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Sporadic colorectal cancer has traditionally been viewed as a malignancy of older individuals. However, as the global prevalence of the disease diagnosed in younger individuals (<50 years) is expected to increase within the next decade, greater recognition is now being given to early-onset colorectal cancer. The cause of the predicted rise in prevalence is largely unknown and probably multifactorial. In this Series paper, we discuss the potential underlying causes of early-onset colorectal cancer, the role of energy balance, biological and genomic mechanisms (including microbiome aspects), and the treatment of early-onset colorectal cancer. We have specifically considered the psychosocial challenges of being diagnosed with colorectal cancer at younger age and the potential financial toxicity that might ensue. This Series paper brings a comprehensive review based on the existing data in the hopes of optimising the overall outcomes for patients with early-onset colorectal cancer.

Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15–33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC. Cibisatamab is a T-cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 epsilon chain on T cells. Here the authors report the results of two clinical trials of cibisatamab as monotherapy (NCT02324257) and in combination with atezolizumab (anti-PD-L1; NCT02650713) in patients with CEA-positive solid tumors.

Background Low-grade appendiceal mucinous neoplasm of uncertain malignant potential are poorly understood lesions characterized by extraluminal mucin or fibrosis with neoplastic cells confined to the appendiceal lumen. The purpose of this study is to investigate the clinical and pathologic parameters of these lesions to optimize our understanding and management of these tumors. Methods Subjects with these tumors were identified from the appendiceal tumor databases at the University of Texas MD Anderson Cancer Center. Univariate and multivariate Cox proportional hazards regression analyses assessed relationships between clinicopathologic variables [including age, gender, margin status and serum levels of the tumor markers carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and CA19-9] disease-free survival, postrecurrence survival and overall survival. Results Ninety-eight subjects with this disease were identified. Most patients did not experience disease recurrence after initial appendectomy. At last follow-up, 25 (26 %) had disease recurrence or died. Of the 20 patients who had disease recurrence, 5 (25 %) died, and 15 (75 %) were alive. Disease-free survival was significantly reduced with positive margin status ( p  = 0.02) and elevated serum levels of CEA ( p  < 0.001), CA19-9 ( p  = 0.01), or CA-125 ( p  = 0.002) at the time of appendectomy. The median postrecurrence survival time was 4.7 years and the 5-year postrecurrence survival rate was 41 % (standard error = 18 %). Conclusions Patients with Low-grade appendiceal mucinous neoplasm of uncertain malignant potential who have negative margins and normal tumor marker levels have a lower risk for recurrence. In these patients, expectant management is sufficient. Elevated tumor marker levels at the time of appendectomy marks an increased risk of recurrence or death and signals the need for closer monitoring or intervention.

Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for 8q gains in anti-EGFR treated patients, potentially linked to MYC amplification, a finding further supported by baseline expression analysis. This work adds to the evidence supporting broader evaluation of EGFR and pan-KRAS inhibitor combinations in CRC patients. It also underscores the utility of EGFR ligands as anti-EGFR efficacy biomarkers and provides a rationale for developing ligand blockers to complement and/or improve conventional anti-EGFR therapies in CRC. Deep understanding of mechanisms of resistance to active therapies in metastatic colorectal cancer is crucial for developing more effective treatments. Here, the authors investigate the genomic landscape of 254 patients receiving anti-VEGF and anti-EGFR treatment, identify potential therapeutic vulnerabilities and suggest combination therapies.

ObjectivesColorectal cancer (CRC) is the second-leading cause of cancer deaths globally, with low-income and middle-income countries (LMICs) disproportionately affected. Estimates of CRC rates in LMIC are scarce. We aimed to (1) estimate sex-specific incidence of CRC, (2) estimate temporal trend and (3) determine regional variations of CRC rates on the African continent.DesignSystematic review and meta-analysisMethodsPubMed (MEDLINE), OVID (MEDLINE), Scopus and Cochrane Library databases were systematically searched from inception to 12 December 2020. We included population-based studies that reported the incidence or prevalence estimates of CRC in Africa. Studies not conducted in humans or did not directly report the rates of CRC were excluded. Random effects model was used to pool the estimates. The methodological quality of studies was assessed with the Newcastle-Ottawa Scale.Outcome measuresOverall and sex-specific annual age-standardised incidence rates (ASIR) of CRC per 100 000 population.ResultsThe meta-analysis included 14 studies consisting of 3365 individuals with CRC (mean age, 58 years, 53% male). The overall ASIR of CRC in Africa per 100 000 population was 5.25 (95% CI 4.08 to 6.75). The rates were slightly higher in males (4.76) than in females (4.18), but not significantly different. Subgroup analysis indicated greater point estimates in North Africa (8.66) compared with sub-Saharan Africa (5.91); and higher estimates in Eastern (8.29) and Northern (8.66) Africa compared with Western (3.55) and Southern (3.57) Africa, but not statistically significant. The overall trend in ASIR has remained constant at nearly 5 per 100 000 population for the last 6 decades.ConclusionCRC estimates in Africa are heterogeneous and could be underestimated. High-quality data collection systems such as population-based cancer registries may facilitate accurate estimation of country-specific rates and provide critical information which would be lucrative to the consideration of resources needed for screening, early detection, treatment and improving overall patient outcomes.

