Multigene Panel Next-Generation Sequencing Techniques in the Management of Patients with Metastatic Colorectal Carcinoma: The Way Forward for Personalized Treatment? A Single-Center Experience.

The efficacy and cost-effectiveness of Multigene Panel Next-Generation Sequencing (NGS) in directing patients towards genomically matched therapies remain uncertain. This study investigated metastatic colorectal cancer (mCRC) patients who underwent NGS analysis on formalin-fixed paraffin-embedded tumor samples. Data from 179 patients were analyzed, revealing no mutations in 39 patients (21.8%), one mutation in 83 patients (46.4%), and two or more mutations in 57 patients (31.8%). KRAS mutations were found in 87 patients (48.6%), including KRAS G12C mutations in 5 patients (2.8%), PIK3CA mutations in 40 patients (22.4%), and BRAF mutations in 26 patients (14.5%). Less common mutations were identified: ERBB2 in five patients (2.8%) and SMO in four patients (2.2%). Additionally, MAP2K1, CTNNB1, and MYC were mutated in three patients (2.4%). Two mutations (1.1%) were observed in ERBB3, RAF1, MTOR, JAK1, and FGFR2. No significant survival differences were observed based on number of mutations. In total, 40% of patients had druggable molecular alterations, but only 1.1% received genomically guided treatment, suggesting limited application in standard practice. Despite this, expanded gene panel testing can identify actionable mutations, aiding personalized treatment strategies in metastatic CRC, although current eligibility for biomarker-guided trials remains limited.

PD-L1 Expression in Paired Samples of Rectal Cancer.

Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes.

Advancing Personalized Medicine in the Treatment of Locally Advanced Rectal Cancer.

Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, distant tumor recurrence remains a concern, prompting the exploration of total neoadjuvant therapy (TNT) as a comprehensive treatment strategy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Nonoperative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving complete clinical response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for the assessment of treatment response. This review synthesizes current evidence on TNT, ICIs, NOM, and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

Inflammatory indices as prognostic markers in metastatic colorectal cancer patients treated with chemotherapy plus Bevacizumab.

Background: Validated predictors of sensitivity or resistance to Bevacizumab (Bev) are not available, and Inflammatory Indexes (IIs) has been reported to be useful prognostic factors in various malignant solid tumours, including metastatic colorectal cancer (mCRC). Objectives: To explore the prognostic value of IIs in mCRC patients treated with first-line chemotherapy plus Bev. Design: One hundred and eighty-two patients diagnosed with mCRC and treated with first line chemotherapy plus Bev were considered for this prospective non-pharmacological study. Neutrophil, lymphocyte, platelet, aspartate transaminase (AST) and lactate dehydrogenase (LDH) tests were carried out at baseline and before each treatment cycle, according to clinical practice. Methods: Pre-treatment Systemic Immune-inflammation Index (SII), Colon Inflammatory Index (CII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) were evaluated to assess a correlation with progression-free survival (PFS) and overall survival (OS). Results: In the overall population, PFS and OS were lower in patients with high SII (HR 1.64, p = 0.006 and HR 1.75, p = 0.004, respectively) and high ALRI (HR 2.13, p = 0.001 and HR 1.76, p = 0.02, respectively), but no difference was detected according to CII value. The multivariate analysis confirmed both SII and ALRI as independent prognostic factors for PFS (HR 1.64 and 2.82, respectively) and OS (HR 1.65 and 2.12, respectively). Conclusion: Our results demonstrate and confirm that IIs, and in particular SII and ALRI, are easy to measure prognostic markers for patient candidates to first line chemotherapy plus Bev for mCRC.

Inflammatory Indexes can predict the efficacy of bevacizumab in metastatic colorectal cancer Bevacizumab (Bev) is a humanized monoclonal antibody with antiangiogenic activity, used in combination with chemotherapy as a standard first line treatment for many metastatic colorectal cancer patients. Validated predictors of sensitivity or resistance to Bevacizumab are not available, although several studies have investigated this issue in recent years. In this study, we investigated whether some selected baseline inflammatory indexes levels, namely Systemic Immune-inflammation Index (SII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) could predict the survival in patients with metastatic colorectal cancer treated with Bevacizumab plus chemotherapy. We enrolled 182 patients diagnosed with mCRC and treated with first line chemotherapy plus Bev. For each patient we tested blood neutrophils, lymphocytes, platelets, aspartate transaminase (AST) and lactate dehydrogenase (LDH) before each treatment cycle, according to clinical practice. We calculated the SII value as platelet count × neutrophil count/lymphocyte count, and ALRI as AST/lymphocyte count. We found that patients with high SII and high ALRI values had lower survival as compared to those with low values. These parameters represent reproducible, inexpensive and easy to measure biomarkers to be used in both clinical practice and clinical trials, for patient selection.

