Application of the NSE score (Neurology-Stability-Epidural compression assessment) to establish the need for surgery in spinal metastases of elderly patients: a multicenter investigation.

PURPOSE: This retropective multicentric study aims to investigate the clinical applicability of the NSE score in the elderly, to verify the role of this tool as an easy help for decision making also for this class of patients. METHODS: All elderly patients (> 65 years) suffering from spinal metastases undergoing surgical or non-surgical treatment at the authors' Institutions between 2015 and 2022 were recruited. An agreement group (AG) and non-agreement group (NAG) were identified accordingly to the agreement between the NSE score indication and the performed treatment. Neurological status and axial pain were evaluated for both groups at follow-up (3 and 6 months). The same analysis was conducted specifically grouping patients older than 75 years. RESULTS: A strong association with improvement or preservation of clinical status (p < 0.001) at follow-up was obtained in AG. The association was not statistically significant in NAG at the 3-month follow-up (p 1.00 and 0.07 respectively) and at 6 months (p 0.293 and 0.09 respectively). The group of patients over 75 years old showed similar results in terms of statistical association between the agreement group and better outcomes. CONCLUSION: Far from the need or the aim to build dogmatic algorithms, the goal of preserving a proper performance status plays a key role in a modern oncological management: functional outcomes of the multicentric study group showed that the NSE score represents a reliable tool to establish the need for surgery also for elderly patients.

Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile.

BACKGROUND: Targeted agents, such as antiangiogenic drugs (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., rucaparib), have been shown to improve outcomes in patients with newly diagnosed or recurrent ovarian cancer. Evidence suggests that combinations of these two classes of targeted agents may result in synergistic antitumor activity. OBJECTIVE: The phase I portion of MITO 25 was designed to determine the maximum tolerated dose, pharmacokinetics, and the safety profile of rucaparib when administered in combination with bevacizumab as maintenance treatment for patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. METHODS: This was a single-arm, phase I dose-escalation study. Cohorts of three patients were recruited to receive increasing rucaparib doses of 400 mg, 500 mg, or 600 mg twice daily for 28 days. Bevacizumab 15 mg/kg was administered at day 1 every 21 days. RESULTS: We enrolled nine patients. Two patients in the rucaparib 600-mg group had four grade 3 treatment-emergent adverse events: increased in alanine aminotransferase and aspartate aminotransferase levels, depression, and hallucinations. These were deemed to be dose-limiting toxicities related to rucaparib. Because these dose-limiting toxicities occurred in the 600-mg group and affected more than one in three patients, the maximum tolerated dose for rucaparib was considered 500 mg twice daily when combined with bevacizumab 15 mg/kg at day 1 every 21 days. There were no new safety concerns from using the combination. No substantial difference in pharmacokinetic parameters was found between the cohorts or in the pharmacokinetic profiles of rucaparib administered alone or with bevacizumab with respect to historical controls. CONCLUSIONS: The maximum tolerated dose of rucaparib is 500 mg twice daily when co-administered with bevacizumab. The plasma concentration-time profiles of rucaparib in combination with bevacizumab suggest no pharmacokinetic interactions between the drugs. The randomized phase II portion of MITO 25 will further investigate rucaparib maintenance treatment with or without bevacizumab in patients with newly diagnosed stage III-IV ovarian cancer who responded to carboplatin-paclitaxel chemotherapy with or without bevacizumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03462212; registered March 2018.

Primary conization overcomes the risk of developing local recurrence following laparoscopic radical hysterectomy in early stage cervical cancer.

