The Role of KRAS Mutation in Colorectal Cancer-Associated Thrombosis.

Venous thromboembolic events (VTE) are common in patients with colorectal cancer (CRC) and represent a significant contributor to morbidity and mortality. Risk stratification is paramount in deciding the initiation of thromboprophylaxis and is calculated using scores that include tumor location, laboratory values, patient clinical characteristics, and tumor burden. Commonly used risk scores do not include the presence of molecular aberrations as a variable. This retrospective study aims to confirm the link between KRAS-activating mutations and the development of VTE in CRC. A total of 166 patients were included in this study. They were split into two cohorts based on KRAS mutational status. We evaluated the frequency and mean time to VTE development stratified by the presence of KRAS mutations. Patients with mutant KRAS had an odds ratio (OR) of 2.758 for VTE compared to KRAS wild-type patients, with an increased risk of thrombosis being maintained in KRAS mutant patients even after adjusting for other known VTE risk factors. Taking into account the results of this study, KRAS mutation represents an independent risk factor for VTE.

Does the Rechallenge with Another CDK 4/6 Inhibitor in Breast Cancer Work? A Case Report and Literature Review.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine therapy are the gold standards for systemic therapy for patients with hormone-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer. Following progression, no prospective randomized data exist to help guide second-line treatment. Moreover, there is a scarcity of data on rechallenge treatment strategies with another CDK4/6 inhibitor after prior limiting toxicity. We report a real-world experience of rechallenging with abemaciclib after the prior reaction of grade 4 liver toxicity to ribociclib, with high transaminases values of more than 27 times the upper limit of normal (ULN) and unexpected grade 3 neutropenia and diarrhea after a few months of abemaciclib. After two years of treatment, the patient had stable oncological disease, with normal complete blood count, hepatic enzymes, and a very good performance status. We believe that our clinical case, along with others gathered from all around the world, will help with the consolidation of an unmet clinical need to readjust the treatment after experiencing toxicity to CDK4/6 inhibitors.

Clinical Insights and Dermatological Recommendations for Non-Melanoma Skin Cancers (NMSCs) in Long-Term Hydroxyurea (HU) Therapy.

Hydroxyurea (HU), an anti-metabolite ribonucleotide reductase inhibitor, is commonly used to treat several myeloproliferative disorders, including polycythemia vera. However, patients receiving long-term treatment with HU may experience a variety of cutaneous side effects, with non-melanoma skin cancers (NMSCs) emerging as the most challenging and destructive. HU-induced carcinogenesis can be attributed to both the drug's mutagenic potential and impaired DNA repair following damage by external triggers such as ultraviolet light. We report a unique case of multiple aggressive NMSCs distributed within sun-exposed areas in an 81-year-old woman receiving chronic therapy with HU for 15 years. The case draws the clinician's attention to the increased incidence of NMSCs in this population and highlights the need for regular dermatologic monitoring. We also elaborate relevant insights and recommendations to assist healthcare providers in managing HU-related NMSCs development and progression.

Local recurrence management of extremity soft tissue sarcoma.

Patients diagnosed with soft tissue sarcoma (STS) present a number of challenges for physicians, due to the vast array of subtypes and aggressive tumor biology. There is currently no agreed-upon management strategy for these tumors, which has led to the ongoing debate surrounding how frequently surveillance scans should be performed following surgery. However, advances in multidisciplinary care have improved patient outcomes over recent years. The early detection of local recurrence reflects a more aggressive tumor, even in association with the same histopathologic entity. Treating the local recurrence of extremity STS is a difficult clinical challenge. The goal should be to salvage limbs when possible, with treatments such as resection and irradiation, although amputation may be necessary in some cases. Regional therapies such as high-intensity, low-dose or interleukin-1 receptor antagonist treatment are appealing options for either definitive or adjuvant therapy, depending on the location of the disease's recurrence. The higher survival rate following late recurrence may be explained by variations in tumor biology. Since long-term survival is, in fact, inferior in patients with high-grade STS, this necessitates the implementation of an active surveillance approach.

Mechanisms of Resistance to CDK4/6 Inhibitors and Predictive Biomarkers of Response in HR+/HER2-Metastatic Breast Cancer-A Review of the Literature.

The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals' responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor's hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance.

Role of Tumor Molecular Profiling With FoundationOne®CDx in Advanced Solid Tumors: A Single-Centre Experience From Romania.

