Rectal sparing approach after preoperative radio - and/or Chemo-therapy (ReSARCh): a prospective, multicentre, observational study.

BACKGROUND: Rectal-sparing approaches for patients with rectal cancer who achieved a complete or major response following neoadjuvant therapy constitute a paradigm of a potential shift in the management of patients with rectal cancer, however their role remains controversial. The aim of this study was to investigate the feasibility of rectal-sparing approaches to preserve the rectum without impairing the outcomes. METHODS: This prospective, multicentre, observational study investigated the outcomes of patients with clinical stage II-III mid-low rectal adenocarcinoma treated with any neoadjuvant therapy, and either transanal local excision or watch-and-wait approach, based on tumor response (major or complete) and patient/surgeon choice. The primary endpoint of the study was rectum preservation at a minimum follow-up of two years. Secondary endpoints were overall, disease-free, local and distant recurrence-free, and stoma-free survival at three years. RESULTS: Of 178 patients enrolled in 16 centres, 112 (62.9%) were managed with local excision and 66 (37.1%) with watch-and-wait. At a median (interquartile range) follow-up of 36.1 (30.6-45.6) months, the rectum was preserved in 144 (80.9%) patients. The 3-year rectum-sparing, overall, disease-free, local recurrence-free, distant recurrence-free survival was 80.6% (95%CI 73.9-85.8), 97.6% (95%CI 93.6-99.1), 90.0% (95%CI 84.3-93.7), 94.7% (95%CI 90.1-97.2), and 94.6% (95%CI 89.9-97.2), respectively. The 3-year stoma-free survival was 95.0% (95%CI 89.5-97.6). The 3-year regrowth-free survival in the watch-and-wait group was 71.8% (95%CI 59.9-81.2). CONCLUSIONS: In rectal cancer patients with major or complete clinical response after neoadjuvant therapy, the rectum can be preserved in about 80% of cases, without compromise the outcomes.

Preoperative Intensified Chemoradiation with Intensity-Modulated Radiotherapy and Simultaneous Integrated Boost Combined with Capecitabine in Locally Advanced Rectal Cancer: Long-Term Outcomes of a Real-Life Multicenter Study.

BACKGROUND: Despite the feasibility and promising activity data on intensity-modulated RT and simultaneous integrated boost (IMRT-SIB) dose escalation in preoperative chemoradiation (CRT) for locally advanced rectal cancer (LARC), few data are currently available on long-term outcomes. PATIENTS AND METHODS: A cohort of 288 LARC patients with cT3-T4, cN0-2, cM0 treated with IMRT-SIB and capecitabine from March 2013 to December 2019, followed by a total mesorectal excision (TME) or an organ-preserving strategy, was collected from a prospective database of 10 Italian institutions. A dose of 45 Gy in 25 fractions was prescribed to the tumor and elective nodes, while the SIB dose was prescribed according to the clinical practice of each institution on the gross tumor volume (GTV). Concurrent capecitabine was administered at a dose of 825 mg/m2 twice daily, 7 days a week. The primary objective of the study was to evaluate long-term outcomes in terms of local control (LC), progression-free survival (PFS) and overall survival (OS). The secondary objective was to confirm the previously reported feasibility, safety and efficacy (pCR, TRG1-2 and downstaging rates) of the treatment in a larger patient population. RESULTS: All patients received a dose of 45 Gy to the tumor and elective nodes, while the SIB dose ranged from 52.5 Gy to 57.5 Gy (median 55 Gy). Acute gastrointestinal and hematologic toxicity rates of grade 3-4 were 5.7% and 1.8%, respectively. At preoperative restaging, 36 patients (12.5%) with complete or major clinical responses (cCR or mCR) were offered an organ-preserving approach with local excision (29 patients) or a watch and wait strategy (7 patients). The complete pathologic response rate (pCR) in radically operated patients was 25.8%. In addition, 4 TME patients had pT0N1 and 19 LE patients had pT0Nx, corresponding to an overall pT0 rate of 31.3%. Of the 36 patients selected for organ preservation, 7 (19.5%) required the completion of TME due to unfavorable pathologic features after LE or tumor regrowth during W-W resulting in long-term rectal preservation in 29 of 288 (10.1%) of the total patient population. Major postoperative complications occurred in 14.2% of all operated patients. At a median follow-up of 50 months, the 5-year PFS and OS rates were 72.3% (95% CI: 66.3-77.4) and 85.9% (95% CI: 80.2-90.1), respectively. The 5-year local recurrence (LR) rate was 9.2% (95% CI: 6.0-13.2), while the distant metastasis (DM) rate was 21.3% (95% CI: 16.5-26.5). The DM rate was 24.5% in the high-risk subset compared to 16.2% in the low-intermediate risk group (p = 0.062) with similar LR rates (10% and 8%, respectively). On multivariable analysis, cT4 and TRG3-5 were significantly associated with worse PFS, OS and metastasis-free survival. CONCLUSIONS: Preoperative IMRT-SIB with the moderate dose intensification of 52.5-57.5 Gy (median 55 Gy) and the full dose of concurrent capecitabine confirmed to be feasible and effective in our real-life clinical practice. Organ preservation was shown to be feasible in carefully selected, responsive patients. The favorable long-term survival rates highlight the efficacy of this intensified treatment program. The incorporation of IMRT-SIB with a more effective systemic therapy component in high-risk patients could represent a new area of investigational interest.

