Streamlining the diagnostic pathway for Lynch syndrome in colorectal cancer patients: a 10-year experience in a single Italian Cancer Center.

BACKGROUND: Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAFV600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT). METHODS: Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients. RESULTS: Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times. CONCLUSION: Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.

The Multidisciplinary Approach of Rectal Cancer: The Experience of "COMRE Group" Model.

Background: Total mesorectal excision (TME) is the gold standard to treat locally advanced rectal cancer. This monocentric retrospective study evaluates the results of laparotomic, laparoscopic and robotic surgery in "COMRE GROUP" (REctalCOMmittee). Methods: 327 selected stage I-II-III patients (pts) underwent TME between November 2005 and April 2020 for low or middle rectal cancer; 91 pts underwent open, 200 laparoscopic and 36 robotic TME. Of these, we analyzed the anthropomorphic, intraoperative, anatomopathological parameters and outcome during the follow up. Results: The length of hospital stay was significantly different between robotic TME and the other two groups (8.47 ± 3.54 days robotic vs. 11.93 ± 5.71 laparotomic, p < 0.001; 8.47 ± 3.54 robotic vs. 11.10 ± 7.99 laparoscopic, p < 0.05). The mean number of harvested nodes was higher in the laparotomic group compared to the other two groups (19 ± 9 laparotomic vs. 15 ± 8 laparoscopic, p < 0.001; 19 ± 9 laparotomic vs. 15 ± 7 robotic, p < 0.05). Median follow-up was 52 months (range: 1−169). Overall survival was significantly shorter in the open TME group compared with the laparoscopic one (Chi2 = 13.36, p < 0.001). Conclusions: In the experience of the "COMRE" group, laparoscopic TME for rectal cancer is a better choice than laparotomy in a multidisciplinary context. Robotic TME has a significant difference in terms of hospital stay compared to the other two groups.

Early onset metastatic colorectal cancer in patients receiving panitumumab-based upfront strategy: Overall and sex-specific outcomes in the Valentino trial.

Anti-EGFRs plus doublet chemotherapy is considered the optimal upfront option for RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). Early-onset (EO) mCRC has an increasing incidence and its prognostic/predictive role and management is debatable. We performed a post hoc analysis of Valentino study, that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after FOLFOX/panitumumab induction. We assessed the safety and efficacy outcomes in patients stratified for age (<50/≥50 years old). We assessed progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of treatment-related and panitumumab-related adverse events (AEs) and quality of life (QoL). In 229 patients enrolled, 35 (15%) had EO mCRC, with a higher rate of female sex (P = .020) and lower rate of primary tumor resection (P = .001). Median PFS and OS were 10.9 vs 10.8 months (P = .593) and 28.1 vs 27.5 months (P = .865) in patients <50 and ≥50 years old, respectively, with no significant impact of maintenance arm. ORR and disease control rate were 74% vs 65% (P = .337) and 97% vs 81% (P = .013) in patients <50 or ≥50 years old. In younger patients, a trend for increased chemotherapy-related AEs (peculiarly anemia) was shown, while significantly decreased EGFR-related hypomagnesemia and increased skin rash were reported. No significant differences in treatment intensity or QoL were observed. In patients with EO mCRC and RAS wild-type status, we found no differences in terms of survival outcomes based on age when selecting maintenance strategies. Management of treatment-related AEs should consider the differential toxicity profile of age and sex.

Incidence and immunomic features of apyretic COVID-19 in patients affected by solid tumors: a prospective cohort study.