OBJECTIVE: To investigate whether primary conization might overcome the risk of local dissemination in patients undergoing laparoscopic radical hysterectomy. METHODS: Consecutive data of 262 patients with early stage cervical cancer were retrieved: 88 women had conization followed by radical hysterectomy. A propensity-matched comparison (1:1) was carried out in order to compare laparoscopy and open surgery. Accumulating data highlighted that minimally invasive surgery has been associated with higher recurrence rates and worse overall survival than open surgery in women with early stage cervical cancer. RESULTS: Data of 35 paired patients (total 70 patients) were analyzed. No between-group differences in baseline, disease, and pathological variables were observed. Patients undergoing laparoscopy correlated with lower blood loss (50 [range 30-100] vs 150 [range 50-500] mL; P<0.001) and shorter length of stay (3 ± 0.8 vs 5.4 ± 1.4 days; P<0.001) compared to open surgery. One local recurrence was observed per group (P=1.00). Type of surgical approach did not influence site of recurrence (P=1.00) or survival outcomes, in terms of 10-year disease-free (P=0.549, log-rank test) and overall survivals (P=0.615, log-rank test). CONCLUSIONS: The data show that primary conization might overcome the risk of local recurrence after laparoscopic radical hysterectomy in early stage cervical cancer. Further prospective evidence is needed.

Prognostic role of early PSA drop in castration resistant prostate cancer patients treated with abiraterone acetate or enzalutamide.

BACKGROUND: Previous studies demonstrated a predictive value of prostate-specific antigen (PSA) kinetics for treatment outcome. Our retrospective study evaluates the prognostic role of early PSA drop in metastatic castration resistant prostate cancer (mCRPC) patients receiving abiraterone acetate (AA) or enzalutamide (E). METHODS: All mCRPC patients treated with AA or E at the San Luigi Hospital in Orbassano between 2010 and 2018 and at the Ordine Mauriziano Hospital in Turin between 2014 and 2018 were included in this retrospective study. Only patients with an early PSA (measured 28-60 days after the beginning of the treatment) were included in the analysis. Patients were divided in early responders and non-early responders according to early PSA response (drop≥50% from baseline). Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were performed. RESULTS: Of 144 patients with early PSA value, 61 (42.4%) patients received E (docetaxel-naïve 42, post-docetaxel 19) and 83 (57.6%) received AA (docetaxel-naïve 44, post-docetaxel 39). Seventy-five (52.1%) patients achieved early PSA drop. In docetaxel-naïve setting (N.=86), median PFS was 14.9 (with early PSA drop) vs. 8.8 months (without early PSA drop, P=0.001). In post-docetaxel setting (N.=58) median PFS was 11.9 vs. 4.5 months (P<0.001). Globally, median PFS was 14.9 vs. 6.3 months in patients with and without early PSA drop, respectively (P<0.001). In docetaxel-naïve setting, patients with early PSA drop had a median OS of 39.5 vs. 18.8 months (P=0.12). In post-docetaxel setting median OS was 29.6 vs. 10.7 months (P=0.01). Comprehensively, median OS was 31.9 vs. 16.3 (P=0.002) in patients with and without early PSA drop, respectively. At multivariate analysis, early PSA drop confirmed an independent association with PFS (HR 0.21; 95% CI: 0.12-0.38, P<0.001) and OS (HR 0.25; 95% CI: 0.12-0.50, P<0.001). CONCLUSIONS: mCRPC patients treated with AA or E, in docetaxel-naïve or post-docetaxel setting, with early PSA drop had significantly better OS and PFS.

Quality of life assessment and reporting in colorectal cancer: A systematic review of phase III trials published between 2012 and 2018.

BACKGROUND: In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials. METHODS: We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals. RESULTS: Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints. CONCLUSIONS: QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.

Quality of life analysis in lung cancer: A systematic review of phase III trials published between 2012 and 2018.

