sparsity of the data still claims more information about toxicity and survival and their association with both dosimetric and geometric aspects of this treatment. AIM: To assess the toxicity and survival outcome of radiosurgery in patients with multiple (four or more lesions) brain metastases. METHODS: In a single institution, data were collected retrospectively from patients who underwent radiosurgery to treat brain metastases from diverse primary sites. Patients with 4-21 brain metastases were treated with a single fraction with a dose of 18 Gy or 20 Gy. The clinical variables collected were relevant to toxicity, survival, treatment response, planning, and dosimetric variables. The Spearman's rank correlation coefficients, Mann-Whitney test, Kruskal-Wallis test, and Log-rank test were used according to the type of variable and outcomes. RESULTS: From August 2017 to February 2020, 55 patients were evaluated. Headache was the most common complaint (38.2%). The median overall survival (OS) for patients with karnofsky performance status (KPS) > 70 was 8.9 mo, and this was 3.6 mo for those with KPS ≤ 70 (P = 0.047). Patients with treated lesions had a median progression-free survival of 7.6 mo. There were no differences in OS (19.7 vs 9.5 mo) or progression-free survival (10.6 vs 6.3 mo) based on prior irradiation. There was no correlation found between reported toxicities and planning, dosimetric, and geometric variables, implying that no additional significant toxicity risks appear to be added to the treatment of multiple (four or more) lesions. CONCLUSION: No associations were found between the evaluated toxicities and the planning dosimetric parameters, and no differences in survival rates were detected based on previous treatment status.

Treatment Outcomes in Patients with Advanced Fibrolamellar Hepatocellular Carcinoma Under Systemic Treatment: Analysis of Clinical Characteristics, Management, and Radiomics.

Purpose: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy often diagnosed at advanced stages. While there are limited data on the efficacy of specific agents, we aim to report outcomes of patients treated with systemic therapies and explore prognostic factors. Patients and Methods: Medical records of patients treated between 2010 and 2022 were reviewed. Treatments were defined after multidisciplinary assessment. Descriptive statistics were used for baseline demographics. Time-to-event outcomes were estimated using the Kaplan-Meier method, compared by log-rank and adjusted by a regression model. Radiomic features (including size, shape, and texture) of the primary lesion were extracted and dimensionality reduced. An unsupervised Gaussian Mixture Model (GMM) clustering was performed, and survival was compared between clusters. Results: We identified 23 patients: 12 males, with a median age of 23.6 years. At diagnosis, 82.6% had metastases, most frequently to the lungs (39.1%), lymph nodes (39.1%), and peritoneum (21.7%). Patients received a median of three lines (1-8) of treatment, including different regimens. Sorafenib (39.1%), capecitabine (30.4%), and capecitabine/interferon (13%) were the most used first-line regimens. The median time-to-failure was 3.8 months (95% CI: 3.2-8.7). Capecitabine + interferon (42.1%) and platinum combinations (39.1%) were the most used second-line regimens, with a time-to-failure of 3.5 months (95% CI: 1.5-11.6). Median overall survival was 26.7 months (95% CI: 15.1-40.4). A high baseline neutrophil-to-lymphocyte ratio (NLR) was associated with worse survival (p=0.02). Radiomic features identified three clusters, with one cluster (n=6) having better survival (40.4 vs 22.6 months, p=0.039). Tumor sphericity in the arterial phase was the most relevant characteristic associated with a better prognosis (accuracy=0.93). Conclusion: FLHCC has unique features compared to conventional HCC, including young onset, gender balance, and absence of hepatopathy. Systemic therapies can provide encouraging survival, but lack of uniformity precludes defining a preferable regimen. Radiomics and NLR were suggested to correlate with prognosis and warrant further validation.

Overall Survival, BRAF, RAS, and MSI Status in Patients Who Underwent Cetuximab After Refractory Chemotherapy for Metastatic Colorectal Cancer.