BACKGROUND AND RATIONALE: Little is known about SARS-CoV-2 seroconversion in asymptomatic patients affected by solid cancer, and whether it is associated with specific transcriptomics changes in peripheral blood mononuclear cells (PBMC). METHODS: Patients affected by solid cancer treated in a top comprehensive cancer center in Italy during the first COVID-19 pandemic wave, and negative for COVID-19-symptoms since the first detection of COVID-19 in Italy, were prospectively evaluated by SARS-CoV-2 serology in the period between April 14th and June 23rd 2020. Follow-up serologies were performed, every 21-28 days, until August 23rd 2020. All SARS-CoV-2 IgM + patients underwent confirmatory nasopharyngeal swab (NPS). PBMCs from a subset of SARS-CoV-2 IgM + patients were collected at baseline, at 2 months, and at 7 months for transcriptome sequencing. RESULTS: SARS-CoV-2 serology was performed on 446 of the 466 recruited patients. A total of 14 patients (3.14%) tested positive for at least one SARS-CoV-2 immunoglobulin in the period between April 14th and August 23rd 2020. Incidence of SARS-CoV-2 IgM decreased from 1.48% in the first month of the accrual to 0% in the last month. Viral RNA could not be detected in any of the NPS. PBMC serial transcriptomic analysis showed progressive downregulation of interleukin 6 upregulated signatures, chemokine-mediated signaling and chemokine-chemokine receptor KEGG pathways. B- and T-cell receptor pathways (p-values = 0.0002 and 0.017 respectively) were progressively upregulated. CONCLUSIONS: SARS-CoV-2 seroconversion rate in asymptomatic patients affected by solid cancer is consistent with that of asymptomatic COVID-19 assessed in the general population through NPS at the peak of the first wave. Transcriptomic features over time in IgM + asymptomatic cases are suggestive of previous viral exposure.

Effect of Geriatric Comanagement in Older Patients Undergoing Surgery for Gastrointestinal Cancer: A Retrospective, Before-and-After Study.

OBJECTIVE: To determine the effect of geriatric comanagement on clinical outcomes of older patients undergoing surgery for gastrointestinal cancer. DESIGN: This was a single-center, nonrandomized, before-and-after study, which compared patient outcomes before and after the implementation of geriatric comanagement in an oncological surgery division. SETTING AND PARTICIPANTS: The study included patients aged 70 or older, who were treated for a gastrointestinal cancer at the Oncological Surgery Division of the Policlinico San Martino Hospital (Genoa, Italy). Patients from the control group were treated between January 2015 and October 2018, and the patients who received geriatric comanagement during their stay in the surgical ward were treated between November 2018 and December 2019. METHODS: Patients from both groups received a preoperative comprehensive geriatric assessment in the preoperative phase and were followed according to the Enhanced Recovery After Surgery model in the perioperative period. In the geriatric comanagement group, targeted interventions during daily geriatrician-led ward rounds were performed. Inverse probability weighting was used to adjust estimates for potential baseline confounders. RESULTS: A total of 207 patients were included: 107 in the control group and 90 who received geriatric comanagement. Overall, patients from both groups had similar demographic and clinical characteristics with a median [interquartile range (IQR)] age of 80.0 (77.0, 84.0) years and a pre-frail phenotype [median (IQR) 40-item Frailty Index 0.15 (0.10, 0.26)]. In the geriatric comanagement group, a significant reduction in grade I-V complications (adjusted odds ratio 0.29; 95% CI 0.21-0.40); P < .001) and in 1-year readmissions (adjusted hazard ratio 0.53; 95% CI 0.28-0.98; P < .044) was observed. No difference between the 2 groups in terms of 1-year mortality was detected. CONCLUSIONS AND IMPLICATIONS: Our study supports the implementation of geriatric comanagement in the care of older patients undergoing surgery for gastrointestinal cancer.

Reinduction of an Anti-EGFR-based First-line Regimen in Patients with RAS Wild-type Metastatic Colorectal Cancer Enrolled in the Valentino Study.

BACKGROUND: In patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy. METHODS: We included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan-Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score-based matching was used. RESULTS: Liver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score-matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction. CONCLUSIONS: Reinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical-molecular selection for re-treatments and the need for prospective strategy trials in selected populations.

Variant allele frequency in baseline circulating tumour DNA to measure tumour burden and to stratify outcomes in patients with RAS wild-type metastatic colorectal cancer: a translational objective of the Valentino study.

INTRODUCTION: In patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in comparison with CEA and RECIST-defined sum of target lesions. METHODS: In this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel. For each patient, the gene with the highest VAF in ctDNA was selected. RESULTS: The final cohort included 135 patients. The median VAF was 12.6% (IQR: 2.0-45.2%). Higher VAF was observed in patients with liver metastases and with synchronous metastases presentation. Patients with high VAF had poorer median OS compared to those with low VAF (21.8 vs 36.5 months; HR: 1.82, 95%CI: 1.20-2.76; p = 0.005). VAF outperformed baseline CEA and target lesion diameter in the prognostic stratification and remained significantly correlated with OS (p = 0.003) in a multivariate model. VAF was not significantly correlated with dimensional response and PFS. CONCLUSION: CtDNA measured by VAF is prognostic in patients with RAS wild-type mCRC. Response and PFS after an anti-EGFR-based first-line strategy are independent from initial tumour burden.