Dynamic Monitoring of Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer.

PURPOSE: Plasma circulating tumor DNA (ctDNA) is a valuable resource for tumor characterization and for monitoring of residual disease during treatment; however, it is not yet introduced in metastatic colorectal cancer (mCRC) routine clinical practice. In this retrospective exploratory study, we evaluated the role of ctDNA in patients with mCRC treated with chemotherapy plus bevacizumab. MATERIALS AND METHODS: Fifty-three patients were characterized for RAS and BRAF status on tumor tissue before the start of treatment. Plasma was collected at baseline, at first clinical evaluation, and at disease progression. ctDNA analysis was performed using Oncomine Colon cfDNA Assay on the Ion S5 XL instrument. RESULTS: At baseline, from a plasma sample, RAS, BRAF, or PIK3CA mutations were detected in 44 patients. A high correspondence was observed between ctDNA and tumor tissue mutations (KRAS 100%, NRAS 97.9%, BRAF 97.9%, PIK3CA 90%). Low baseline variant allele frequency (VAF) was found to be associated with longer median progression-free survival (PFS) compared with those with high VAF (15.9 v 12.2 months, P = .02). A higher PFS {12.29 months (95% CI, 9.03 to 17.9) v 8.15 months (95% CI, 2.76 to not available [NA]), P = .04} and overall survival (34.1 months [95% CI, 21.68 to NA] v 11.1 months [95% CI, 3.71 to NA], P = .003) were observed in patients with large decline in VAF at first evaluation. CONCLUSION: ctDNA analysis is useful for molecular characterization and tumor response monitoring in patients with mCRC. Quantitative variations of released ctDNA are associated with clinical outcomes.

Association between Pre-Treatment Biological Indicators and Compliance to Neoadjuvant/Perioperative Chemotherapy in Operable Gastric Cancer.

BACKGROUND AND AIMS: Perioperative treatment is currently the gold standard approach in Europe for locally advanced gastric cancer (GC). Unfortunately, the phenomenon of patients dropping out of treatment has been frequently observed. The primary aims of this study were to verify if routine blood parameters, inflammatory response markers, sarcopenia, and the depletion of adipose tissues were associated with compliance to neoadjuvant/perioperative chemotherapy. METHODS AND STUDY DESIGN: Blood samples were considered before the first and second cycles of chemotherapy. Sarcopenia and adipose indices were calculated with a CT scan before starting chemotherapy and before surgery. Odds ratios (OR) from univariable and multivariable models were calculated with a 95% confidence interval (95% CI). RESULTS: A total of 84 patients with locally advanced GC were identified between September 2010 and January 2021. Forty-four patients (52.4%) did not complete the treatment according to the number of cycles planned/performed. Eight patients (9.5%) decided to suspend chemotherapy, seven patients (8.3%) discontinued because of clinical decisions, fourteen patients (16.7%) discontinued because of toxicity and fifteen patients (17.9%) discontinued for miscellaneous causes. Seventy-nine (94%) out of eighty-four patients underwent gastrectomy, with four patients having surgical complications, which led to a suspension of treatment. Sarcopenia was present in 38 patients (50.7%) before chemotherapy began, while it was present in 47 patients (60%) at the CT scan before the gastrectomy. At the univariable analysis, patients with basal platelet to lymphocyte ratio (PLR) ≥ 152 (p = 0.017) and a second value of PLR ≥ 131 (p = 0.007) were more frequently associated with an interruption of chemotherapy. Patients with increased PLR (p = 0.034) compared to the cut-off were associated with an interruption of chemotherapy, while patients with increased monocytes between the first and second cycles were associated with a lower risk of treatment interruption (p = 0.006); patients who underwent 5-fluorouracil plus cisplatin or oxaliplatin had a higher risk of interruption (p = 0.016) compared to patients who underwent a 5-fluorouracil plus leucovorin, oxaliplatin and docetaxel (FLOT) regimen. The multivariable analysis showed a higher risk of interruption for patients who had higher values of PLR compared to the identified cut-off both at pretreatment and second-cycle evaluation (OR: 5.03; 95% CI: 1.34-18.89; p = 0.017) as well as for patients who had a lower PLR than the identified cut-off at pretreatment evaluation and had a higher PLR value than the cut-off at the second cycle (OR: 4.64; 95% CI: 1.02-21.02; p = 0.047). Becker regression was neither affected by a decrease of sarcopenia ≥ 5% (p = 0.867) nor by incomplete compliance with chemotherapy (p = 0.281). CONCLUSIONS: Changes in PLR values which tend to increase more than the cut-off seem to be an immediate indicator of incomplete compliance with neoadjuvant/perioperative treatment. Fat loss and sarcopenia do not appear to be related to compliance. More information is needed to reduce the causes of interruption.

Prospective validation of VEGF and eNOS polymorphisms as predictors of first-line bevacizumab efficacy in patients with metastatic colorectal cancer.

Bevacizumab (Bev) plus chemotherapy is a standard first-line treatment in metastatic colorectal cancer (mCRC), however to date no predictive factors of response have been identified. Results of our previous analysis on patients enrolled in a randomized prospective phase III multicenter study (ITACa study) showed a predictive value of Vascular Endothelial Growth Factor (VEGF) polymorphism (VEGF + 936), a 27-nucleotide variable number tandem repeat (VNTR) of the endothelial nitric oxide synthase (eNOS) gene and eNOS + 894 polymorphism. mCRC patients, treated with Bev plus chemotherapy, were included in this prospective validation trial. eNOS + 894G > T was analyzed by Real time PCR, while the eNOS VNTR and VEGF + 936C > T were determined by standard PCR and direct sequencing analysis. These polymorphisms were assessed in relation to progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). These three polymorphisms were not predictive of PFS (p 0.91, 0.59 and 0.09, respectively), and OS (p 0.95, 0.32 and 0.46, respectively). Moreover, the haplotype analyses did not confirm what was found in our previous study; patients bearing a specific haplotype of eNOS had not significantly improved outcomes. This prospective study failed to validate the predictive impact of eNOS and VEGF polymorphisms for response to Bev plus first-line chemotherapy in mCRC patients.

Analysis of EVs from patients with advanced pancreatic cancer identifies antigens and miRNAs with predictive value.

The identification of predictive factors for treatment of pancreatic cancer (PC) is an unmet clinical need. In the present work, we analyzed blood-derived extracellular vesicles (EVs) from patients with advanced PC in order to find a molecular signature predictive of response to therapy. We analyzed samples from 21 patients with advanced PC, all receiving first-line treatment with gemcitabine + nab-paclitaxel. Isolated EVs have been analyzed, and the results of laboratory have been matched with clinical data in order to investigate possible predictive factors. EV concentration and size were similar between responder and non-responder patients. Analysis of 37 EV surface epitopes showed a decreased expression of SSEA4 and CD81 in responder patients. We detected more than 450 expressed miRNAs in EVs. A comparative survey between responder and non-responder patients showed that at least 44 miRNAs were differently expressed. Some of these miRNAs have already been observed in relation to the survival and gemcitabine sensitivity of tumor cells. In conclusion, we showed the ability of our approach to identify EV-derived biomarkers with predictive value for therapy response in PC. Our findings are worthy of further investigation, including the analysis of samples from patients treated with different schedules and in different settings.

Digital Guardian Angel Supported by an Artificial Intelligence System to Improve Quality of Life, Well-being, and Health Outcomes of Patients With Cancer (ONCORELIEF): Protocol for a Single Arm Prospective Multicenter Pilot Study.

BACKGROUND: According to Europe's Beating Cancer Plan, the number of cancer survivors is growing every year and is now estimated at over 12 million in Europe. A main objective of the European Commission is to ensure that cancer survivors can enjoy a high quality of life, underlining the role of digital technology and eHealth apps and tools to achieve this. OBJECTIVE: The main objective of this study is the development of a user-centered artificial intelligence system to facilitate the input and integration of patient-related biopsychosocial data to improve posttreatment quality of life, well-being, and health outcomes and examine the feasibility of this digitally assisted workflow in a real-life setting in patients with colorectal cancer and acute myeloid leukemia. METHODS: A total of 60 patients with colorectal cancer and 30 patients with acute myeloid leukemia will be recruited from 2 clinical centers: Universitätsmedizin der Johannes Gutenberg-Universität Mainz (Mainz, Germany) and IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST, Italy). Psychosocial data (eg, emotional distress, fatigue, quality of life, subjective well-being, sleep problems, and appetite loss) will be collected by questionnaires via a smartphone app, and physiological data (eg, heart rate, skin temperature, and movement through step count) will be collected by a customizable smart wrist-worn sensor device. Each patient will be assessed every 2 weeks over their 3-month participation in the ONCORELIEF study. Inclusion criteria include patients with the diagnosis of acute myeloid leukemia or colorectal cancer, adult patients aged 18 years and older, life expectancy greater than 12 months, Eastern Cooperative Oncology Group performance status ≤2, and patients who have a smartphone and agree to use it for the purpose of the study. Exclusion criteria include patients with a reduced cognitive function (such as dementia) or technological illiteracy and other known active malignant neoplastic diseases (patients with a medical history of treated neoplastic disease are included). RESULTS: The pilot study started on September 1, 2022. As of January 2023, we enrolled 33 patients with colorectal cancer and 7 patients with acute myeloid leukemia. As of January 2023, we have not yet started the data analysis. We expect to get all data in June 2023 and expect the results to be published in the second semester of 2023. CONCLUSIONS: Web-based and mobile apps use methods from mathematical decision support and artificial intelligence through a closed-loop workflow that connects health professionals and patients. The ONCORELIEF system has the potential of continuously identifying, collecting, and processing data from diverse patient dimensions to offer health care recommendations, support patients with cancer to address their unmet needs, and optimize survivorship care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) 00027808; https://drks.de/search/en/trial/DRKS00027808. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45475.