PURPOSE: Evaluate overall survival (OS), RAS, BRAF, and MSI frequencies in patients with metastatic colorectal cancer (mCRC), refractory to chemotherapy, and finally treated with cetuximab. METHODS: A retrospective cohort study to evaluate 211 mCRC patients with wild-type KRAS treated with cetuximab. BRAF V600E, KRAS, NRAS gene mutations, and MSI status were identified using PCR techniques in a population of pre-treated patients who were refractory to fluoropyrimidines, oxaliplatin, and irinotecan. In addition, we evaluated the mutation frequency of the BRAF and NRAS genes and the MSI status of this population. Uni- and multivariate analyses were performed for independent prognostic factors of OS. RESULTS: The median OS was 10.4 months, 6.6 months for patients with right and 11.5 months for left colon cancers (p = 0.02). The frequencies of mutations were BRAF at 3.9% (median OS of 4.9 months), NRAS at 3.38% (median OS of 6.9 months), and MSI-High status at 3.3% (median OS of 4.6 months). The OS, NRAS, and MSI frequencies were similar to those found in other studies that evaluated cetuximab in poly-treated patients and were associated with lower survival rates in univariate analyses. The frequency of BRAF mutations was lower than that found in previous studies. The only variable that remained significant for OS in the multivariate model was tumour laterality, with patients with right colon cancer presenting a worse prognosis (HR = 2.81). CONCLUSION: Although BRAF, NRAS mutations, and MSI-High status were associated with shorter OS in univariate analyses, only tumour laterality remained an independent prognostic factor in the multivariate analysis.

Laparoscopic or Open Adrenalectomy for Stage I-II Adrenocortical Carcinoma: A Retrospective Study.

Surgical resection of adrenocortical carcinoma (ACC) is the only curative treatment. Even in localized (I-II) stages, open adrenalectomy (OA) is the gold standard, though laparoscopic adrenalectomy (LA) can be proposed in selected patients. Despite the postoperative benefits of LA, its role in the surgical management of patients with ACC remains controversial regarding oncologic outcomes. The aim of this retrospective study was to compare the outcomes of patients with localized ACC submitted to LA or OA in a referral center from 1995 to 2020. Among 180 consecutive patients operated on for ACC, 49 presented with localized ACC (19 LA and 30 OA). Baseline characteristics were similar between groups, except for tumor size. Kaplan-Meier estimates of 5-year overall survival were similar in both groups (p = 0.166) but 3-year disease-free survival was in favor of OA (p = 0.020). Though LA could be proposed in highly selected patients, OA should still be considered the standard approach in patients with known or suspected localized ACC.

Is it possible to adopt the same oncological approach in urgent surgery for colon cancer?

BACKGROUND: Locoregional complications may occur in up to 30% of patients with colon cancer. As they are frequent events in the natural history of this disease, there should be a concern in offering an oncologically adequate surgical treatment to these patients. AIM: To compare the oncological radicality of surgery for colon cancer between urgent and elective cases. METHODS: One-hundred and eighty-nine consecutive patients with non-metastatic colon adenocarcinoma were studied over two years in a single institution, who underwent surgical resection as the first therapeutic approach, with 123 elective and 66 urgent cases. The assessment of oncological radicality was performed by analyzing the extension of the longitudinal margins of resection, the number of resected lymph nodes, and the percentage of surgeries with 12 or more resected lymph nodes. Other clinicopathological variables were compared between the two groups in terms of sex, age, tumor location, type of urgency, surgical access, staging, compromised lymph nodes rate, differentiation grade, angiolymphatic and perineural invasion, and early mortality. RESULTS: There was no difference between the elective and urgency group concerning the longitudinal margin of resection (average of 6.1 in elective vs 7.3 cm in urgency, P = 0.144), number of resected lymph nodes (average of 17.7 in elective vs 16.6 in urgency, P = 0.355) and percentage of surgeries with 12 or more resected lymph nodes (75.6% in elective vs 77.3% in urgency, P = 0.798). It was observed that the percentage of patients aged 80 and over was higher in the urgency group (13.0% in elective vs 25.8% in urgency, P = 0.028), and the early mortality was 4.9% in elective vs 15.2% in urgency (P = 0.016, OR: 3.48, 95%CI: 1.21-10.06). Tumor location (P = 0.004), surgery performed (P = 0.016) and surgical access (P < 0.001) were also different between the two groups. There was no difference in other clinicopathological variables studied. CONCLUSION: Oncological radicality of colon cancer surgery may be achieved in both emergency and elective procedures.

Oncologic aspects of the decision-making process for surgical approach for colorectal liver metastases progressing during chemotherapy.

Colorectal cancer represents the third most diagnosed malignancy in the world. The liver is the main site of metastatic disease, affected in 30% of patients with newly diagnosed disease. Complete resection is considered the only potentially curative treatment for colorectal liver metastasis (CRLM), with a 5-year survival rate ranging from 35% to 58%. However, up to 80% of patients have initially unresectable disease, due to extrahepatic disease or bilobar multiple liver nodules. The availability of increasingly effective systemic chemotherapy has contributed to converting patients with initially unresectable liver metastases to resectable disease, improving long-term outcomes, and accessing tumor biology. In recent years, response to preoperative systemic chemotherapy before liver resection has been established as a major prognostic factor. Some studies have demonstrated that patients with regression of hepatic metastases while on chemotherapy have improved outcomes when compared to patients with stabilization or progression of the disease. Even if disease progression during chemotherapy represents an independent negative prognostic factor, some patients may still benefit from surgery, given the role of this modality as the main treatment with curative intent for patients with CRLM. In selected cases, based on size, the number of lesions, and tumor markers, surgery may be offered despite the less favorable prognosis and as an option for non-chemo responders.

