David Páez

Introduction: Colorectal neuroendocrine neoplasms (CR-NENs) are traditionally classified into midgut and hindgut derivatives, a binary classification that potentially oversimplifies the underlying developmental continuum. We investigated whether CR-NEN phenotype and prognosis follow a continuous proximal-to-distal gradient to identify the optimal stratification strategy. Methods: We analyzed 1,158 patients from the RGETNE registry. Anatomical location was modeled as a continuous variable using restricted cubic splines to dissect spatial trends in proliferation (Ki-67), differentiation, and survival. Prognostic performance of the continuous spatial model was formally compared with categorical approaches (right/left/rectum and midgut/hindgut) using the Akaike Information Criterion (AIC). Results: A distinct proximal-to-distal gradient was observed. The continuous spline-based model provided the superior fit for Ki-67 (R2=0.494), outperforming categorical approaches. Anatomical position was an independent prognostic factor, with risk increasing distally in localized disease (HR 1.79; 95% CI 1.31–2.45 for rectum vs. cecum) and significant mortality differences in metastatic disease (p<0.001). Adjuvant benefit was also heterogeneously distributed, being concentrated in distal segments. Despite the biological continuum, the embryological midgut–hindgut dichotomy yielded the most efficient statistical fit (lowest AIC) for predicting clinical recurrence. Conclusion: CR-NENs exhibit a topographical biological continuum. Continuous modeling is optimal for molecular research and characterizing tumor aggressiveness. However, for clinical risk stratification and trial design, the traditional discrete classifications (midgut–hindgut or anatomical segments) remain the most robust, parsimonious, and practically applicable surrogates.

Purpose:Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy.Experimental Design:Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome.Results:One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with “early molecular response” (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P < 0.001) compared with patients with “early molecular progression” (increase in trunk and/or increase in resistant mutations).Conclusions:ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations.See related commentary by Eluri et al., p. 302

Transgender people encounter unique health disparities in oncology. They face substantial barriers in accessing healthcare that are exaggerated by bias/discrimination from healthcare professionals and systems, and socio-economic marginalisation. This review explores the current landscape of cancer risk, screening and management in transgender individuals from a Spanish perspective. Nationwide data are lacking, but estimates from Madrid suggest that 22 per 100,000 individuals are transgender. The needs of the transgender individual for gender-affirming surgeries and gender-affirming hormone therapy may alter the individual’s oncological risk profile and likelihood of receiving appropriate screening, and when diagnosed with cancer may have to be balanced against treatment requirements (e.g., endocrine therapy for breast cancer). There remain unmet needs in the oncological care of the transgender patient. Concerted effort is required to address clinical research gaps, and reform healthcare education and policy, in order to develop inclusive clinical practices that enhance patient care and outcomes.

Histopathological and molecular features have been proposed to hold prognostic information, but few have been validated. The aim of this retrospective study was to validate the Genetic And Morphological Evaluation (‘GAME’) score and assess the impact of histological characteristics on the prognosis in patients with colorectal liver metastases. Data were collected from 176 patients with metastatic colorectal cancer undergoing liver resection at Hospital de la Santa Creu i Sant Pau. Patients were classified into Genetic And Morphological Evaluation score groups and relapse-free survival and overall survival were calculated. Histopathological changes in colorectal liver metastases were documented and prognostic variables were selected to create a post-surgery score, called the Histopathological, Clinical, And Molecular (‘HICAM’) score. Regarding the Genetic And Morphological Evaluation score, the high-risk group had a median relapse-free survival of 8.8 months, compared with 20.5 months for the low-risk group (P = 0.005), and the high-risk group had a median overall survival of 37.8 months, compared with 67.0 months for the low-risk group (P = 0.005). Histological examination of 144 liver samples showed that the desertic immune phenotype was associated with worse overall survival in the multivariable analysis (P = 0.020). The Histopathological, Clinical, And Molecular score variables were age at diagnosis, tumour burden score, carcinoembryonic antigen levels greater than or equal to 20 ng/ml, primary tumour resection, TNM stage at diagnosis, molecular status, histopathological growth patterns, and immune phenotypes of the liver. The high-risk group had a median relapse-free survival of 8.4 months, compared with 20.4 months for the low-risk group (P < 0.001), and a median overall survival of 30.4 months, compared with 105.0 months for the low-risk group (P < 0.001). The Genetic And Morphological Evaluation score was validated as a preoperative prognostic tool to predict candidacy for liver resection. The Histopathological, Clinical, And Molecular score could be useful to assess adjuvant treatment after hepatic resection.

Purpose Renal injury is common in cancer patients and its etiology is multifactorial. Different patterns of renal histological lesions have been described in relation to oncologic treatments, notably acute tubular necrosis and tubulointerstitial nephritis, but also thrombotic microangiopathy (TMA). Methods We report a case of TMA secondary to capecitabine in an 82-year-old woman diagnosed with localized colon adenocarcinoma. Results The patient, with previous normal kidney function, presented with renal impairment during the fourth cycle of chemotherapy. After potential nephrotoxic factors were ruled out, capecitabine was discontinued and a kidney biopsy was performed, which displayed TMA lesions. An improvement in renal function was observed after definitive cessation of cytotoxic chemotherapy. Although rare, renal toxicity in the form of TMA may be associated with the use of cytotoxic agents such as gemcitabine, but there is no reported evidence of its association to capecitabine. Early withdrawal of the drug and nephrology consultation is necessary to prevent irreversible damage. Conclusion We describe, to our knowledge, the first case reported in the literature regarding the possible association of TMA and capecitabine.