Diversity of Cardiologic Issues in a Contemporary Cohort of Women With Breast Cancer.

Background: Women with breast cancer (BC) represent a special population particularly exposed to cardiovascular disease (CVD) risk. However, cardiologic assessment in BC is mostly limited to detection of left ventricular dysfunction cardiotoxicity (LVD-CTX) due to anticancer treatments. Our aim was to comprehensively investigate CV profile and events in a contemporary BC cohort. Methods and Results: Records of BC patients referred for a Cardio-Oncologic evaluation before starting anticancer treatments, between 2016 and 2019, were retrospectively reviewed (n = 508). Information regarding prevalence and control of CV risk factors, and novel CVD diagnoses were extracted. Occurrence of LVD-CTX, CV events other than LVD-CTX and mortality was assessed. Mean age of study population was 64 ± 13 years; 287 patients were scheduled to receive anthracycline and 165 anti-HER2 therapy. Overall, 53% of BC women had ≥2 CV risk factors, and 67% had at least one of arterial hypertension, dyslipidaemia or diabetes mellitus not adequately controlled. Eighteen (4%) patients were diagnosed a previously unknown CVD. Over a mean follow-up of 2.5 ± 1 years, 3% of BC patients developed LVD-CTX, 2% suffered from other CV events and 11% died. CV risk factors were not associated with LVD-CTX, except for family history of CAD. On the contrary, patients with other CV events exhibited a worse CV profile. Those who died more commonly experienced CV events other than LVD-CTX (p = 0.02). Conclusions: BC women show a suboptimal CV risk profile and are at risk of CV events not limited to LVD-CTX. A baseline Cardio-Oncologic evaluation was instrumental to implement CV prevention and to optimize CV therapies.

Safety and Feasibility of Fasting-Mimicking Diet and Effects on Nutritional Status and Circulating Metabolic and Inflammatory Factors in Cancer Patients Undergoing Active Treatment.

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients' nutritional status. We assessed the feasibility and safety of a 5-day "Fasting-Mimicking Diet" (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutritional risk and undergoing active medical treatment received periodic FMD cycles. The body weight, handgrip strength and body composition were monitored throughout the study. Growth factors, adipokines and cyto/chemokines were assessed by ELISA. Ninety patients were enrolled, and FMD was administered every three weeks/once a month with an average of 6.3 FMD cycles/patient. FMD was largely safe with only mild side effects. The patients' weight and handgrip remained stable, the phase angle and fat-free mass increased, while the fat mass decreased. FMD reduced the serum c-peptide, IGF1, IGFBP3 and leptin levels, while increasing IGFBP1, and these modifications persisted for weeks beyond the FMD period. Thus, periodic FMD cycles are feasible and can be safely combined with standard antineoplastic treatments in cancer patients at low nutritional risk. The FMD resulted in reduced fat mass, insulin production and circulating IGF1 and leptin. This trial was registered on Clinicaltrials.gov in July 2018 with the identifier NCT03595540.

TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study.

In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer.