Preoperative Radiotherapy with a Simultaneous Integrated Boost Compared to Chemoradiotherapy for cT3-4 Rectal Cancer: Long-Term Results of a Multicenter Randomized Study.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is the standard treatment for T3-4 rectal cancer. Here, we compared image-guided and intensity-modulated RT (IG-IMRT) with a simultaneous integrated boost (SIB) (instead of concomitant chemotherapy) versus CRT in a multi-centric randomized trial. METHODS: cT3-4 rectal cancer patients were randomly assigned to receive preoperative IG-IMRT 46 Gy/23 fractions plus capecitabine 825 mg/m² twice daily (CRT arm) or IG-IMRT 46 Gy/23 fractions with an SIB to the rectal tumor up to a total dose of 55.2 Gy (RTSIB arm). RESULTS: A total of 174 patients were randomly assigned between April 2010 and May 2014. Grade 3 acute toxicities were 6% and 4% in the CRT and RTSIB arms, respectively. The mean fractional change in SUVmax at 5 weeks after completion of preoperative RT were -55.8% (±24.0%) and -52.9% (±21.6%) for patients in the CRT arm and RTSIB arm, respectively (p = 0.43). The pathologic complete response rate was 24% with CRT compared to 14% with RTSIB. There were no differences in 5-year overall survival (OS), progression-free survival (PFS) or local control (LC). CONCLUSIONS: The preoperative RTSIB approach was not inferior to CRT in terms of metabolic response, toxicity, OS, PFS and LC, and could be considered an available option for patients unfit for fluorouracil-based CRT.

Pattern of care for re-irradiation in locally recurrent rectal cancer: a national survey on behalf of the AIRO gastrointestinal tumors study group.

PURPOSE: Radical resection (R0) represents the best curative treatment for local recurrence (LR) rectal cancer. Re-irradiation (re-RT) can increase the rate of R0 resection. Currently, there is a lack of guidelines on Re-RT for LR rectal cancer. The Italian Association of Radiation and clinical oncology for gastrointestinal tumors (AIRO-GI) study group released a national survey to investigate the current clinical practice of external beam radiation therapy in these patients. MATERIAL AND METHODS: In February 2021, the survey was designed and distributed to members of the GI working group. The questionnaire consisted of 40 questions regarding center characteristics, clinical indications, doses, and treatment techniques of re-RT for LR rectal cancer. RESULTS: A total of 37 questionnaires were collected. Re-RT was reported as an option for neoadjuvant treatment in resectable and unresectable disease by 55% and 75% of respondents, respectively. Long-course treatment with 30-40 Gy (1.8-2 Gy/die, 1.2 Gy bid) and hypofractionated regimen of 30-35 Gy in 5 fractions were used in most centers. A total dose of 90-100 Gy as EqD2 dose (α/ß = 5 Gy) was delivered by 46% of the respondents considering the previous treatment. Modern conformal techniques and daily image-guided radiation therapy protocols were used in 94% of centers. CONCLUSION: Our survey showed that re-RT treatment is performed with advanced technology that allow a good management of LR rectal cancer. Significant variations were observed in terms of dose and fractionation, highlighting the need for a consensus on a common treatment strategy that could be validated in prospective studies.