Background In the field of precision oncology, comprehensive genomic profiling tests play a very important role by providing a complex understanding of the molecular characteristics of malignant tumors. Therefore, next-generation sequencing (NGS) has become a valuable tool in various aspects of cancer care from diagnosis and monitoring to treatment selection and personalized cancer treatment. Our aim was to evaluate the role of tumor molecular profiling in tailored treatment selection. Methods In our study, we conducted a retrospective analysis to assess the practicality of utilizing NGS testing in patients with metastatic solid tumors. The genomic testing was performed on blood or tissue samples from a fresh biopsy, less than six months old, and the expression of programmed death-ligand 1 was evaluated by immunohistochemistry. Results A total of 75 tests were performed on 66 patients between 2019 and 2022, with a success rate of 80%. The most common pathologies were gastro-intestinal tract cancer (26%), breast cancer (14%), non-small cell lung cancer (11%), and pancreatic cancer (11%). There were 9% liquid biopsies and 91% tissue biopsies. From all 66 patients tested, 55 had at least one genetic alteration. The most frequent genetic alteration found was TP53 (n=32) followed by KRAS (n=15) and BRCA1/2 (n=12) mutations. There were nine patients tested (14%) that presented a high tumor mutational burden, and only one patient presented high microsatellite instability. There were 37 patients (56%) with actionable alterations found from which 14 received matched therapy and four patients were enrolled in clinical trials. The NGS testing played a significant role in determining the next therapeutic strategy in 20 out of 66 patients (30.3%). Conclusion From all the patients included in our analysis, 83% had at least one mutation that is known to be of pathogenic significance but only 23% received treatment selected by the analysis of the tumor's genome, and only 6% were included in a clinical trial. This moderate success of personalized medicine using NGS testing highlights the importance of evaluating the factors that could lead to further improvement.

Infection and reinfection with SARS-CoV-2 in cancer patients: A cohort study.

COVID-19 reinfection, although a controversial issue, is an important clinical problem in cancer patients and beyond. The present study aimed to identify the risk factors associated with worse outcomes in cancer patients with Covid-19 in both first infection and reinfection and to describe the involvement of vaccines in reinfection outcome. The present study enrolled 85 patients with solid tumors who had Covid-19 infection and had not been previously vaccinated. Classical risk factors associated with worse outcomes in cancer patients with second SARS-Cov infection were considered. The patients were followed up retrospectively, measuring mortality at the first and second infection and the vaccination rate after the first infection. The factors associated with the highest risk of mortality at the first infection were, in order of importance: intensive care unit (ICU) admission, unfavorable performance status, radiologically quantifiable presence of oncological disease, and administration of cytotoxic chemotherapy in the period immediately before infection. The risk factors associated with higher mortality from reinfection were ECOG 3-4 performance status and administration of cytotoxic chemotherapy in the period immediately before infection. In the studied patients, mortality from reinfection was not affected by prior vaccination. Thus, bearing in mind all of these risk factors for poor outcomes in cancer patients with solid tumors presenting with Covid-19 can help the treating oncologists make personalized decisions about patient care during the pandemic.

Desensitization Protocol to Carboplatin: A Technical Report.

Carboplatin is one of the most widely used chemotherapy agents for solid tumors. One of the most common major side effects is the hypersensitivity reaction, and the likelihood of it increases with the number of courses given. Permanent discontinuation of carboplatin is not required if this side effect occurs. Using an effective desensitization protocol, this type of event can be avoided so that the patient continues to benefit from the maximum antitumor effect. This technical report is meant to detail the desensitization protocol designed and followed in the Oncology Clinic of the University Emergency Hospital, Bucharest.

Use of Immune Checkpoint Inhibitors in Elderly Patients With Chronic Kidney Disease and Renal Cell Carcinoma Metastasis of the Parotid Gland: Case Report and Review of the Literature.

Renal cell carcinoma metastasis of the parotid gland is extremely rare, and the present literature review found only 23 cases reported in the last two decades. We present a case of a 75-year-old woman with a colon cancer history who had parotid gland metastasis as the first manifestation of second primary kidney cancer. The presence of multiple comorbidities affected medical decision-making. Therefore the patient was treated primarily with immunotherapy. After four cycles of dual immune checkpoint blockade, this advanced patient still benefited and was changed to nivolumab monotherapy as maintenance therapy.

Correlation Between Pretreatment Neutrophil-to-Lymphocyte Ratio and Programmed Death-Ligand 1 Expression as Prognostic Markers in Non-Small Cell Lung Cancer.

