Effects of a Personalized Diet on Nutritional Status and Renal Function Outcome in Nephrectomized Patients with Renal Cancer.

Nutritional therapy (NT) based on a controlled protein intake represents a cornerstone in managing chronic kidney disease (CKD). However, if a CKD patient is at the same time affected by cancer, oncologists and nutritionists tend to suggest a dietary regimen based on high protein intake to avoid catabolism and malnutrition. International guidelines are not clear when we consider onco-nephrological patients and, as a consequence, no clinical shared strategy is currently applied in clinical practice. In particular, no precise nutritional management is established in nephrectomized patients for renal cell carcinoma (RCC), a specific oncological cohort of patients whose sudden kidney removal forces the remnant one to start a compensatory mechanism of adaptive hyperfiltration. Our study aimed to investigate the efficacy of a low-normal-protein high-calorie (LNPHC) diet based on a Mediterranean model in a consecutive cohort of nephrectomized RCC patients using an integrated nephrologist and nutritionist approach. A consecutive cohort of 40 nephrectomized RCC adult (age > 18) patients who were screened for malnutrition (malnutrition screening tool, MST < 2) were enrolled in a tertiary institution between 2020 and 2022 after signing a specific informed consent form. Each patient underwent an initial nephrological and nutritional evaluation and was subsequently subjected to a conventional CKD LNPHC diet integrated with aproteic foods (0.8 g/Kg/die: calories: 30-35 kcal per kg body weight/die) for a period of 6 months (±2 months). The diet was structured after considering eGFR (CKD-EPI 2021 creatinine formula), comorbidities, and nutritional status. MST, body mass index (BMI), phase angle (PA), fat mass percentage (FM%), fat-free mass index (FFMI), body cell mass index (BCMI), extracellular/intracellular water ratio (ECW/ICW), extracellular matrix/body cell mass ratio (ECM/BCM), waist/hip circumference ratio (WHC), lab test exams, and clinical variables were examined at baseline and after the study period. Our results clearly highlighted that the LNPHC diet was able to significantly improve several nutritional parameters, avoiding malnutrition and catabolism. In particular, the LNPHC diet preserved the BCM index (delta on median, ΔM + 0.3 kg/m2) and reduced the ECM/BCM ratio (ΔM - 0.03 *), with a significant reduction in the ECW/ICW ratio (ΔM - 0.02 *), all while increasing TBW (ΔM + 2.3% *). The LNPHC diet was able to preserve FFM while simultaneously depleting FM and, moreover, it led to a significant reduction in urea (ΔM - 11 mg/dL **). In conclusion, the LNPHC diet represents a new important therapeutic strategy that should be considered when treating onco-nephrological patients with solitary kidney due to renal cancer.

Platinum dose in neoadjuvant therapy for triple-negative breast cancer: A systematic review and network meta-analysis.

INTRODUCTION: There are multiple neoadjuvant regimens, including platinum agents for triple-negative breast cancer (TNBC), each with a different safety profile, outcome, and pathologic complete response rate (pCR%). We performed a systematic review and network meta-analysis to compare the efficacy and safety of different platinum-based neoadjuvant CT treatments for TNBC. METHODS: Bibliographic databases (PubMed, Embase, and Cochrane Library) were searched from their inception to October 31, 2022. Eligible studies were randomized clinical trials that evaluated the addition of carboplatin or cisplatin to standard neoadjuvant CT for TNBC. The primary endpoints were pCR rates and DFS/EFS, while the secondary endpoints were grade (G)3-4 hematological toxicity and OS. RESULTS: Thirteen trials involving 3154 patients comparing six treatments (carboplatin AUC 5, carboplatin AUC 6, carboplatin AUC 2, carboplatin AUC 1.5, cisplatin 75 mg/m2, and standard anthracycline-and/or taxane-based CT) were identified. Based on the most effective treatments added to neoadjuvant CT, carboplatin AUC 2 was associated with the least improvement in pCR% (RR, 1.49; 95%CI, 1.23, 1.8), carboplatin AUC 6 was associated with similar improvement in pCR% (RR 1.58, 95%CI, 1.35, 1.84) and carboplatin AUC 5 with the highest improvement in pCR% (RR 2.23, 95%CI, 1.6,32). The treatment associated with the most considerable improvement in DFS when added to neoadjuvant CT was carboplatin AUC 5 (HR 0.36, 95%CI 0.18, 0.73). It was also better than AUC 6 and AUC 2 (HR= 0.45, 95%CI 0.21-0.96 and HR=0.48, 95%CI 0.23-0.98). All schedules exhibited similar outcomes in terms of OS; however, only AUC 2 demonstrated a significant improvement compared to the no-platinum arms. Neutropenia, thrombocytopenia, and anemia G3-4 were significantly increased by carboplatin AUC 6. CONCLUSIONS: Based on this network meta-analysis, carboplatin AUC 5 added to standard neoadjuvant CT may provide substantial pCR and DFS benefits with a low toxicity risk compared to other carboplatin doses.