Integration of Cellular and Humoral Immune Responses as an Immunomonitoring Tool for SARS-CoV-2 Vaccination in Healthy and Fragile Subjects.

Cellular and humoral immunity are both required for SARS-CoV-2 infection recovery and vaccine efficacy. The factors affecting mRNA vaccination-induced immune responses, in healthy and fragile subjects, are still under investigation. Thus, we monitored the vaccine-induced cellular and humoral immunity in healthy subjects and cancer patients after vaccination to define whether a different antibody titer reflected similar rates of cellular immune responses and if cancer has an impact on vaccination efficacy. We found that higher titers of antibodies were associated with a higher probability of positive cellular immunity and that this greater immune response was correlated with an increased number of vaccination side effects. Moreover, active T-cell immunity after vaccination was associated with reduced antibody decay. The vaccine-induced cellular immunity appeared more likely in healthy subjects rather than in cancer patients. Lastly, after boosting, we observed a cellular immune conversion in 20% of subjects, and a strong correlation between pre- and post-boosting IFN-γ levels, while antibody levels did not display a similar association. Finally, our data suggested that integrating humoral and cellular immune responses could allow the identification of SARS-CoV-2 vaccine responders and that T-cell responses seem more stable over time compared to antibodies, especially in cancer patients.

Predictive and prognostic value of inflammatory markers in locally advanced rectal cancer (PILLAR) - A multicentric analysis by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Gastrointestinal Study Group.

Background: Patients (pts) affected with locally advanced rectal cancer (LARC) may respond differently to neoadjuvant chemoradiotherapy (nCRT). The identification of reliable biomarkers able to predict oncological outcomes could help in the development of risk-adapted treatment strategies. It has been suggested that inflammation parameters may have a role in predicting tumor response to nCRT and survival outcomes and in rectal cancer, but no definitive conclusion can be drawn at present. The aim of the current study is to evaluate the role of baseline inflammatory markers as prognostic and predictive factors in a large multicentric Italian cohort of LARC pts. Methods: Patients diagnosed with LARC from January 2002 to December 2019 in 9 Italian centers were retrospectively collected. Patients underwent long-course RT with chemotherapy based on fluoropyrimidine ± oxaliplatin followed by surgery. Inflammatory markers were retrieved based on a pre-treatment blood sample including HEI (hemo-eosinophils inflammation index), SII (systemic index of inflammation), NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio) and MLR (monocyte-to-lymphocyte ratio). Outcomes of interest were pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Results: 808 pts were analyzed. pCR rate was 22 %, 5yOS and 5yDFS were 84.0% and 63.1% respectively. Multivariate analysis identified that a NLR cut-off value >1.2 and SII cut-off value >500 could predict pCR (p = 0.05 and 0.009 respectively). In addition to age, extramesorectal nodes and RT dose, MLR >0.18 (p = 0.03) and HEI = 3 (p = 0.05) were independent prognostic factors for DFS. Finally, age, RT dose, MLR with a cut-off >0.35 (p = 0.028) and HEI = 3 (p = 0.045) were independent predictors of OS. Conclusions: Higher values of baseline composite inflammatory markers can serve as predictors of lower pCR rates and worse survival outcomes in LARC patients undergoing nCRT. More reliable data from prospective studies could lead to the integration of these inexpensive and easy-to-derive tools into clinical practice.

Predictive and Prognostic Value of Oncogene Mutations and Microsatellite Instability in Locally-Advanced Rectal Cancer Treated with Neoadjuvant Radiation-Based Therapy: A Systematic Review and Meta-Analysis.