OBJECTIVES: We previously reported that quality of life (QoL) is not included among trial endpoints and QoL results are underreported in a significant proportion of phase III oncology trials. Here we describe QoL adoption, reporting and methodology of QoL analysis in lung cancer trials. MATERIALS AND METHODS: We selected all primary publications of lung cancer phase III trials assessing anticancer drugs published between 2012 and 2018 by 11 major journals. RESULTS: 122 publications were included. In 39 (32.0%) publications, QoL was not listed among endpoints: in 10/17 (58.8%) early stage/locally advanced NSCLC, in 15/54 (27.8%) first-line of advanced NSCLC; in 10/41 (24.4%) second and further lines of advanced NSCLC, in 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. Out of 83 trials including QoL among endpoints, QoL results were absent in 36 primary publications (43.4%). Proportion of trials without QoL results in primary publication increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p = 0.005). Overall, QoL data were not available in 75/122 (61.5%) primary publications, due to the absent endpoint or unpublished results. QoL data were lacking in 48/68 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement comparing 2012-2015 vs. 2016-2018. CONCLUSION: QoL is not assessed or published in many phase III lung cancer trials, a setting where QoL value should be highly considered, due to high symptom burden and generally limited life expectancy. Timely inclusion of results in primary publications is worsening in recent years.

Quality-of-Life Assessment and Reporting in Prostate Cancer: Systematic Review of Phase 3 Trials Testing Anticancer Drugs Published Between 2012 and 2018.

Quality of life (QoL) is not included among the end points in many studies, and QoL results are underreported in many phase 3 oncology trials. We performed a systematic review to describe QoL prevalence and heterogeneity in QoL reporting in recently published prostate cancer phase 3 trials. A PubMed search was performed to identify primary publications of randomized phase 3 trials testing anticancer drugs in prostate cancer, issued between 2012 and 2018. We analyzed QoL inclusion among end points, presence of QoL results, and methodology of QoL analysis. Seventy-two publications were identified (15 early-stage, 20 advanced hormone-sensitive, and 37 castration-resistant prostate cancer [CRPC]). QoL was not listed among study end points in 23 studies (31.9%) (40.0% early stage, 40.0% advanced hormone sensitive, and 24.3% CRPC). QoL results were absent in 15 (30.6%) of 49 primary publications of trials that included QoL among end points. Overall, as a result of absent end point or unpublished results, QoL data were lacking in 38 (52.8%) primary publications (53.3% early stage, 55.0% in advanced hormone sensitive, and 51.4% in CRPC). The most commonly used QoL tools were Functional Assessment of Cancer Therapy-Prostate (FACT-P) (21, 53.8%) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (14, 35.9%); most common methods of analysis were mean changes or mean scores (28, 71.8%), time to deterioration (14, 35.9%), and proportion of patients with response (10, 25.6%). In conclusion, QoL data are lacking in a not negligible proportion of recently published phase 3 trials in prostate cancer, although the presence of QoL results is better in positive trials, especially in CRPC. The methodology of QoL analysis is heterogeneous for type of instruments, analysis, and presentation of results.

Systematic Review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy.

Aim: Reporting toxicities of targeted therapies (TTs) and immunotherapy in oncology requires special attention. Materials & methods: We identified TTs and immunotherapies approved by the US FDA for solid malignancies in the adult population. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials guidance. Results: We identified 81 trials (>45,000 patients). The experimental drug was studied as single agent in 51% of the cases; setting of disease was mainly (95%) advanced/metastatic. Lowest scores in adverse event (AE) description regarded: reporting recurrent/late toxicities and duration of the AEs (>90%), time of occurrence and indication of all-grade AEs (>75%). Conclusion: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AE descriptions should be a priority in ongoing trials.

RECIST 1.1 criteria predict recurrence-free survival in advanced ovarian cancer submitted to neoadjuvant chemotherapy.

OBJECTIVE: Neoadjuvant chemotherapy plus interval debulking surgery is growing treatment strategy for advanced ovarian cancer patients with unresectable disease. Here, we aimed to assess predictors of surgical unresectability and survival of patients submitted to neoadjuvant chemotherapy plus interval debulking surgery. METHODS: Data of consecutive 193 patients undergoing neoadjuvant chemotherapy plus interval debulking surgery were retrospectively evaluated in four Italian oncologic centers. RECIST 1.1 guidelines were used to assess response to neoadjuvant chemotherapy. Survival outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: Overall, 155 (80.3%) and 38 (19.7%) patients had optimal and non-optimal cytoreduction at the time of interval debulking surgery. Via multivariate analysis, age (OR: 2.87 (95%CI: 1.29, 6.36) per 10-year increase) and radiological response to neoadjuvant chemotherapy (OR: 48.1 (95%CI: 6.33, 365.3)) impact on the inability to perform a complete cytoreduction. Patients having complete or partial response experienced a significant better disease-free survival than patients having stable or progressive disease at radiological examination (median disease-free survival 16.8 vs. 11.0 months; HR: 0.42 (95%CI: 0.09, 0.78); p = .001). Radiological response did not predict for overall survival (p = .719). CONCLUSIONS: RECIST1.1 response criteria might be helpful to predict surgical resectability and disease-free survival of advanced stage ovarian cancer patients undergoing neoadjuvant chemotherapy plus interval debulking surgery.