Background Colorectal cancer (CRC) is diagnosed during approximately 1 in 13,000 pregnancies and is associated with worse outcomes, including a higher incidence of metastatic disease at diagnosis and reduced maternal survival compared to non-pregnant patients. In this study, we investigated two key contributors to this phenomenon: (1) the increased cancer aggressiveness driven by elevated prolactin (PRL) levels during pregnancy and (2) the limited treatment options available to pregnant CRC patients. Results For the first time, we demonstrate that pregnancy-level PRL directly enhances JAK2/STAT3 and JAG1/NOTCH1 signaling in CRC cells, promoting epithelial-mesenchymal transition (EMT) and cancer stem-like protein expression. We developed and fitted a computational model of the JAK2/STAT3 signaling pathway to our in vitro data, identifying specific nodes within the cascade that are most sensitive to PRL fluctuations during pregnancy. Clinically, we highlight data from CRC cases at Vanderbilt University Medical Center, which underscore the more advanced stage at diagnosis in pregnant patients and the limited treatment options available due to concerns about fetal safety. Additionally, we show that PRL exposure sensitizes CRC cells to TRAIL-induced apoptosis, supporting the potential of TRAIL-based therapies, particularly in liposomal form, as a pregnancy-compatible treatment approach. Conclusions This study provides the first mechanistic link between pregnancy-level prolactin and increased CRC aggressiveness through JAK2/STAT3 and JAG1/NOTCH1 signaling. It also suggests a novel therapeutic direction by demonstrating that PRL sensitizes CRC cells to TRAIL-induced apoptosis. Together, our findings highlight the need for new therapeutic strategies for safe and effective treatment of CRC in pregnant patients. Resumen El cáncer colorrectal (CRC) se diagnostica durante aproximadamente 1 de cada 13.000 embarazos y se asocia con peores pronósticos, incluyendo una mayor incidencia de metastásis en el momento del diagnóstico y una menor supervivencia en comparación con pacientes no embarazadas. En este estudio investigamos dos factores clave que contribuyen a este fenómeno: (1) el aumento de la agresividad de las células cancerígenas causado por los niveles elevados de prolactina (PRL) durante el embarazo, y (2) las limitaciones de las opciones terapéuticas disponibles para pacientes embarazadas con CRC. Resultados Por primera vez demostramos que los niveles de PRL durante el embarazo aumentan la señalización JAK2/STAT3 y JAG1/NOTCH1 en células de CRC, incrementando la transición epitelio-mesénquima (EMT) y la expresión de proteínas asociadas a un fenotipo de células madre cancerosas. Desarrollamos y ajustamos un modelo in silico de la vía de señalización JAK2/STAT3 basado en nuestros datos in vitro, identificando nodos específicos dentro de la cascada que son especialmente sensibles a las fluctuaciones de PRL durante el embarazo. Clínicamente, destacamos datos de casos de CRC del Vanderbilt University Medical Center, que muestran un estadío más avanzado en el diagnóstico en pacientes embarazadas y las opciones terapéuticas restringidas debido a preocupaciones sobre la seguridad fetal. Además, mostramos que la exposición a PRL sensibiliza a las células de CRC a la apoptosis inducida por TRAIL, lo que respalda el potencial de terapias basadas en TRAIL, particularmente en liposomas, como un enfoque terapéutico compatible con el embarazo. Conclusiones Este estudio proporciona el primer vínculo mecanístico entre los niveles de prolactina durante el embarazo y el aumento de la agresividad del CRC a través de la señalización JAK2/STAT3 y JAG1/NOTCH1. También sugerimos una nueva dirección terapéutica al demostrar que la PRL sensibiliza las células de CRC a la apoptosis inducida por TRAIL. En conjunto, el estudio subraya la necesidad de nuevas estrategias terapéuticas para el tratamiento seguro y eficaz del CRC en pacientes embarazadas.