Markers of pathological complete response (pCR) to preoperative radiation-based therapy in locally advanced rectal cancer (LARC) are strongly needed. This meta-analysis aimed at elucidating the predictive/prognostic role of tumor markers in LARC. We systematically reviewed the impact of RAS, TP53, BRAF, PIK3CA, and SMAD4 mutations and MSI status on response (pCR, downstaging) and prognosis (risk of recurrence, survival) in LARC according to PRISMA guidelines and the PICO model. PubMed, Cochrane Library, and Web of Science Core Collection were systematically searched to identify relevant studies published before October 2022. KRAS mutations were significantly associated with the risk of not achieving pCR after preoperative treatment (summary OR = 1.80, 95% CI: 1.23-2.64). This association was even more significant in patients not receiving cetuximab (summary OR = 2.17, 95% CI: 1.41-3.33) than in patients receiving cetuximab (summary OR = 0.89, 95% CI: 0.39-20.05). MSI status was not associated with pCR (summary OR = 0.80, 95% CI: 0.41-1.57). No effect of KRAS mutation or MSI status on downstaging was detected. Meta-analysis of survival outcomes was not possible due to the large heterogeneity among studies in endpoint assessment. The minimum number of eligible studies to assess the predictive/prognostic role of TP53, BRAF, PIK3CA, and SMAD4 mutations was not reached. KRAS mutation, but not MSI status, proved to be a detrimental marker for response to preoperative radiation-based therapy in LARC. Translating this finding into the clinic could improve the management of LARC patients. More data are needed to clarify the clinical impact of TP53, BRAF, PIK3CA, and SMAD4 mutations.

Rectal Sparing Approaches after Neoadjuvant Treatment for Rectal Cancer: A Systematic Review and Meta-Analysis Comparing Local Excision and Watch and Wait.

Local Excision (LE) or Watch and Wait (WW) for patients with complete clinical response or near-complete clinical response after neoadjuvant chemoradiotherapy (nCRT) were proposed to avoid morbidity and impairment of quality of life after rectal resection. The aim of this study is to perform a systematic review of the literature, and to compare rectal-sparing approaches, in terms of rectum-preservation rate, local control, and distant recurrences. A systematic review and meta-analysis were performed of studies published until July 2022 (PROSPERO, registration CRD42022341480), and the quality of evidence was assessed using a GRADE approach. Seven retrospective studies and one prospective trial were included. In six studies, patients were treated with standard long-course nCRT, and in two with Total Neoadjuvant Therapy (TNT). Overall, there were 213 and 188 patients in WW and LE group, respectively, and no difference was found between WW and LE when considering rectum-preservation rate (OR 0.80 95%CI 0.31-2.01, p = 0.63), local disease (OR 1.60 95%CI 0.75-3.42, p = 0.22), locoregional failure (OR 0.85 95%CI 0.20-3.66, p = 0.83) and distant recurrence (OR 0.76 95%CI 0.37-1.55, p = 0.45). Studies directly comparing WW and LE are still lacking, even though no differences between WW and LE in terms of rectum-preservation, local control, and distant recurrences have been found.

External validation of a composite bio-humoral index in anal cancer patients undergoing concurrent chemoradiation.

BACKGROUND AND PURPOSE: A prognostic scoring system based on laboratory inflammation parameters, [Hemo-Eosinophils-Inflammation (HEI) index], including baseline hemoglobin level, the systemic inflammatory index and eosinophil count was recently proposed in patients with squamous cell carcinoma of the anus (ASCC). HEI was shown to discriminate disease-free (DFS) and overall (OS) survival in ASCC patients treated with concurrent chemoradiation (CRT). We tested the accuracy of the model on a multicentric cohort for external validation. MATERIALS AND METHODS: Patients treated with CRT were enrolled. The Kaplan-Meier curves for DFS and OS based on HEI risk group were calculated and the log-rank test was used. Cox proportional hazards models were used to assess the prognostic factors for DFS and OS. The exponential of the regression coefficients provided an estimate of the hazard ratio (HR). For model discrimination, we determined Harrell's C-index, Gönen & Heller K Index and the explained variation on the log relative hazard scale. RESULTS: A total of 877 patients was available. Proportional hazards were adjusted for age, gender, tumor-stage, and chemotherapy. Two-year DFS was 77 %(95 %CI:72.0-82.4) and 88.3 %(95 %CI:84.8-92.0 %) in the HEI high- and low- risk groups. Two-year OS was 87.8 %(95 %CI:83.7-92.0) and 94.2 %(95 %CI:91.5-97). Multivariate Cox proportional hazards model showed a HR = 2.02(95 %CI:1.25-3.26; p = 0.004) for the HEI high-risk group with respect to OS and a HR = 1.53(95 %CI:1.04-2.24; p = 0.029) for DFS. Harrel C-indexes were 0.68 and 0.66 in the validation dataset, for OS and DFS. Gonen-Heller K indexes were 0.67 and 0.71, respectively. CONCLUSION: The HEI index proved to be a prognosticator in ASCC patients treated with CRT. Model discrimination in the external validation cohort was acceptable.