Quantitative and Qualitative Radiological Assessment of Sarcopenia and Cachexia in Cancer Patients: A Systematic Review.

Sarcopenia, an extremely common condition in cancer patients, is described as a progressive and generalized musculoskeletal disorder that is associated with an increased likelihood of adverse outcomes, including falls, fractures, physical disability, and mortality. By contrast, cachexia is defined as a syndrome characterized by weight loss with the concomitant loss of muscle and/or fat mass. Cancer cachexia leads to functional impairment, reduced physical performance, and decreased survival, and is often accompanied by cancer progression and reduced response to therapy. The literature states that cancer patients with cachexia or sarcopenia have many more complications than patients without these conditions. The interplay between physiologic sarcopenia and cancer cachexia is, in part, responsible for the complexity of studying wasting disorders in the cancer population, particularly in the geriatric population. For these reasons, a comprehensive assessment of the body composition and physical function of these patients is necessary. There are several modalities adapted to measure skeletal muscle mass, such as dual-energy X-ray absorptiometry (DEXA), bioelectrical impedance analysis (BIA), computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US). The gold standard for the measurement of quantitative and qualitative changes in body composition in patients with cancer is the analysis of tissue density using a CT scan. However, this technique remains poorly implemented in clinical practice because of the use of ionizing radiation. Similarly, DEXA, MRI, and US have been proposed, but their use is limited. In this review, we present and compare the imaging techniques that have been developed so far for the nutritional assessment of cancer patients.

Corrigendum: Aromatase inhibitors: the journey from the state of the art to clinical open questions.

[This corrects the article DOI: 10.3389/fonc.2023.1249160.].

Artificial Intelligence for Precision Oncology of Triple-Negative Breast Cancer: Learning from Melanoma.

Thanks to new technologies using artificial intelligence (AI) and machine learning, it is possible to use large amounts of data to try to extract information that can be used for personalized medicine. The great challenge of the future is, on the one hand, to acquire masses of biological data that nowadays are still limited and, on the other hand, to develop innovative strategies to extract information that can then be used for the development of predictive models. From this perspective, we discuss these aspects in the context of triple-negative breast cancer, a tumor where a specific treatment is still lacking and new therapies, such as immunotherapy, are under investigation. Since immunotherapy is already in use for other tumors such as melanoma, we discuss the strengths and weaknesses identified in the use of immunotherapy with melanoma to try to find more successful strategies. It is precisely in this context that AI and predictive tools can be extremely valuable. Therefore, the discoveries and advancements in immunotherapy for melanoma provide a foundation for developing effective immunotherapies for triple-negative breast cancer. Shared principles, such as immune system activation, checkpoint inhibitors, and personalized treatment, can be applied to TNBC to improve patient outcomes and offer new hope for those with aggressive, hard-to-treat breast cancer.

Different Chemotherapy Regimens and Pathologic Complete Response in Triple-Negative Breast Cancer: An Updated Network Meta-Analysis of Phase 3 Trials.

Background and Objectives: Currently, the standard treatment for non-metastatic triple-negative breast cancer (TNBC) consists of a systemic neoadjuvant (or perioperative) anthracycline plus taxane-based chemotherapy, delivered either sequentially or concomitantly. We performed a network meta-analysis (NMA) to compare the relative efficacy of different neoadjuvant treatments for TNBC in terms of pathologic complete response (pCR). Materials and Methods: The MEDLINE, Embase, and Cochrane databases were searched from database inception to 1 November 2023. Randomized clinical trials were used that enrolled adults with stage I-III TNBC and provided data on pCR defined as residual ypT0/TisN0M0. Between-group comparisons were estimated using risk ratios (RRs) with 95% credible intervals (95% CrIs). The primary outcome was the pCR rate. Results: 1129 citations were screened, and 12 randomized clinical trials were included. In Bayesian comparisons, all regimens, except anthracycline/taxanes plus gemcitabine or capecitabine, resulted in a higher pCR than the standard regimen in both direct and indirect comparisons. In particular, immunotherapy-based regimens resulted in more than double the pCR compared to historical regimens (RR = 2.3, 95% CI 1.9-2.9) and ranked as being the optimal regimen with a probability of 97%. Disease-free survival was better for immune checkpoint inhibitor-based chemotherapy (HR = 0.36, 95% 1.21-2.09) than for historical regimens. Conclusion: This meta-analysis confirmed that incorporating immunotherapy with neoadjuvant platinum-based chemotherapy is the best option to guarantee remarkable pathologic downstaging and improve clinical outcomes.

Basosquamous Carcinoma: Comprehensive Clinical and Histopathological Aspects, Novel Imaging Tools, and Therapeutic Approaches.

Basosquamous carcinoma (BSC), an uncommon and aggressive nonmelanoma skin cancer exhibiting characteristics ranging from basal cell carcinoma (BCC) to squamous cell carcinoma (SCC), is a subject of controversy in terms of its classification, pathogenesis, histologic morphology, biologic behavior, prognosis, and management. This narrative review is based on an electronic search of English-language articles in PubMed that included the terms "basosquamous carcinoma" and/or "metatypical carcinoma of the skin" in their titles. The review aims to succinctly present and assess current data on the epidemiology, clinical presentation, dermoscopic, LC-OCT, and histopathologic characteristics, as well as the genetics and management of BSC, providing insight into this intriguing entity. As a conclusion, dermoscopy, deep incisional biopsies, and immunohistologic techniques should be applied in clinically suspicious lesions to achieve an early diagnosis and better prognosis of this tumor. Surgical treatments, including wide excision and Mohs' micrographic surgery, remain the treatment of choice. Finally, Hedgehog pathway inhibitors and checkpoint inhibitors, must be thoroughly investigated with large controlled trials, since they may offer an alternative solution to irresectable or difficult-to-treat locally advanced cases of basosquamous carcinoma.

A Multidisciplinary Approach to Patients with Psoriasis and a History of Malignancies or On-Treatment for Solid Tumors: A Narrative Literature Review.

Psoriasis is a chronic immune-mediated disease that is linked to an increased risk of cancer. Although numerous studies have explored whether neoplasms are concurrent conditions or are induced by psoriasis, a definitive definition remains elusive. In this study, we conducted a comprehensive narrative literature review to offer practical guidance to oncologists and dermatologists regarding the initiation and discontinuation of biologics for psoriasis. The findings indicate that a customized approach is recommended for each patient, and that a history of malignancies does not constitute an absolute contraindication for biologics. Growing evidence supports the treatment of selected patients, emphasizing a nuanced assessment of benefits and risks. There is a lack of data specifying a safe timeframe to initiate biologics following a neoplasm diagnosis due to influences from cancer-related and patient-specific characteristics impacting prognosis. Some patients may continue anti-psoriasis therapy during cancer treatments. Enhanced comprehension of the biological mechanisms in cancer progression and the immune microenvironment of psoriasis holds promise for refining therapeutic strategies. In conclusion, a personalized treatment approach necessitates collaboration between oncologists and dermatologists, considering factors such as cancer prognosis, psoriasis clinical manifestations, patient characteristics, and preferences when making treatment decisions.