Clinical Course, Genetic, and Immunohistochemical Characterization of Solid Pseudopapillary Tumor of the Pancreas (Frantz Tumors) in a Brazilian Cohort.

Frantz tumors or solid pseudopapillary pancreatic neoplasm (SPN) are rare exocrine neoplasms that carry a favorable prognosis; they represent up to 3% of all tumors located in the region of the pancreas and have specific age and gender predispositions. In recent years, the rising curve of diagnosis is entitled to the evolution and access of diagnostic imaging. In this paper, we have retrospectively reviewed and described the clinical course of 40 patients with SPN from three institutions in Brazil, who had their diagnosis between 2005 and 2020, and analyzed the clinicopathological, genetic, and surgical aspects of these individuals. In accordance with the literature, most patients were women, 60% with unspecified symptoms at diagnosis, with tumors mainly located in the body and tail of the pancreas, of whom 70% underwent a distal pancreatectomy with sparing splenectomy as a standard procedure, and none of the cases have experienced recurrence to date. Surgery still remains the mainstay of treatment given the low metastatic potential, but more conservative approaches as observed in this cohort are evolving to become the standard of care. Herein, we present an in-depth analysis of cases focusing on the latest literature and report some of the smallest tumor cases in the literature. To our knowledge, this is the first report evaluating germline genetic testing and presenting a case of detected Li-Fraumeni syndrome.

Combination approaches in hepatocellular carcinoma: How systemic treatment can benefit candidates to locoregional modalities.

The management of hepatocellular carcinoma (HCC) is challenging because most patients have underlying cirrhosis, and the treatment provides, historically, a limited impact on the natural history of patients with advanced-stage disease. Additionally, recurrence rates are high for those patients who receive local and locoregional modalities, such as surgical (resection and transplantation) or image-guided (ablation and intra-arterial) therapies. Translational research has led to new concepts that are reshaping the current clinical practice. Substantial advancements were achieved in the understanding of the hallmarks that drive hepatocarcinogenesis. This has primed a successful incorporation of novel agents with different targets, such as anti-angiogenic drugs, targeted-therapies, and immune-checkpoint inhibitors. Although clinical trials have proven efficacy of systemic agents in advanced stage disease, there is no conclusive evidence to support their use in combination with loco-regional therapy. While novel local modalities are being incorporated (e.g., radioembolization, microwave ablation, and irreversible electroporation), emerging data indicate that locoregional treatments may induce tumor microenvironment changes, such as hyperexpression of growth factors, release of tumor antigens, infiltration of cytotoxic lymphocytes, and modulation of adaptative and innate immune response. Past trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial improvement. Current efforts are directed to investigate the role of immunotherapy-based regimens in this context. The present review aims to describe the current landscape of systemic and locoregional treatments for HCC, present evidence to support combination approaches, and address future perspectives.

Counter-Clockwise Approach for Robotic Pylorus-Preserving Pancreatoduodenectomy.

PURPOSE: This multi-media article aims to describe a counter-clockwise approach for pancreatoduodenectomy (CCA-PD) in robotic surgery. METHODS: A CCA-PD was used as a strategy for robotic surgery to treat a 69-year-old woman without comorbidities who presented a ductal adenocarcinoma of the head of the pancreas (2.7 cm) in contact with the portal vein (less than 180°), preoperatively treated with FOLFIRINOX. The procedure was entirely done in the abdominal right upper quadrant (RUQ) following the main steps of CCA-PD resection: section of the first portion of the duodenum; biliary duct transection; Kocherization of the duodenum and retropancreatic lymphadenectomy; section of the jejunum; portal vein dissection; transection of the pancreas and uncinate detachment. The reconstruction also followed the counter-clockwise direction with a single jejunal loop with end-to-side anastomoses: pancreato-jejunal; choledoco-jejunal; duodenojejunal. RESULTS: The total operation time was 435 min, and the estimated blood loss was 200 mL. The postoperative course was uneventful without complications, with hospital discharge on the fifth postoperative day. The final pathology was ductal adenocarcinoma (G2), ypT2ypN2 (07/31), with negative surgical margins. DISCUSSION: The entire surgery happens in a unique surgical field, the RUQ, which saves time by avoiding unnecessary mobilization of the bowel and favors a layer-by-layer dissection with enough space for both dissections and sutures on each step of the procedure and improving bleeding control if necessary.

Analysis of cathepsin S expression in gastric adenocarcinoma and in Helicobacter pylori infection.

BACKGROUND: Recent experimental studies have suggested a potential link between cathepsin S (CTTS) and gastric adenocarcinoma progression. Herein, we aimed to evaluate the expression of CTTS in gastric adenocarcinoma in patients who underwent curative-intent surgical resection. METHODS: This was a cross-sectional study that included two groups: gastric adenocarcinoma (n = 42) and gastritis (n = 50). The gastritis group was then subdivided into H. pylori-positive (n = 25) and H. pylori-negative (n = 25) groups. Gastric tissue samples were analysed to determine CTTS expression through immunohistochemistry. Samples were obtained by oesophagogastroduodenoscopy or surgical specimens. RESULTS: In patients with gastritis, the age ranged from 18 to 78 years. Among them, 34% were male, and 66% were female. In patients with gastric adenocarcinoma, the age ranged from 37 to 85 years. Among them, 50% were male. When comparing the expression of CTTS between the two groups, only 16% of the gastritis samples had an expression higher than 25%. Alternatively, among patients with gastric adenocarcinoma, 19% had expression between 25-50%, 14.3% between 51-75%, and 26.2% had expression higher than 75% (p < 0.001). In the gastritis group, CTTS expression was significantly higher in patients with a positive test for H. pylori than negative test for H. pylori: 87.5% and 38.5%, respectively (p<0.001). There was no statistically significant association between CTTS positivity and clinicopathological variables, including tumour staging, histological type, angiolymphatic invasion, recurrence, current status and death. CONCLUSION: CTTS expression is higher in gastric adenocarcinoma samples. Patients with gastritis due to H. pylori also show a higher expression of CTTS than patients with negative results for this bacterium.

Incidence and risk factors for Chyle leak after pancreatic surgery for cancer: A comprehensive systematic review.

BACKGROUND: Chyle leak (CL) is a clinically relevant complication after pancreatectomy. Its incidence and the associated risk factors are ill defined, and various treatments options have been described. There is no consensus, however, regarding optimal management. The present study aims to systematically review the literature on CL after pancreatectomy. METHODS: A systematic review from PubMed, Scopus and Embase database was performed. Studies using a clear definition for CL and published from January 2000 to January 2021 were included. The PRISMA guidelines were followed during all stages of this systematic review. The MINORS score was used to assess methodological quality. RESULTS: Literature search found 361 reports, 99 of which were duplicates. The titles and abstracts of 262 articles were finally screened. The references from the remaining 181 articles were manually assessed. After the exclusions, 43 articles were thoroughly assessed. A total of 23 articles were ultimately included for this review. The number of patients varied from 54 to 3532. Incidence of post pancreatectomy CL varied from 1.3% to 22.1%. Main risk factors were the extent of the surgery and early oral or enteral feeding. CL dried up spontaneously or after conservative management within 14 days in 53% to 100% of the cases. CONCLUSIONS: The extent of surgery is the most common predictor of risk of CL. Conservative treatment has been shown to be effective in most cases and can be considered the treatment of choice. We propose a management algorithm based on the current available evidence.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of oesophageal cancer.

Oesophageal cancer is among the ten most common types of cancer worldwide. More than 80% of the cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of oesophageal and oesophagogastric junction (OGJ) carcinomas. The Brazilian Group of Gastrointestinal Tumours invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy (including checkpoint inhibitors) and follow-up, which was followed by presentation, discussion and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of oesophageal and OGJ carcinomas in several scenarios and clinical settings.

Metformin plus lrinotecan in patients with refractory colorectal cancer: a phase 2 clinical trial.

BACKGROUND: Patients with refractory colorectal (CRC) cancer have few treatment options. This trial tests the combination of metformin and irinotecan in this setting. METHODS: A phase 2 single-arm trial was conducted, patients received metformin 2500 mg orally a day plus irinotecan 125 mg/m2 intravenously weekly D1 and D8 every 21 days. The primary endpoint was the disease control rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks. RESULTS: Between December 2015 and January 2018, 41 patients were enrolled. Seventeen patients (41%) met the primary endpoint of disease control in 12 weeks; hence, the study was deemed positive. The median progression-free survival was 3.3 months (CI 95%, 2.0-4.5 months), and the median overall survival was 8.4 months (CI 95%, 5.9-10.8 months). Both mutation RAS status and disease control at 12 weeks impacted overall survival in the multivariate model (HR 2.28, CI 95%, 1.12-4.7, p = 0.02; and HR 0.21, CI 95%, 0.08-0.5, p = 0.001, respectively). The most common adverse event was diarrhoea (29.2% grade 3). CONCLUSIONS: In this trial, metformin plus irinotecan demonstrated disease control in patients with refractory CRC. Further trials with optimised diarrhoea control are needed to confirm these results.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of gastric cancer.