An Exceptional Response to Dostarlimab in Mismatch Repair Deficient, Microsatellite Instability-High and Platinum Refractory Endometrial Cancer.

Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency.

A Panel of Tumor Biomarkers to Predict Complete Pathological Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer.

Pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients is related to a favorable prognosis. The identification of early biomarkers predictive of pathological complete response would help optimize the multimodality management of the patients. A panel of 11 tumor-related proteins was investigated by immunohistochemistry in the pretreatment biopsy of a group of locally advanced rectal cancer patients to identify early biomarkers of pathological complete response to neoadjuvant chemoradiotherapy. A mono-institutional retrospective cohort of 95 stage II/III locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy and surgery was selected based on clinicalpathological characteristics and the availability of a pretreatment tumor biopsy. Eleven selected protein marker expression (MLH1, GLUT1, Ki67, CA-IX, CXCR4, COX2, CXCL12, HIF1, VEGF, CD44, and RAD51) was investigated. The optimal cutoff values were calculated by receiver operating characteristic curve analysis. Classification and regression tree analysis was performed to investigate the biomarker interaction. Patients presenting either Ki-67 or HIF1 or RAD51 below the cutoff value, or CXCR4 or COX2 above the cutoff value, were more likely to get a pathological complete response. Classification and regression tree analysis identified three groups of patients resulting from the combination of Ki-67 and CXCR4 expression. Patients with high expression of Ki-67 had the lowest chance to get a pathological complete response (18%), as compared to patients with low expression of both Ki-67 and CXCR4 (29%), and patients with low Ki-67 and high CXCR4 expression (70%). Pretreatment Ki-67, CXCR4, COX2, HIF1, and RAD51 in tumor biopsies are associated with pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. A combined evaluation of Ki-67 and CXCR4 would increase their predictive potential. If validated, their optimal cutoff could be used to select patients for a tailored multimodality treatment.

A Pattern of Care Report on the Management of Patients with Squamous Cell Carcinoma of the Anus-A Study by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Gastrointestinal Tumors Study Group.

Background and objectives: The diagnosis and therapy of squamous cell carcinoma of the anus may vary significantly in daily clinical practice, even if international guidelines are available. Materials and Methods: We conducted a pattern of care survey to assess the management of patients with anal cancer in Italy (38 questions). We analyzed 58 questionnaires. Results: Most of the respondents work in public and/or university hospitals (75.8%) in northern Italy (65.5%). The majority (88.0%) treat less than 20 patients/year. Common examinations for diagnosis and staging are anorectal endoscopy (84.5%), computed tomography scan (86.2%) and pelvic magnetic resonance imaging (MRI) (96.5%). The most frequently prescribed dose to primary tumor is 50-54 Gy (46.5-58.6%) for early stage disease and 54-59.4 Gy (62.1-32.8%) for locally advanced cases. Elective volumes are prescribed around 45 Gy (94.8%). Most participants use volumetric intensity modulated radiotherapy (89.7%) and a simultaneous integrated boost (84.5%). Concurrent radiotherapy, 5-fluorouracil and mitomycin is considered the standard of care (70.6%). Capecitabine is less frequently used (34.4%). Induction chemotherapy is an option for extensive localized disease (65.5%). Consolidation chemotherapy is rarely used (18.9%). A response evaluation is conducted at 26-30 weeks (63.9%) with a pelvic MRI (91.4%). Follow-up is generally run by the multidisciplinary tumor board (62.1%). Conclusions: Differences were observed for radiotherapy dose prescription, calling for a consensus to harmonize treatment strategies.

Radiotherapy with Intensity-Modulated (IMRT) Techniques in the Treatment of Anal Carcinoma (RAINSTORM): A Multicenter Study on Behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology) Gastrointestinal Study Group.