Baseline Values of Circulating IL-6 and TGF-ß Might Identify Patients with HNSCC Who Do Not Benefit from Nivolumab Treatment.

BACKGROUND: The immunotherapy of head and neck cancer induces a limited rate of long-term survivors at the cost of treating many patients exposed to toxicity without benefit, regardless of PD-L1 expression. The identification of better biomarkers is warranted. We analyzed a panel of cytokines, chemokines and growth factors, hereinafter all referred to as 'cytokines', as potential biomarkers in patients with head and neck cancer treated with nivolumab. MATERIALS AND METHODS: A total of 18 circulating cytokines were analyzed. Samples were gathered at baseline (T0) and after 3 courses of nivolumab (T1) in patients with relapsed/metastatic disease. The data extracted at T0 were linked to survival; the comparison of T0-T1 explored the effect of immunotherapy. RESULTS: A total of 22 patients were accrued: 64% current heavy smokers, 36% female and 14% had PS = 2. At T0, ROC analysis showed that IL-6, IL-8, IL-10 and TGF-ß were higher in patients with poor survival. Cox analysis demonstrated that only patients with the IL-6 and TGF-ß discriminate had good or poor survival, respectively. Longitudinal increments of CCL-4, IL-15, IL-2 and CXCL-10 were observed in all patients during nivolumab treatment. CONCLUSION: In this small population with poor clinical characteristics, this study highlights the prognostic role of IL-6 and TGF-ß. Nivolumab treatment is associated with a positive modulation of some Th1 cytokines, but it does not correlate with the outcome.

SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials.

PURPOSE: In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. EXPERIMENTAL DESIGN: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. RESULTS: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). CONCLUSIONS: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.

Cemiplimab in Ultra-Octogenarian Patients with Cutaneous Squamous Cell Carcinoma: The Real-Life Experience of a Tertiary Referral Center.

BACKGROUND: The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, paralleling the aging of the population. cSCC predominantly affects chronically sun-exposed areas, such as the head and neck region. At our tertiary center, a multidisciplinary approach to non-melanoma skin cancer is provided for locally advanced cSCC. METHODS: We retrospectively revised all patients with locally advanced/metastatic cSCC treated with anti-PD1 antibody (Cemiplimab) at our Institution from January 2020 to March 2023 (minimum follow-up of 4 months on treatment). RESULTS: Overall, we consecutively treated 20 ultra-octogenarian patients, of whom 15 were males and 5 were females (median age: 86.9 years). Despite age, a median number of concomitant drugs, and comorbidities, efficacy, and safety were superimposable with the available literature. No patients reported treatment-related adverse events of grade 3 or higher. Grade 2 adverse events were reported in 25% of patients. Overall, the response rate was 65%, with 50% partial responses and 20% long-lasting stable disease. The median duration of response was 14 months. The G8 elderly score was assessed in all patients, and the median score was 12 (range 9-14). CONCLUSIONS: Among ultra-octogenarian patients, a clinical benefit from Cemiplimab was obtained in most, including tumor shrinkage and pain relief. Cemiplimab confirmed its effectiveness in elderly patients in a real-life setting, with no new safety concerns.