FOLFOX activity in a rare case of metastatic colonic adenocarcinoma of the tongue: a case report.

BACKGROUND: Adenocarcinomas of the oral cavity are rare neoplasms, and only four cases of primary colonic adenocarcinoma of the tongue have ever been described in literature. Very few information about chemotherapy sensitiveness of this type of neoplasia is available, with only one regimen that showed some activity in a metastatic patient. CASE PRESENTATION: We describe the case of a patient bearing a metastatic colonic adenocarcinoma of the tongue submitted to a first-line chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen). After chemotherapy the patient obtained the complete disappearance of the primitive neoplasia located in the body of the tongue, and a tumor size reduction > 50% of liver and lung metastases. CONCLUSIONS: This case demonstrated the activity of the combination of oxaliplatin and 5-fluorouracil in this very rare neoplasia. The FOLFOX regimen might be considered either in advanced and especially in the neoadjuvant setting, when the reduction of the primary tumor is highly needed.

A systematic review of the safety profile of the different combinations of fluoropyrimidines and oxaliplatin in the treatment of colorectal cancer patients.

The available fluoropyrimidines and oxaliplatin combinations for colorectal cancer patients have different safety profiles. The aim of this systematic review was to compare their toxicities. The eligible studies were classified as: no bolus; 5-FU single bolus; 5-FU double bolus; capecitabine. We calculated the incidence of "any-grade" and "severe" toxicity for haematological and non-haematological adverse events of each group. We identified 184 treatment groups; compared to 5-FU double bolus, except for high-grade anaemia, all the groups showed reduced risk of haematological toxicities, with the most relevant advantages for single bolus regimens. Concerning non-haematological toxicities, compared to double bolus, the single bolus group showed a statistically significant reduced risk for many gastrointestinal toxicities and for pheripheral neuropathy. This is the first systematic review of the toxicity profile of different 5-FU or capecitabine and oxaliplatin regimens. Single 5-FU bolus is associated with a definitely favourable toxicity profile, both for haematological and non-haematological toxicity.

MMC/UFT/LV in refractory colorectal cancer: phase II study and analysis of predictive variables of progression.

BACKGROUND: The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate. PATIENTS AND METHODS: We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression. RESULTS: We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis. CONCLUSION: The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.

Treatment of Patients With Metastatic Colorectal Cancer in a Real-World Scenario: Probability of Receiving Second and Further Lines of Therapy and Description of Clinical Benefit.

BACKGROUND: The optimal therapeutic strategy for metastatic colorectal cancer patients is still a matter of debate. There are no prognostic variables indicating how many lines individual patients ought to receive, and whether later lines could be effective even when earlier ones were not. PATIENTS AND METHODS: We retrospectively collected data from 420 consecutive patients with metastatic colorectal cancer at our institution, describing the proportion of patients who received second or later lines of therapy and the chance of a line of treatment being active when the previous line was not. For each line of treatment, we defined clinical benefit as the probability of not having had evidence of disease progression 6 months after the start of chemotherapy. RESULTS: Of the 373 patients with disease progression after first-line chemotherapy (1L), 277 received a second line (2L) (probability of being submitted to a 2L (P(2L)) = 74.3%): 143 (63.3%) of 226 received a 3L (P(3L)), and 56 (45.9%) of 122 were submitted to a 4L (P(4L)). