The interplay of KRAS mutational status with tumor laterality in non-metastatic colorectal cancer: An international, multi-institutional study in patients with known KRAS, BRAF, and MSI status.

BACKGROUND: Although the prognostic relevance of KRAS status in metastatic colorectal cancer (CRC) depends on tumor laterality, this relationship is largely unknown in non-metastatic CRC. METHODS: Patients who underwent resection for non-metastatic CRC between 2000 and 2018 were identified from institutional databases at six academic tertiary centers in Europe and Japan. The prognostic relevance of KRAS status in patients with right-sided (RS), left-sided (LS), and rectal cancers was assessed. RESULTS: Of the 1093 eligible patients, 378 had right-sided tumors and 715 had left-sided tumors. Among patients with RS tumors, the 5-year overall (OS) and recurrence-free survival (RFS) for patients with KRASmut versus wild-type tumors was not shown to differ significantly (82.2% vs. 83.2% and 72.1% vs. 76.7%, respectively, all p > .05). Among those with LS tumors, KRAS mutation was associated with shorter 5-year OS and RFS on both the univariable (OS: 79.4% vs. 86.1%, p = .004; RFS: 68.8% vs. 77.3%, p = .005) and multivariable analysis (OS: HR: 1.52, p = .019; RFS: HR: 1.32, p = .05). CONCLUSIONS: KRAS mutation status was independently prognostic among patients with LS tumors, but this association failed to reach statistical significance in RS and rectal tumors. These findings confirm reports in metastatic CRC and underline the possible biologic importance of tumor location.

Biomarkers in pancreatic neuroendocrine tumors.

The aim of biomarkers is to identify patients most likely to benefit from a therapeutic strategy. Pancreatic neuroendocrine tumors are rare neoplasms that arise in the endocrine tissues of the pancreas. Pancreatic neuroendocrine tumors represent 3% of primary pancreatic neoplasms and their incidence has risen. The SMAD4 gene is located on chromosome 18q and someday the SMAD4 gene status may be useful for prognostic stratification and therapeutic decision. The cells respond to environmental signals by modulating the expressions of genes contained within the nucleus, when genes are activated are transcribed to generate messenger RNA (mRNA). The examination of multiple expressed genes and proteins provides more useful information for prognostication of individual tumors. Here we summarize and discuss findings presented at the 2014 ASCO Gastrointestinal Cancers Symposium. Anna Karpathakis et al. (Abstract #212) reported data about the role of DNA methylation in gastrointestinal neuroendocrine tumors. Christina Lynn Roland et al. (Abstract #250) looked the impact Of SMAD4 on oncologic outcomes. Bong Kynn Kang et al. (Abstract #251) investigated prognostic biomarker using microRNA array technology.

Optimal Volume Assessment for Serous Fluid Cytology.

OBJECTIVE: This study aimed to investigate the optimal volume of serous fluid needed for accurate diagnosis using The International System for Reporting Serous Fluid Cytopathology (TIS), as well as to provide information on the distribution of serous effusion cases in the TIS categories (ND: non-diagnostic, NFM: negative for malignancy, AUS: atypia of undetermined significance, SFM: suspicious for malignancy, MAL: malignant) and relevant epidemiological data. METHODS: A retrospective analysis of 2340 serous effusion cases (pleural, peritoneal, and pericardial) from two hospitals between 2018 and 2020 was conducted. TIS categories were assigned to each case, and for 1181 cases, these were correlated with the volume of the analyzed fluid. RESULTS: Our study found statistically significant differences in volume distributions between certain TIS categories. Statistically lower volumes were observed in NFM compared to MAL, in UNCERTAIN (ND, AUS, SFM) compared to both MAL and NFM, and in NOT MAL (ND, NFM, AUS, SFM) compared to MAL. However, these differences were not substantial enough to hold any clinical relevance. CONCLUSIONS: This study suggests that while fluid volume may slightly influence the TIS category, it does not impact the diagnostic accuracy of serous effusion cytology. Therefore, the ideal serous effusion specimen volume can be defined solely by practical parameters.

The Long Journey towards Personalized Targeted Therapy in Poorly Differentiated Thyroid Carcinoma (PDTC): A Case Report and Systematic Review.

BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) has an intermediate prognosis between indolent well-differentiated thyroid carcinoma (TC) and anaplastic carcinoma. Herein, we present a case report with a PDTC component, along with a systematic review of the literature. CASE REPORT: We report a case of a 45-year-old man diagnosed with a PDTC component, along with hobnail and tall-cell variant features positive for BRAFV600E mutation, after a total thyroidectomy and neck dissection. Radioactive iodine (RAI)-131 therapy was applied, but an early recurrence led to complementary surgeries. The anti-Tg rise, the presence of new lymph nodes, and the negative whole-bodyradioiodine scan were suggestive of a radioiodine-resistant tumor. Lenvatinib, sorafenib, dabrafenib/trametinib, cabozantinib and radiotherapy were all administered, controlling the tumor for a period of time before the patient ultimately died post-COVID infection. Systematic Review: We searched PubMed, Scopus, and WebofScience to identify studies reporting clinicopathological characteristics, molecular marker expression, and management of non-anaplastic TC with any proportion of PDTC in adult patients. Of the 2007 records retrieved, 82were included in our review (PROSPERO-ID545847). CONCLUSIONS: Our case, together with the systematic review, imply that a combination of molecular-targetedtreatments may be safe and effective in patients with RAI-resistantBRAF-mutated advanced PDTC when surgery has failed to control tumor progression.

Impact of Minimally Invasive Intrathoracic Hand-sewn Esophago-gastric Anastomosis in Esophagectomy for Cancer.

BACKGROUND/AIM: Ivor Lewis esophagectomy is considered the gold standard approach for the treatment of distal esophageal and gastro-esophageal junction Siewert I-II tumors. Minimally invasive esophagectomy has provided improved outcomes compared to the open approach, offering reduced morbidity, and improved clinical and oncological outcomes. This is the largest study so far reporting the impact of hand-sewn esophago-gastric anastomosis in the prone position, during the 2-stage totally minimally invasive esophagectomy. PATIENTS AND METHODS: A retrospective analysis of prospectively collected data regarding consecutive patients with distal-esophageal and gastroesophageal junction Siewert I-II tumors was conducted. All patients underwent 2-stage totally minimally invasive esophagectomy with thoracoscopic manual esophago-gastric anastomosis in the prone position. Clinical and oncological outcomes were examined and presented. RESULTS: One hundred and fifty consecutive patients were included in the study during a period of five years. Median operative time was 320 minutes, while median time for the construction of anastomosis was 45 minutes. We had no conversions to open esophagectomy. Anastomotic leakage was observed in 2% of the patients; anastomotic stricture rate reached up to 7.33%. Respiratory complications were seen in 18% and cardiac complications in 6.66% of the patients, respectively. Thirty-day mortality and 90-day mortality rates were 1.33% and 2.66%, accordingly. CONCLUSION: Intrathoracic hand-sewn esophago-gastric anastomosis in the prone position during totally minimally invasive esophagectomy has provided favorable outcomes in our cohort of patients, offering significantly reduced anastomotic-related complications, compared to other standardized techniques. Further prospective comparative studies are needed, to better interpret and amplify our results, that may lead to a paradigm shift regarding the preferred method of reconstruction from esophageal surgeons.

Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction.

Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.

Latest evidence on immune checkpoint inhibitors in metastatic colorectal cancer: A 2022 update.

The long-term remissions induced by immune-checkpoint inhibitors (ICIs) in many types of cancers have opened up the possibility of a broader use of immunotherapy in less immunogenic but genetically heterogeneous tumours. Regarding metastatic colorectal cancer (mCRC), in first-line setting, pembrolizumab has been approved as preferred option and nivolumab, alone or in combination with ipilimumab as alternative option for patients with mismatch-repair-deficient and microsatellite instability-high (dMMR/MSI-H) disease, independently of their eligibility for intensive chemotherapy. In subsequent lines, both these immunotherapeutic regimens (e.g., pembrolizumab and nivolumab+/-ipilimumab) as well as dostarlimab-gxly are currently recommended for patients with dMMR/MSI-H chemo-resistant mCRC who have not previously received an ICI. Beginning from the rationale behind the immune-mediated interplay in the dMMR/MSI-H bowel microenvironment, we provide here an update on the evolution status of all available, approved or not, ICIs in mCRC, describing their efficacy and toxicity profile with an emphasis on the pivotal trials supporting current colorectal indications. For each ICI agent, the results from combinations under investigation, particularly for those being upgraded in clinical phasing, the perspectives but also the limitations of main ongoing trials are thoroughly discussed. In the close future, upcoming data are expected to confirm the clinical benefit of ICIs and to further expand their role in mCRC.

Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal desmoid tumors.

Desmoid-type fibromatosis (DF) is a distinctly rare condition, mostly of younger adults, characterized by the development of locally aggressive tumors of mesenchymal origin. Desmoid tumors (DT) arise either sporadically or in association with FAP (familial adenomatous polyposis), although certain risk factors have also been identified, including pregnancy and antecedent surgical trauma. They can emerge from any connective tissue including muscle, fascia and aponeurosis and are therefore classified, according to location, as intra-abdominal, of the abdominal wall and extra-abdominal. Despite the lack of metastasizing potential, the course can be unpredictable. Various mutations of APC and ß-catenin genes, among others, play a catalytic role in the pathogenesis of this neoplastic entity. Surgery has lost its traditional role as first line treatment of the disease and several other treatment methods are being considered. Cytotoxic chemotherapy, non-cytotoxic systemic therapy and targeted therapy have been revealed as part of different treatment regimens. Recent progress regarding DT biology and molecular pathways has led to the development of promising novel biological agents. In any case, a multidisciplinary approach is required and is gradually employed, espe-cially in intra-abdominal DTs. In this review, we aim to present current knowledge on DF and summarize current treatment regimens as well as their effectiveness, with emphasis on the intraperitoneal type of DT.

Combining BRAF/MEK Inhibitors with Immunotherapy in the Treatment of Metastatic Melanoma.

The management and prognosis of BRAF-mutant metastatic melanoma have changed drastically following the introduction of immune checkpoint inhibitors and molecularly targeted agents. These treatment options present different mechanisms of action and toxicities but also totally distinct kinetics of their response, including a "relatively" short-lasting benefit in subsets of patients treated with BRAF/MEK inhibitors and a lower response rate in patients treated with immune checkpoint inhibitors. BRAF/MEK inhibitors, when administered prior to or concurrently with immune checkpoint inhibitors, at least transiently alter some immunosuppressive parameters of the tumor microenvironment and theoretically improve sensitivity to immunotherapy. Preclinical data from mouse models with oncogene-addicted melanoma confirmed this beneficial immune/targeted synergy and supported the clinical testing of combinations of BRAF/MEK inhibitors and immune checkpoint inhibitors to improve the activity of upfront anti-melanoma therapies. The first positive phase III results were published in 2020, and triggered the discussion about the benefits, the limitations, as well as the possible implications of combining or sequencing targeted therapies with immune checkpoint inhibitors in everyday practice. Beginning from the interplay of immune/targeted agents within the melanoma microenvironment, this review outlines available information from the retrospective experience up to the late-stage randomized evidence on combinatorial treatments. Many clinical trials are currently underway exploring open questions about optimal timing, new immune biomarkers, and eligible patient subsets for these immune/targeted regimens. Awaiting these results, decision making in the first-line setting for BRAF-mutant melanoma is still guided by the patients' characteristics and the biological aspects of melanoma.

Notch-Mediated Generation of Monocyte-Derived Langerhans Cells: Phenotype and Function.

Langerhans cells (LCs) in the skin are a first line of defense against pathogens but also play an essential role in skin homeostasis. Their exclusive expression of the C-type lectin receptor Langerin makes them prominent candidates for immunotherapy. For vaccine testing, an easily accessible cell platform would be desirable as an alternative to the time-consuming purification of LCs from human skin. Here, we present such a model and demonstrate that monocytes in the presence of GM-CSF, TGF-ß1, and the Notch ligand DLL4 differentiate within 3 days into CD1a+Langerin+cells containing Birbeck granules. RNA sequencing of these monocyte-derived LCs (moLCs) confirmed gene expression of LC-related molecules, pattern recognition receptors, and enhanced expression of genes involved in the antigen-presenting machinery. On the protein level, moLCs showed low expression of costimulatory molecules but prominent expression of C-type lectin receptors. MoLCs can be matured, secrete IL-12p70 and TNF-α, and stimulate proliferation and cytokine production in allogeneic CD4+ and CD8+ T cells. In regard to vaccine testing, a recently characterized glycomimetic Langerin ligand conjugated to liposomes demonstrated specific and fast internalization into moLCs. Hence, these short-term in vitro‒generated moLCs represent an interesting tool to screen LC-based vaccines in the future.

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma.

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.

Characteristics and Prognosis of Hepatocellular Carcinoma in Multi-Transfused Patients with ß-Thalassemia. Experience of a Single Tertiary Center.

BACKGROUND/AIM: The incidence of hepatocellular carcinoma (HCC) in patients with transfusion dependent thalassemia (TDT) has been increasing, where viral hepatitis and iron overload are the two established HCC risk factors. The aim of this study was to investigate the etiological factors of HCC development and to evaluate the possible factors associated with survival in our cohort of TDT patients with HCC. METHODS: Records of patients with TDT diagnosed with HCC from 2008 to 2018 were reviewed. Liver iron concentration (LIC) has been assessed by the signal-intensity-ratio MRI. The diagnosis of HCC was made by a 3-phase contrast magnetic resonance imaging (MRI) and patients were staged and treated for HCC according to Barcelona Clinic Liver Cancer (BCLC) grading system. RESULTS: Forty-two TDT patients with HCC have been included. Most of them (78.5%) were anti-HCV positive, 59.5% HCV-RNA positive, and 16.5% had serological markers of resolved HBV infection. Patients with HCV infection have been treated successfully with either Peg-IFNa±Ribavirin or with the new direct antivirals (DAAs). At the time of HCC diagnosis, all patients with chronic HCV infection were HCV-RNA negative, 78.5% had underlying cirrhosis, and the vast majority (98%) had average or mild elevated LIC values. According to the BCLC system, patients were classified as 0-A: 28.5%, B: 57% and C-D: 14.5%. HCC has been treated with loco-regional treatment in 78.5% of our patients, while the rest have received sorafenib. Twenty-eight patients (66.5%) died due to HCC with a median survival time of 6 months (range: 2-60). Using the Cox proportional hazard model, the only factors associated with poor survival were BCLC stages C and D. CONCLUSIONS: In conclusion, BCLC staging is the main prognostic factor of survival in patients with TDT who develop HCC.

Advances in the treatment of soft tissue sarcoma: focus on eribulin.

Eribulin mesylate is a synthetic derivative of halichondrin B isolated from a marine sponge. Its mechanism of action is through microtubule inhibition, which is different from that of taxanes. Eribulin has been approved for the treatment of metastatic breast cancer and more recently for non-operable or metastatic liposarcoma in patients who have received prior anthracycline chemotherapy. The major side effects of eribulin are bone marrow suppression including neutropenia, leukopenia, anemia, and fatigue/weakness, which can be well managed. In this article, we reviewed evidence from the latest published data on eribulin and its use in the treatment of soft tissue sarcomas. We explored the drug's mechanism of action, pharmacodynamics, pharmacokinetics, and metabolism. Lastly, we reviewed all preclinical studies as well as clinical trials that investigated eribulin.

A Case of Organizing Pneumonia (OP) Associated with Pembrolizumab.

Until recently, chemotherapy for metastatic melanoma had disappointing results. The identification of immune checkpoints such as CTLA-4 and PD-1/PD-L1 has led to the development of an array of monoclonal antibodies (Mabs). These immunologic approaches against tumoral cells come with a novel kind of side effects that the clinician needs to be familiarized with. Herein, we report for the first time a case of organizing pneumonia, based on imaging and cytological analyses of bronchoalveolar lavage, possibly associated with the use of pembrolizumab, an anti-PD-1 Mab recently approved for the treatment of metastatic melanoma.

A case of paraneoplastic autoimmune pancreatitis: mini-review of paraneoplastic syndromes in breast cancer.

Breast cancer (BC), the most common type of cancer in women of the Western world, is often associated with paraneoplastic syndromes (PNS). Autoimmune pancreatitis is a recently recognized entity belonging to the spectrum of IgG4-related systemic diseases, which are characterized by target-organ plasmacytic infiltration and fibrosis. In this report we review PNS associated with BC and we present the first case of BC-associated autoimmune pancreatitis as well as its successful management with steroids and immunosuppressive BC-tailored chemotherapy.