PURPOSE: The routine use of liquid biopsy is not recommended for the choice of initial treatment for patients with metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: We included patients with left-sided, RAS/BRAF wild-type, HER2-negative, and microsatellite stable mCRC, treated with upfront panitumumab/FOLFOX-4 in the Valentino study. We performed amplicon-based genomic profiling of 14 genes in baseline plasma samples and compared these data with tumor tissue ultra-deep sequencing results. Specific gene mutations in circulating tumor DNA (ctDNA) and their clonality were associated with progression-free survival (PFS), overall survival (OS), and radiological dynamics. RESULTS: Ten and 15 of 120 patients had a mutation of RAS and PIK3CA in ctDNA, with a positive concordance with tissue deep sequencing of only 31.3% and 47.1%, respectively. Presence of RAS or PIK3CA mutations in baseline ctDNA was associated with worse median PFS [8 vs. 12.8 months; HR, 2.49; 95% confidence interval (CI), 1.28-4.81; P = 0.007 and 8.5 vs. 12.9 months; HR, 2.86; 95% CI, 1.63-5.04; P < 0.001] and median OS (17.1 vs. 36.5 months; HR, 2.26; 95% CI, 1.03-4.96; P = 0.042 and 21.1 vs. 38.9 months; HR, 2.18; 95% CI, 1.16-4.07; P = 0.015). RAS mutations in ctDNA were associated with worse RECIST response, early tumor shrinkage, and depth of response, while PIK3CA mutations were not. Patients with higher levels of RAS/PIK3CA variant allele fraction (VAF) in ctDNA had the worst outcomes (VAF ≥ 5% vs. all wild-type: median PFS, 7.7 vs. 13.1 months; HR, 4.02; 95% CI, 2.03-7.95; P < 0.001 and median OS, 18.8 vs. 38.9 months; HR, 4.07; 95% CI, 2.04-8.12; P < 0.001). CONCLUSIONS: Baseline ctDNA profiling may add value to tumor tissue testing to refine the molecular hyperselection of patients with mCRC for upfront anti-EGFR-based strategies.

Systemic doxycycline for pre-emptive treatment of anti-EGFR-related skin toxicity in patients with metastatic colorectal cancer receiving first-line panitumumab-based therapy: a post hoc analysis of the Valentino study.

INTRODUCTION: The combination of anti-EGFRs and doublet chemotherapy is considered the optimal upfront option for patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). The prophylactic or reactive treatment with tetracyclines for EGFR inhibitor-induced skin toxicity is currently clinical practice, though non-conclusive results are available. METHODS: We performed a post hoc analysis of the Valentino study that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after the first-line induction, aimed at assessing the safety and efficacy of the administration of a pre-emptive doxycycline prophylaxis for anti-EGFR-related skin toxicity. We assessed the rate of treatment-related and panitumumab-related adverse events (AEs), treatment intensity, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 226 patients, out of the 229 enrolled in the Valentino study, were eligible for the analysis. Overall, 143 (63%) and 83 (37%) patients received or not the antibiotic prophylaxis for skin toxicity. Any grade and G3/4 panitumumab-related AEs were reported in 89% versus 92% (p = 0.650) and 27% versus 27% (p = 1.000) patients who received or not the pre-emptive prophylaxis, respectively. Any grade and G3/4 skin rash occurred in 81% versus 90% (p = 0.085) and 27% versus 25% (p = 0.876) patients receiving or not the prophylaxis, respectively. No significant differences in terms of treatment duration, treatment delays or dose reductions, PFS, and OS were observed in the two sub-populations. CONCLUSION: The adequate management of anti-EGFR-related skin toxicity is fundamental to optimize the outcome of mCRC patients, balancing the survival benefit with patients' quality of life, especially in the first-line setting.

Impact of early tumor shrinkage and depth of response on the outcomes of panitumumab-based maintenance in patients with RAS wild-type metastatic colorectal cancer.

BACKGROUND: In patients with metastatic colorectal cancer (mCRC) receiving highly active first-line combination treatments, early tumor shrinkage (ETS) and depth of response (DoR) are associated with survival, but their influence on outcomes during maintenance therapy is unknown. The Valentino study showed inferior PFS in 229 RAS wild-type mCRC patients randomized to panitumumab plus FOLFOX followed by maintenance with panitumumab vs. panitumumab + 5-FU/LV. PATIENTS AND METHODS: After blinded independent central review of ETS (≥20% reduction of the sum of target lesions) and DoR in patients enrolled in Valentino, the prognostic and predictive role of such parameters was investigated, along with their combination with PRESSING panel (uncommon genomic alterations associated with anti-EGFRs resistance beyond RAS and BRAF). RESULTS: One hundred and ninety-six patients were included (ETS in 132 [67.3%], median DoR: 44.1%). Both ETS and DoR ≥34% were associated with longer mPFS (p = 0.010 and p < 0.001) and mOS (p = 0.006 and p < 0.001). The PFS benefit of 5-FU/LV added to panitumumab maintenance, reported in the study, was independent from ETS and DoR status (interaction tests NS for both PFS and OS). However, outcomes were extremely poor in patients who received single-agent panitumumab and had no-ETS (mPFS and mOS: 7.7 and 18.7 months) or DoR < 34% (mPFS and mOS: 6.5 and 18 months). Combining PRESSING panel ('molecular hyperselection') and response dynamics allowed to stratify both PFS (p < 0.001 and p < 0.001 for ETS and DoR, respectively) and OS (p < 0.001 and p = 0.017 for ETS and DoR, respectively). CONCLUSIONS: ETS and DoR allow on-treatment anticipation of outcomes following an anti-EGFR-based strategy planning de-escalation, and poor radiological response may guide enrolment in crossover strategy trials. As in vivo markers of drug sensitivity, ETS and DoR may be integrated with several patient- and tumor-related factors to wisely drive decision-making on upfront treatment duration and intensity.

Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with panitumumab-based first-line treatment strategy: A pre-specified secondary analysis of the Valentino study.

BACKGROUND: Quality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point. METHODS: PROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item. RESULTS: In arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score. CONCLUSION: In patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity.

The Pan-Immune-Inflammation Value is a new prognostic biomarker in metastatic colorectal cancer: results from a pooled-analysis of the Valentino and TRIBE first-line trials.

BACKGROUND: Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy. METHODS: In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan-Meier method and Cox hazards regression models were used for survival analyses. RESULTS: A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36-2.03, P < 0.001) and worse OS (HR, 2.01; 95% CI, 1.57-2.57; P < 0.001) compared to patients with low PIV. PIV outperformed the other IIBs in the GBR model and in the multivariable models. CONCLUSION: PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy.

A multidisciplinary expert opinion on CINV and RINV, unmet needs and practical real-life approaches.

Introduction: A range of combination chemotherapy regimens are currently used in clinical practice. However, international antiemetic guidelines often only categorize the emetogenic potential of single agents rather than the emetogenicity of combination chemotherapy regimens. To manage the nausea and vomiting induced by antineoplastic combinations, guidelines suggest antiemetics that are appropriate for the component drug with the highest emetogenic potential. Furthermore, antiemetic guidelines generally do not consider the influence of other factors, including individual patient characteristics, on the emetic effects of cancer treatments. Similarly, the emetogenic potential of radiotherapy is stratified only according to the site of radiation, while other factors contributing to emetic risk are overlooked.Areas covered: An Expert Panel was convened to examine unresolved issues and summarize the current clinical research on managing nausea and vomiting associated with combination chemotherapy and radiotherapy.Expert opinion: The panel identified the incidence of nausea and vomiting induced by multi-drug combination therapies currently used to treat cancer at different anatomic sites and by radiotherapy in the presence of other risk factors. Based on these data and the clinical experience of panel members, several suggestions are made for a practical approach to prevent or manage nausea and vomiting due to chemotherapy regimens and radiation therapy.

Development of a long non-coding RNA signature for prediction of response to neoadjuvant chemoradiotherapy in locally advanced rectal adenocarcinoma.

Standard treatment for locally advanced rectal adenocarcinoma (LARC) includes a combination of chemotherapy with pyrimidine analogues, such as capecitabine, and radiation therapy, followed by surgery. Currently no clinically useful genomic predictors of benefit from neoadjuvant chemoradiotherapy (nCRT) exist for LARC. In this study we assessed the expression of 8,127 long noncoding RNAs (lncRNAs), poorly studied in LARC, to infer their ability in classifying patients' pathological complete response (pCR). We collected and analyzed, using lncRNA-specific Agilent microarrays a consecutive series of 61 LARC cases undergoing nCRT. Potential lncRNA predictors in responders and non-responders to nCRT were identified with LASSO regression, and a model was optimized using k-fold cross-validation after selection of the three most informative lncRNA. 11 lncRNAs were differentially expressed with false discovery rate < 0.01 between responders and non-responders to NACT. We identified lnc-KLF7-1, lnc-MAB21L2-1, and LINC00324 as the most promising variable subset for classification building. Overall sensitivity and specificity were 0.91 and 0.94 respectively, with an AUC of our ROC curve = 0.93. Our study shows for the first time that lncRNAs can accurately predict response in LARC undergoing nCRT. Our three-lncRNA based signature must be independently validated and further analyses must be conducted to fully understand the biological role of the identified signature, but our results suggest lncRNAs may be an ideal biomarker for response prediction in the studied setting.