A multi-institutional retrospective study was conducted to evaluate the pattern of care and clinical outcomes of anal cancer patients treated with intensity-modulated radiotherapy (IMRT) techniques. In a cohort of 987 patients, the clinical complete response (CR) rate (beyond 6 months) was 90.6%. The 3-year local control (LC) rate was 85.8% (95% CI: 84.4-87.2), and the 3-year colostomy-free survival (CFS) rate was 77.9% (95% CI: 76.1-79.8). Three-year progression-free survival (PFS) and overall survival (OS) rates were 80.2% and 88.1% (95% CI: 78.8-89.4) (95% CI: 78.5-81.9), respectively. Histological grade 3 and nodal involvement were associated with lower CR (p = 0.030 and p = 0.004, respectively). A statistically significant association was found between advanced stage and nodal involvement, and LC, CFS, PFS, OS and event-free survival (EFS). Overall treatment time (OTT) ≥45 days showed a trend for a lower PFS (p = 0.050) and was significantly associated with lower EFS (p = 0.030) and histological grade 3 with a lower LC (p = 0.025). No statistically significant association was found between total dose, dose/fraction and/or boost modality and clinical outcomes. This analysis reports excellent clinical results and a mild toxicity profile, confirming IMRT techniques as standard of care for the curative treatment of anal cancer patients. Lymph node involvement and histological grade have been confirmed as the most important negative prognostic factors.

Feasibility and Oncological Outcome of Preoperative Chemoradiation With IMRT Dose Intensification for Locally Advanced Esophageal and Gastroesophageal Cancer.

PURPOSE: To explore the feasibility and efficacy of a dose intensification with Intensity Modulated Radiation Therapy and Simultaneous Integrated Boost (IMRT-SIB) in locally advanced esophageal and gastroesophageal cancer (GEJ). METHODS AND MATERIALS: We retrospectively analyzed a series of 69 patients with esophageal or GEJ cancer treated at our Institute, between 2016 and 2019, with preoperative IMRT and SIB up to 52.5-54 Gy in 25 fractions in 5 weeks and concurrent carboplatin (AUC2) and paclitaxel (50 mg/m2), as in the CROSS regimen. RESULTS: All patients completed the planned IMRT-SIB program with a median of four (range 1-5) cycles of concurrent paclitaxel/carboplatin. Compliance to IMRT-SIB was 93%, whereas 54% of patients received four to five cycles and 87% at least three cycles of concurrent carboplatin/paclitaxel. Grade 3 toxicity was reported in 19% of patients. Complete clinical response (cCR) was achieved in 48%, and 13% had disease progression after chemoradiation (CRT). Overall, 49% of patients underwent surgery; reasons for non-operation included cCR in cervical tumor location (10%) or cCR and patient decision (13%). A pathologic complete response (pCR) was achieved in 44% of resected patients. Postoperative complications and mortality rates were 21 and 6%, respectively. At a median follow-up of 12 months (6-25), 2-year overall and progression-free (PFS) survival rates were 81 and 54%, respectively. No difference in PFS by histologic type in operated patients was reported. Non-operated cCR patients had higher PFS, including cervical locations and selected cCR patients who decided for non-operation (75 vs 30%, p < 0.01). CONCLUSION: The study reported favorable results in safety and feasibility of the IMRT-SIB dose intensification in our preoperative CRT program. The toxicity was acceptable, allowing a high compliance to intensified radiation doses with dose reduction of concurrent paclitaxel/carboplatin in some patients. The high rate of cCR and pCR suggested this intensified program is effective in the preoperative CRT and, for selected responsive patients, in the non-operative approach to esophageal and GEJ cancer. The 2-year survival rates were promising. A prospective study is being planned to confirm these observations.

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy.

Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group (n = 378), a set of SMAD3 polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity >55% (OR:10.36, p = 0.0004), or moderate/high intensity (OR:5.20, p = 0.0038), or an H-score≥1 (OR:9.84, p = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48, p = 0.0093), a longer OS (HR:0.65, p = 0.0307), and a trend for longer PFS (HR:0.75, p = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45, p = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens.

Germline and Somatic Pharmacogenomics to Refine Rectal Cancer Patients Selection for Neo-Adjuvant Chemoradiotherapy.

Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the standard of care for patients with Locally Advanced Rectal Cancer (LARC). Current selection for nCRT is based on clinical criteria regardless of any molecular marker. Pharmacogenomics may be a useful strategy to personalize and optimize nCRT in LARC. This review aims to summarize the most recent and relevant findings about the role of germline and somatic pharmacogenomics in the prediction of nCRT outcome in patients with LARC, discussing the state of the art of their application in the clinical practice. A systematic literature search of the PubMed database was completed to identify relevant English-language papers published up to January 2020. The chemotherapeutic backbone of nCRT is represented by fluoropyrimidines, mainly metabolized by DPD (Dihydro-Pyrimidine Dehydrogenase, DPYD). The clinical impact of testing DPYD*2A, DPYD*13, c.2846A > T and c.1236G > A-HapB3 before a fluoropyrimidines administration to increase treatment safety is widely acknowledged. Other relevant target genes are TYMS (Thymidylate Synthase) and MTHFR (Methylene-Tetrahydro-Folate Reductase), whose polymorphisms were mainly studied as potential markers of treatment efficacy in LARC. A pivotal role of a TYMS polymorphism in the gene promoter region (rs34743033) was reported and was pioneeringly used to guide nCRT treatment in a phase II study. The pharmacogenomic analysis of other pathways mostly involved in the cellular response to radiation damage, as the DNA repair and the activation of the inflammatory cascade, provided less consistent results. A high rate of somatic mutation in genes belonging to PI3K (Phosphatidyl-Inositol 3-Kinase) and MAPK (Mitogen-Activated Protein Kinase) pathways, as BRAF (V-raf murine sarcoma viral oncogene homolog B1), KRAS (Kirsten Rat Sarcoma viral oncogene homolog), NRAS (Neuroblastoma RAS viral (v-ras) oncogene homolog), PIK3CA (Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase, Catalytic Subunit Alpha), as well as TP53 (Tumor Protein 53) was reported in LARC. Their pharmacogenomic role, already defined in colorectal cancer, is under investigation in LARC with promising results concerning specific somatic mutations in KRAS and TP53, as predictors of tumor response and prognosis. The availability of circulating tumor DNA in plasma may also represent an opportunity to monitor somatic mutations in course of therapy.

Beyond MicroRNAs: Emerging Role of Other Non-Coding RNAs in HPV-Driven Cancers.

Persistent infection with high-risk Human Papilloma Virus (HPV) leads to the development of several tumors, including cervical, oropharyngeal, and anogenital squamous cell carcinoma. In the last years, the use of high-throughput sequencing technologies has revealed a number of non-coding RNA (ncRNAs), distinct from micro RNAs (miRNAs), that are deregulated in HPV-driven cancers, thus suggesting that HPV infection may affect their expression. However, since the knowledge of ncRNAs is still limited, a better understanding of ncRNAs biology, biogenesis, and function may be challenging for improving the diagnosis of HPV infection or progression, and for monitoring the response to therapy of patients affected by HPV-driven tumors. In addition, to establish a ncRNAs expression profile may be instrumental for developing more effective therapeutic strategies for the treatment of HPV-associated lesions and cancers. Therefore, this review will address novel classes of ncRNAs that have recently started to draw increasing attention in HPV-driven tumors, with a particular focus on ncRNAs that have been identified as a direct target of HPV oncoproteins.

Immunogenetic markers in IL17F predict the risk of metastases spread and overall survival in rectal cancer patients treated with neoadjuvant chemoradiotherapy.