Prognostic Value of HER2-low Status in ER+ Early Breast Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND/AIM: Low human epidermal growth factor receptor 2 expression (HER2-low: 1+/2+ by immunohistochemistry without HER2 amplification) is emerging as defining a specific breast cancer (BC) subgroup owing to its distinct biological features. However, its prognostic role has not been confirmed in clinical practice. We conducted a systematic review and meta-analysis to determine the prognostic role of HER2-low status in patients with estrogen receptor-positive (ER+) early BC. MATERIALS AND METHODS: We searched PubMed, EMBASE, and the Cochrane Library for prospective or retrospective studies that reported data on overall (OS) or disease-free (DFS) survival for HER2-low compared to HER2-negative BC. Data were pooled using hazard ratios (HR) with confidence intervals (CI) for OS/DFS of HER2-low vs. HER2-negative subgroups according to the random-effects model. OS was the primary outcome measure, and DFS and pathological complete response were the secondary endpoints. RESULTS: An analysis was made of 25 studies collected, including 34,965 patients with HER2-low BC. A HER2-low status was associated with an HR for OS of 0.83 (95% CI=0.76-0.9, p<0.0.01). Similarly, a pooled HR of 0.89 (95% CI=0.840.94, p<0.0.01) showed that patients with HER2-low BC had an increased DFS. Pathological complete response was significantly lower in HER2-low BC in 13 studies (OR=0.72, 95% CI=0.58-0.91; p<0.01). CONCLUSION: Based on these data, HER2-low status should be identified as a potential prognostic factor in early stage ER+ BC. This should be taken into account when considering treatment in (neo)adjuvant settings, and it should be a potential stratification factor in future investigations.

Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study.

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.

Comparison of different second line treatments for metastatic pancreatic cancer: a systematic review and network meta-analysis.

BACKGROUND: In metastatic pancreatic ductal adenocarcinoma (mPDAC), first line treatment options usually include combination regimens of folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX or mFOLFIRINOX) or gemcitabine based regimens such as in combination with albumin-bound paclitaxel (GEM + nab-PTX). After progression, multiple regimens including NALIRI + 5-FU and folinic acid, FOLFIRINOX, 5-FU-based oxaliplatin doublets (OFF, FOLFOX, or XELOX), or 5-FU-based monotherapy (FL, capecitabine, or S-1) are considered appropriate by major guidelines. This network meta-analysis (NMA) aimed to compare the efficacy of different treatment strategies tested as second-line regimens for patients with mPDAC after first-line gemcitabine-based systemic treatment. METHODS: Randomized phase II and III clinical trials (RCTs) were included if they were published or presented in English. Trials of interest compared two active systemic treatments as second-line regimens until disease progression or unacceptable toxicity. We performed a Bayesian NMA with published hazard ratios (HRs) and 95%confidence intervals (CIs) to evaluate the comparative effectiveness of different second-line therapies for mPDAC. The main outcomes of interest were overall survival (OS) and progression free survival (PFS), secondary endpoints were grade 3-4 toxicities. We calculated the relative ranking of agents for each outcome as their surface under the cumulative ranking (SUCRA). A higher SUCRA score meant a higher ranking for efficacy outcomes. RESULTS: A NMA of 9 treatments was performed for OS (n = 2521 patients enrolled). Compared with 5-FU + folinic acid both irinotecan or NALIRI + fluoropyrimidines had a trend to better OS (HR = 0.76, 95%CI 0.21-2.75 and HR = 0.74, 95%CI 0.31-1.85). Fluoropyrimidines + folinic acid + oxaliplatin were no better than the combination without oxaliplatin. The analysis of treatment ranking showed that the combination of NALIRI + 5-FU + folinic acid was most likely to yield the highest OS results (SUCRA = 0.7). Furthermore, the NMA results indicated that with the highest SUCRA score (SUCRA = 0.91), NALIRI + 5-FU + folinic acid may be the optimal choice for improved PFS amongst all regimens studied. CONCLUSIONS: According to the NMA results, NALIRI + 5-FU, and folinic acid may represent the best second-line treatment for improved survival outcomes in mPDAC. Further evidence from prospective trials is needed to determine the best treatment option for this group of patients.

The Tumor Microenvironment and the Estrogen Loop in Thyroid Cancer.