Development of a predictor of one-year mortality in older patients with cancer by geriatric and oncologic parameters.

OBJECTIVES: More than 60% of the new cancer diagnoses are currently made in older adults, a highly heterogeneous population. Reliable and time-saving tools to define older adults' prognosis are needed to inform the oncologist's decisions in routine clinical practice. We sought to define a multi-domain classification tool for the prediction of all-cause one-year mortality in a cohort of older adults with solid tumors. MATERIALS AND METHODS: We conducted a single-centre, prospective study of patients with solid cancer aged 65 or older and with G8 score ≤ 14. All patients underwent a comprehensive geriatric assessment (CGA) before starting their surgical or medical treatment. One-year mortality was recorded. A CGA-based prediction tool of one-year mortality was developed and subsequently validated in two independent training and testing cohorts with a 70/30 split, respectively. RESULTS: 162 patients were enrolled. Mean patient age was 78 ±â€¯5.5 years. Forty-three percent of the patients were men. Colorectal and breast cancer were the most common diagnoses. The clinical variables selected for the development of the new classifier (MetaGENUA®) were: mini-nutritional assessment (MNA), instrumental day life activities (IADL), Cumulative Illness Rating Scale (CIRS), geriatric depression scale (GDS), age, and cancer stage. In our independent validation cohort, MetaGENUA® showed high specificity (0.86) and AUC = 0.71 (95% CI = 0.55-0.87). CONCLUSIONS: MetaGENUA® predicts one-year mortality in older patients with cancer with high specificity. As such, MetaGENUA® is predicted to reveal as a useful tool to guide the oncologist's decisions in clinical practice.

Role of Baseline and Post-Therapy 18F-FDG PET in the Prognostic Stratification of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated with Radium-223.

: Radium-223 dichloride (Ra223) represents the unique bone-directed treatment option that shows an improvement in overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC). However, there is an urgent need for the identification of reliable biomarkers to non-invasively determine its efficacy (possibly improving patients' selection or identifying responders' after therapy completion). 18F-Fluorodeoxyglucose (FDG)-avidity is low in naïve prostate cancer, but it is enhanced in advanced and chemotherapy-refractory mCRPC, providing prognostic insights. Moreover, this tool showed high potential for the evaluation of response in cancer patients with bone involvement. For these reasons, FDG Positron Emission Tomography (FDG-PET) might represent an effective tool that is able to provide prognostic stratification (improving patients selection) at baseline and assessing the treatment response to Ra223. We conducted a retrospective analysis of 28 mCRPC patients that were treated with Ra223 and submitted to bone scan and FDG-PET/CT for prognostic purposes at baseline and within two months after therapy completion. The following parameters were measured: number of bone lesions at bone scan, SUVmax of the hottest bone lesion, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). In patients who underwent post-therapy 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT), (20/28), PET Response Criteria in Solid Tumors (PERCIST), and European Organization for Research and Treatment of Cancer (EORTC) criteria were applied to evaluate the metabolic treatment response. The difference between end of therapy and baseline values was also calculated for Metabolic Tumor Volume (MTV), TLG, prostate-specific antigen (PSA), alkaline phosphatase (AP), and lactate dehydrogenase (LDH) (termed deltaMTV, deltaTLG, deltaPSA, deltaAP and deltaLDH, respectively). Predictive power of baseline and post-therapy PET- and biochemical-derived parameters on OS were assessed by Kaplan-Meier, univariate and multivariate analyses. At baseline, PSA, LDH, and MTV significantly predicted OS. However, MTV (but not PSA nor LDH) was able to identify a subgroup of patients with worse prognosis, even after adjusting for the number of lesions at bone scan (which, in turn, was not an independent predictor of OS). After therapy, PERCIST criteria were able to capture the response to Ra223 by demonstrating longer OS in patients with partial metabolic response. Moreover, the biochemical parameters were outperformed by PERCIST in the post-treatment setting, as their variation after therapy was not informative on long term OS. The present study supports the role of FDG-PET as a tool for patient's selection and response assessment in mCRPC patients undergoing Ra223 administration.