Gastric cancer is among the ten most common types of cancer worldwide. Most cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of gastric carcinomas. The Brazilian Group of Gastrointestinal Tumors (GTG) invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy and follow-up, which was followed by presentation, discussion, and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of gastric carcinomas in several scenarios and clinical settings.

Overview and perspectives about the robotic surgical certification process in Brazil: the new statement and a national web-survey.

OBJECTIVE: to appraise the general profile of the Brazilian robotic surgeon and the acknowledgment of the new certification process for robotic surgery upon the Associação Médica Brasileira (AMB - Brazilian Medical Association) statement. According to the AMB statement, medical societies and proctors have to achieve leading roles in training and certification of surgeons, acting in partnership with industry. METHODS: a national web-based survey was promoted by the Colégio Brasileiro de Cirurgiões (CBC - Brazilian College of Surgeons) among their members. RESULTS: the 294 answers were split into two groups: 133 (45.3%) who had robotic console certification, and 161 (54.8%) who did not have it. The overall median age was 46, but the non-robotic group presented more surgeons with at least 30 years of experience than to the robotic group (32.3% versus 23.3%, p=0.033). Surgeons with robotic certification more frequently work in a city with at least one million inhabitants than surgeons who were not certified (85.7 versus 63.4%, p<0.001). The majority of surgeons in both groups have similar positioning for all main points of the statement. However, the agreement proportions for the preceptors responsibility during the procedures were higher among non-robotic surgeons that expected the preceptor to assume co-responsibility for the procedure (85% versus 60.9%, p<0.001), and intervene during the procedure as much as necessary (97.5% versus 91.7%, p=0.033). CONCLUSION: the overall agreement of the answers to the AMB statement seems to be a promising pathway to increase the participation of the medical entities into the robotic certification in Brazil.

MicroRNAs in Lung Cancer Oncogenesis and Tumor Suppression: How it Can Improve the Clinical Practice?

BACKGROUND: Lung cancer (LC) development is a process that depends on genetic mutations. The DNA methylation, an important epigenetic modification, is associated with the expression of non-coding RNAs, such as microRNAs. MicroRNAs are particularly essential for cell physiology, since they play a critical role in tumor suppressor gene activity. Furthermore, epigenetic disruptions are the primary event in cell modification, being related to tumorigenesis. In this context, microRNAs can be a useful tool in the LC suppression, consequently improving prognosis and predicting treatment. CONCLUSION: This manuscript reviews the main microRNAs involved in LC and its potential clinical applications to improve outcomes, such as survival and better quality of life.

Educational note: teaching and training in robotic surgery. An opinion of the Minimally Invasive and Robotic Surgery Committee of the Brazilian College of Surgeons.

With the expansion of robotic surgical procedures, the acquisition of specific knowledge and skills for surgeons to reach proficiency seems essential before performing surgical procedures on humans. In this sense, the authors present a proposal to establish a certification based on objective and validated criteria for carrying out robotic procedures. A study was carried out by the Committee on Minimally Invasive and Robotic Surgery of the Brazilian College of Surgeons based on a reviewing strategy of the scientific literature. The study serves as a reference for the creation of a standard for the qualification and certification in robotic surgery according to a statement of the Brazilian Medical Association (AMB) announced on December 17, 2019. The standard proposes a minimum curriculum, integrating training and performance evaluation. The initial (pre-clinical) stage aims at knowledge and adaptation to a specific robotic platform and the development of psychomotor skills based on surgical simulation. Afterwards, the surgeon must accompany in person at least five surgeries in the specialty, participate as a bedside assistant in at least 10 cases and perform 10 surgeries under the supervision of a preceptor surgeon. The surgeon who completes all the steps will be considered qualified in robotic surgery in his specialty. The final certification must be issued by the specialty societies affiliated to AMB. The authors conclude that the creation of a norm for habilitation in robotic surgery should encourage Brazilian hospitals to apply objective qualification criteria for this type of procedure to qualify assistance.