BACKGROUND AND PURPOSE: The role of the immune system in tumor response to chemo-radiotherapy (CRT) is an emerging issue. This work aimed at identifying predictive and prognostic immunogenetic variants in LARC patients after preoperative (po)-CRT and surgery. MATERIALS AND METHODS: A set of 192 polymorphisms in 34 candidate genes involved in the regulation of the immune response signalling network, was selected and analyzed in 370 LARC patients treated with po-CRT and surgery, split into a Test Set (n = 233) and a Validation Set (n = 137). Immunogenetic markers were selected based on a concordant significant effect on 2-year relapse-free survival (2-yrRFS) (bootstrapped P < 0.05) in both patients Sets. The effect of the selected immunogenetic variants on 5-year metastases-free (5yrMFS), 5-year disease-free (5yrDFS), and 10-year overall (10yrOS) survival was tested in the entire Set of 370 patients. RESULTS: Two immunogenetic IL17F (IL17F-rs641701 and IL17F-rs9463772) markers predictive of 2yrRFS, 5yrDFS, 5yrMFS, and 10yrOS were identified. The combination of tumor regression grade (TRG) and patients genotype for IL17F-rs641701 and IL17F-rs9463772 allowed the identification of subgroups of patients with differential prognosis in term of both 5yrDFS (HR 11.29, P-value <0.001, and HR 5.86, P-value = 0.001, respectively) and 10yrOS (HR 7.07, P-value = 0.005, and HR 6.05, P-value = 0.002, respectively). CONCLUSION: IL17F-rs641701 and IL17F-rs9463772 were highlighted as promising immunogenetic markers significantly associated with the prognosis of LARC patients. After a prospective validation of the herein reported findings, the combination of TRG and patients genotype should be considered to provide additional stratification criteria for the selection of a personalized multimodality treatment.

Electron radiotherapy (IOERT) for applications outside of the breast: Dosimetry and influence of tissue inhomogeneities.

PURPOSE: The purpose of study is to investigate the dosimetry of electron intraoperative radiotherapy (IOERT) of the Intraop Mobetron 2000 mobile LINAC in treatments outside of the breast. After commissioning and external validation of dosimetry, we report in vivo results of measurements for treatments outside the breast in a large patient cohort, and investigate if the presence of inhomogeneities can affect in vivo measurements. METHODS AND MATERIALS: Applicator factors and profile curves were measured with a stereotactic diode. The applicators factors of the 6 cm flat and beveled applicators were also confirmed with radiochromic films, parallel-plate ion chamber and by an external audit performed with ThermoLuminescent Dosimeters (TLDs). The influence of bone on dose was investigated by using radiochromic films attached to an insert equivalent to cortical bone, immersed in the water phantom. In vivo dosimetry was performed on 126 patients treated with IOERT using metal oxide-silicon semiconductor field effect transistors (MOSFETs) placed on the tumor bed. RESULTS: Relatively small differences were found among different detectors for measurements of applicator factors. In the external audit, the agreement with the TLD was mostly within ±0.2%. The largest increase of dose due to the presence of cortical bone insert was +6.0% with energy 12 MeV and 3 cm applicator. On average, in vivo dose was significantly (+3.1%) larger than prescribed dose. CONCLUSION: IOERT in applications outside the breast results in low discrepancies between in vivo and prescribed doses, which can be also explained with the presence of tissue inhomogeneity.

Direct health-care cost of head and neck cancers: a population-based study in north-eastern Italy.

Improvements in prognosis of head-and-neck squamous cell carcinoma (HNSCC) have paralleled with an increase in health-care costs, so that an economic evaluation is of growing importance. Presently, most of the evidence is from insurance-based studies in the USA. Between 2007 and 2010, 879 HNSCC patients were identified through the population-based cancer registry of the Friuli Venezia Giulia region, including 266 oral, 187 oropharyngeal, 136 hypopharyngeal, and 290 laryngeal cancers. Health-care costs from diagnosis to treatment initiation and in the following 2 years were retrieved through a record linkage with the regional health data warehouse. This database collected comprehensive health information on all resident citizens. Generalized linear models with a gamma distribution and log-link function were applied to model costs. The average health-care cost from diagnosis up to 2 years after treatment initiation was €20,184 (95% confidence interval: €19,634 - 20,733). Heterogeneity emerged according to cancer site, elective treatment, and retreatment for cancer persistence/recurrence (no: €13,896; yes: €24,599; p < 0.001). An advanced stage was associated with increased costs stage (I: €12,969; II: €18,276; III: €26,229; IV: €25,574; p < 0.001) as the result of treatment complexity and elevated frequency of patients retreatment due to recurrence. These findings further support strategies to diagnose patients at an earlier cancer stage and the accurate definition of diagnostic and treatment pathways, to start treating patients when radical unimodal approach is still feasible. Besides the advantage in prognosis due to timely curative treatments, this would reduce the economic burden of cancer treatment.