This pilot randomized controlled trial investigated massage therapy for symptomatic relief of chemotherapy-induced peripheral neuropathy (CIPN) to determine the ideal weekly frequency and number of weeks of providing massage. We evaluated the feasibility and initial efficacy of a Swedish massage protocol to treat lower extremity (LE) CIPN. Inclusion criteria: LE neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, with no other attributable causes; ≥ 6 months since last chemotherapy; self-reported neuropathy score ≥ 3, 0–10 scale; age ≥ 18. Participant randomization (2:2:1:1) to one of four groups: LE (2) or head/neck/shoulder (control; 1) massage 3 times (3X) a week for 4 weeks; LE (2) or control (1) massage 2X/week for 6 weeks. Completion rate and the Pain Quality Assessment Scale (PQAS) was measured at baseline and 10 weeks later. 71 patients participated: 77.5% women; 57.7% (breast cancer), and 42.3% (GI cancer); mean age 60.3 y/o (range: 40–77); average > 3 years since last chemotherapy. Massage was deemed feasible: mean completion rates (max = 12) were 8.9 (SD 4.2) for 3X/week and 9.8 (SD 4.0) for 2X/week with no statistically significant differences. There were no statistically significant treatment group interactions in PQAS scores at 10-weeks follow-up. There was a statistically significant treatment schedule main effect for PQAS subscales ( p  < 0.05) at 10 weeks, with lower CIPN symptoms for 3X/week groups versus 2X/week groups. Improvements considered clinically significant favored the LE 3X/week group. Completion rates met pre-defined feasibility criteria. We seemed to observe better outcomes (CIPN symptom reduction) with the more intensive (3X/week for 4 weeks) massage intervention with no differences in adherence, regardless of whether the massage was directly to the CIPN-affected area or not. However, there was some suggestion that the massage program targeting the CIPN-affected area directly provided 3X a week for 4 weeks resulted in the best outcomes.

Background The impact of molecular aberrations on survival after resection of colorectal liver metastases (CLM) in patients with early-age-onset (EOCRC) versus late-age-onset colorectal cancer (LOCRC) is unknown. Methods Patients who underwent liver resection for CLM with known RAS, BRAF and MSI status were retrospectively studied. The prognostic impact of RAS mutations by age was analysed with age as a categorical variable and a continuous variable. Results The study included 573 patients, 192 with EOCRC and 381 with LOCRC. The younger the age of onset of CRC, the greater the negative impact on overall survival of RAS mutations in the LOCRC, EOCRC, and ≤40 years (hazard ratio (HR), 1.64 (95% confidence interval (CI), 1.23–2.20), 2.03 (95% CI, 1.30–3.17), and 2.97 (95% CI, 1.44–6.14), respectively. Age-specific mortality risk and linear regression analysis also demonstrated that RAS mutations had a greater impact on survival in EOCRC than in LOCRC (slope: −4.07, 95% CI −8.10 to 0.04, P  = 0.047, R 2  = 0.08). Conclusion Among patients undergoing CLM resection, RAS mutations have a greater negative influence on survival in patients with EOCRC, more so in patients ≤40 years, than in patients with LOCRC and should be considered as a prognostic factor in multidisciplinary treatment planning.

Circulating angiogenic factors are altered in patients with mCRC receiving bevacizumab. Evaluation of alterations in levels of VEGF ligands may provide insights into possible resistance mechanisms. PlGF, VEGF-A, VEGF-C, and VEGF-D were measured from two cohorts of patients. Sequential plasma samples were obtained from a discovery cohort of 42 patients treated with chemotherapy and bevacizumab. A validation cohort included plasma samples from a cross-sectional of 403 patients prior to chemotherapy, or after progression on a regimen with or without bevacizumab. In the discovery cohort, VEGF-C was increased prior to progression and at progression (+49% and +95%, respectively, p<0.01), consistent with previously reported elevations in PlGF. Levels of VEGF-D were increased (+23%) at progression (p=0.05). In the validation cohort, samples obtained from patients after progression on a regimen with bevacizumab had higher levels of PlGF and VEGF-D (+43% and +6%, p=0.02, p=0.01, respectively) compared to untreated patients, but failed to validate the increase in VEGF-C seen in the first cohort. Patients who progressed on chemotherapy with bevacizumab had significantly elevated levels of PlGF (+88%) but not VEGF-C and VEGF-D compared to patients treated with chemotherapy alone. Elevations of PlGF and VEGF-D appeared transient and returned to baseline with a half-life of 6 weeks. Increases in PlGF and VEGF-D were observed after progression on chemotherapy with bevacizumab. These changes appear to be reversible after discontinuing therapy. These ligands are associated with resistance to bevacizumab-containing chemotherapy in mCRC, but causation remains to be established.