Thyroid cancer (TC) cells employ multiple signaling pathways, such as PI3K/AKT/mTOR and RAS/Raf/MAPK, fostering cell proliferation, survival and metastasis. Through a complex interplay with immune cells, inflammatory mediators and stroma, TC cells support an immunosuppressive, inflamed, pro-carcinogenic TME. Moreover, the participation of estrogens in TC pathogenesis has previously been hypothesized, in view of the higher TC incidence observed among females. In this respect, the interactions between estrogens and the TME in TC could represent a relevant, unexplored area of research. We thereby collectively reviewed the available evidence concerning the potential carcinogenic role of estrogens in TC, specifically focusing on their crosstalk with the TME.

Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

The oligometastatic setting in HNSCC: A critical review by the Rete Oncologica Piemonte e Valle d'Aosta multidisciplinary team.

INTRODUCTION: The oligometastatic disease is a low burden metastatic disease that might still benefit from curable treatment. Squamous cell carcinoma of the head and neck (HNSCC) is a complex group of malignancies, with high rates of loco-regional recurrences. Distant metastases are less frequent, and a single or few deposits are often observed (oligometastatic disease). The optimal management of oligometastatic HNSCC remains to be defined. MATERIALS AND METHODS: Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. RESULTS: This paper contains a narrative report and a critical discussion of the available evidence on the management of oligometastatic HNSCC patients, with a focus on metastasis-directed therapy (MDT), particularly stereotactic ablative radiotherapy (SABR). CONCLUSIONS: in line with literature data, the multidisciplinary evaluation emerged as the key element in the management of oligometastatic HNSCC patients.

Baseline Cytokine Profile Identifies a Favorable Outcome in a Subgroup of Colorectal Cancer Patients Treated with Regorafenib.

Metastatic colorectal cancer is frequently associated with poor clinical conditions that may limit therapeutic options. Regorafenib is a small molecule approved for the treatment of metastatic colorectal cancer, but it is hampered by significative toxicities. Moreover, only a relatively limited number of patients benefit from the treatment. Therefore, the identification of reliable markers for response is an unmet need. Eighteen cytokines, selected based on their prevalent Th1 or Th2 effects, were collected. Peripheral blood samples were gathered at baseline in 25 metastatic colorectal cancer patients treated with regorafenib. Data extracted have been linked to progression-free survival. ROC identified the best cytokines associated with outcome. The relative value of the selected cytokines was determined by PCA. Data analysis identified 8 cytokines (TGF-ß, TNF-α, CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21), used to create a signature (TGF-ß, TNF-α high; CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21 low) corresponding to patients with a significantly longer progression-free survival. This report suggests that the analysis of multiple cytokines might identify a cytokine signature related to a patient's outcome that is able to recognize patients who will benefit from treatment. If confirmed, future studies, also based on different drugs, using this approach and including larger patient populations, might identify a signature allowing the a priori identification of patients to be treated.

Clinical Significance of Molecular Subtypes in Western Advanced Gastric Cancer: A Real-World Multicenter Experience.

In recent years, the molecular subtyping of gastric cancer has led to the identification of novel clinically relevant biomarkers as well as promising therapeutic targets. In parallel, the advent of checkpoint inhibitors has expanded treatment options beyond conventional chemotherapy. Compelling evidence has shown unprecedented efficacy results for anti-PD1-based therapies in the molecular subgroups of dMMR/MSI-h, EBV+ and PD-L1 CPS+ patients, to the point that these are granted approval for gastric cancer adenocarcinoma (AGC) in several countries. Despite this, cytotoxic chemotherapy remains the only treatment choice for the considerable proportion of biomarkers-negative patients. In this context, little is known about the association between subtypes-defining biomarkers (HER2, MMR/MSI, PD-L1, and EBV) and the efficacy of standard chemotherapy in non-Asian AGC. Here, we aimed to investigate the prevalence, the clinic-pathologic features, and the impact on treatment outcome of clinical molecular subtypes in a new-diagnosed Western cohort of AGC.