Background The neutrophil-to-lymphocyte ratio (NLR) at baseline treatment is an important marker of systemic inflammation, which is correlated with survival benefits in lung, breast, ovarian, bladder, and colorectal cancer. Programmed death-ligand 1 (PD-L1) expression is a biomarker with discording results regarding survival benefits in lung cancer. In our research, we studied the relationship between these two markers in patients with lung cancer. Methods Patients with stage I, II, III, and IV lung cancer (n = 80) were included in this retrospective study. The NLR baseline was recorded before the initiation of treatment. The NLR cut-off value was 4. PD-L1 expression was determined by immunohistochemical staining. Univariate and multivariate survival analyses were conducted to test their prognostic value. Results NLR proved to be a significant prognostic factor for progression-free survival (PFS) (p=0.002, Log Rank) with a mean PFS of 27.7 months for low NLR patients and 12.8 months for high NLR patients. It was also significant for overall survival (OS) (p=0.007, Log Rank) with a mean OS of 52 months for low NLR patients and 41.6 months for high NLR patients. The prognostic impact of PD-L1 expression on PFS and OS was not statistically significant with a mean PFS of 23.1 months for PD-L1-negative patients and 15.8 months for PD-L1-positive patients (p=0.422, Log Rank). Mean OS was 49 months for PD-L1-negative patients while for PD-L1-positive patients, it was 43.3 months (p=0.550 Log Rank). Regarding the correlation between PD-L1 expression and NLR value, PFS mean survival times were 13.1 months for PD-L1(+)/NLR>4, 15.1 months for PD-L1(-)/NLR>4, 16.4 months for PD-L1(+)/NLR<4 and 27.8 months for PD-L1(-)/NLR<4. This correlation between PFS and the combined PD-L1 and NLR prognostic factor was statistically relevant (p=0.04). For OS, the PD-L1/NLR combined prognostic factor was not statistically relevant (p=0.055). A mean PFS time of 27.8 months was reported for PD-L1(-)/NLR<4 group patients while for the other groups, the mean PFS was 14.9 months (p=0.045). In univariate analysis, the elevated NLR was significantly associated with a decreased PFS time (HR=2.31, 95% CI =1.323- 4.051, p=0.03) as well as OS (HR=3.555, 95% CI=1.310- 9.652, p=0.013). In multivariate analysis, NLR remained statistically significant for PFS (HR=2.160, 95% CI=1.148- 4.062, p=0.013) and OS (HR=4.364, 95% CI=1.474- 12.921, p=0.008) after adjusting for the factors of age, gender, tumor stage, lymph node stage, clinical stage, histology, and PD-L1 expression. PD-L1 expression was not a valid prognostic factor for progression or death in either univariate or multivariate analysis. We also stratified the disease control rate (DCR) depending on PD-L1/NLR combined factor expression. In the PD-L1(-)/NLR<4 group, we had the highest number of partial responses (PRs) and only one complete response (CR) compared to the other groups (p=0.006). Conclusions As the number of patients is limited in the present analysis, it is hypothesized that these two markers can be useful in dividing patients into two prognostic groups: the good prognostic group reunites PD-L1(+)/NLR<4 and PD-L1(-)/NLR<4 and the poor prognostic group reunites PD-L1(+)/NLR>4 and PD-L1(-)/NLR>4.

Prognostic Models for Renal Cell Carcinoma in the Era of Immune Checkpoint Therapy.

With recent advances in oncology, immune checkpoint inhibitors (ICIs) have become a milestone in immuno-oncology. Unfortunately, although ICIs have demonstrated improved clinical efficacy in a broad spectrum of cancers, many patients do not respond to this newer therapy. As a result, it is crucial to identify predictive factors of response to immunotherapy in patients with kidney cancer. This review discusses the research investigating potential biomarkers of response to ICIs in renal cell carcinoma.

Possible Influence of Weight Gain and Creatinine Levels in Predicting Response to Nivolumab: A Multicenter Analysis.

BACKGROUND: Literature suggests that high body mass index can be correlated with better response to immune checkpoint inhibitors. On the other hand, sarcopenia seems to be a negative predictive marker. Materials and methods: The present analysis is a retrospective, multicenter trial that included patients with metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma treated with nivolumab between 2018 and 2020. Patients were stratified by creatinine levels both at treatment initiation and at first follow-up (at three months) and by BMI for the same intervals, as recorded in the patients' charts. Creatinine was considered a surrogate marker for sarcopenia. IBM SPSS version 20 was used for statistical analysis. Results: A total of 57 (n = 57) patients were included in the trial. Overall response rate (ORR) for the entire population was 38.59% (p = 0.02). Patients with BMI lower than 25 had an ORR of 28.5% (p = 0.003), whereas patients with BMI higher than 25 had an ORR of 42.3% (p = 0.002). Patients who gained weight during treatment had a lower probability of having progressive disease (OR = 0.4 [95% CI; 0.4-1.2]), as did patients with creatinine higher than 0.9 (OR = 0.39 [95% CI: 0.13-1.14]). No superiority was found in progression-free survival (PFS) when patients were dichotomized for BMI = 25 or BMI = 18.5. Mean PFS in the BMI under 18.5 group was 10.2 months [95% CI: 5.8-23.1], versus 11.2 for BMI over 18.5 [95% CI: 5.3-25.3], p < 0.03. Mean PFS for the BMI under 25 was 11.2 months [95% CI: 7.2-20.1], vs. 13.3 months [95% CI: 6.4-22] for the BMI over 25, p < 0.001. There were also differences in PFS in the patients with baseline creatinine over 0.9 when compared with under 0.9 values. Mean PFS in the first group was 19.78 months [95% CI: 16.23-22.9] vs. 16.1 [95% CI: 12.2-20.3], p < 0.001. Conclusion: Patients treated with nivolumab who have weight gain during treatment have a better PFS than the ones who do not. Creatinine levels of over 0.9 at treatment initiation also have positive predictive value.