Hemophagocytic lymphohistiocytosis in gastric cancer: A rare syndrome for the oncologist. Case report and brief review.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by uncontrolled activation of the immune system. HLH is a reactive mononuclear phagocytic response that occurs in association with a constellation of conditions such as malignancies and infections. The clinical diagnosis of HLH remains challenging because HLH can present with symptoms that significantly overlap with other causes of cytopenia, such as sepsis, autoimmune diseases, hematological cancers, and multiorgan failure. A 50-year-old man went to the emergency room (ER) for hyperchromic urine, melena, gingivorrhagia, and spontaneous abdominal wall hematomas. The first blood tests showed severe thrombocytopenia, alteration of the INR, and consumption of fibrinogen, and therefore, a diagnosis of disseminated intravascular coagulation (DIC) was made. A bone marrow aspirate showed numerous images of hemophagocytosis. With the suspicion of immune-mediated cytopenia, oral etoposide, intravenous immunoglobulin, and intravenous methylprednisolone were administered. Then, a diagnosis of gastric carcinoma was performed with a lymph node biopsy and gastroscopy. On the 30th day, the patient was transferred to the oncology ward of another hospital. On admission, he had serious piastrinopenia, anemia, hypertriglyceridemia, and hyperferritinemia. He was supported with a platelet transfusion and underwent a bone biopsy that showed a picture compatible with myelophthisis from diffuse medullary localization of a carcinoma of gastric origin. A diagnosis of HLH secondary to solid neoplasm was formulated. The patient started chemotherapy with oxaliplatin, calcium levofolinate, 5-fluorouracil bolus, 5-fluorouracil for 48 h (mFOLFOX6), and methylprednisolone. Six days after the third cycle of mFOLFOX6, the patient was discharged with the stabilization of his piastrinopenia condition. The patient continued chemotherapy with an improvement in his clinical conditions and normalization of hematological values. After 12 cycles of mFOLFOX, it was decided to start maintenance chemotherapy with capecitabine but, unfortunately, after only one cycle, HLH reappeared. The oncologist has to keep in mind the existence of HLH when there is an unusual clinical presentation of cancer, such as cytopenia affecting ≥2 lineages and alterations of ferritin and triglycerides other than fibrinogen and coagulation. Increased attention and additional research as well as a close collaboration with hematologists are needed to benefit patients with solid tumors complicated by HLH.

Takotsubo Syndrome (TTS) in Onco-Hematologic Patients: Retrospective Analysis and Focus on the Correlation or Not With Anticancer Drugs. Case Reports and Review of the Literature.

Takotsubo syndrome (TTS) is an uncommon cardiovascular condition also known as stress-induced cardiomyopathy or broken heart disease. The syndrome, characterized by acute non-coronary segmental ventricular dysfunction, commonly occurs as a reaction to severe emotional or physical stress and can cause significant problems. Several classes of chemotherapeutic agents that are known to be cardiotoxic have been shown to be associated with TTS in cancer patients. Describing a case of TTS from chemotherapy and/or monoclonal antibody is important because these drugs are widely used and their temporary or permanent suspension could compromise the success of treatment. The detection and reporting of suspected adverse drug reactions in clinical practice are the foundations of postmarketing surveillance. We performed a retrospective analysis of a large number of patients followed at our cancer centre to identify drugs that could lead to the onset of TTS, focusing our attention on 2 monoclonal antibodies, bevacizumab and rituximab plus chemotherapy. A search was carried out for the word "Takotsubo" in database sources such as in PubMed, in medical oncology, radiology and cardiology electronic clinical records. From October 2007 to March 2021, of the 79,005 patients seen or treated for any kind of malignancy at our institute, 9 had a diagnosis of TTS (4 before and 5 after the diagnosis of malignancy). Only 2 patients had TTS after treatment with the anticancer drugs, bevacizumab and rituximab plus chemotherapy. These two patients were hospitalised, one for subocclusion while the other for pulmonary embolism (PE) with a life threatening condition and in need of intravenous catecholamines. For both patients, an ECG, echocardiography and coronary angiography were performed as well as blood tests with a subsequent diagnosis of TTS and both received cardiological treatment with resolution of the clinical picture. A reassessment of the two cases found that a subocclusion and intravenous catecholamines appeared to be the most likely triggers. In conclusion, TTS is rare in cancer patients. Identifying TTS triggers could be useful because it could induce therapeutic changes.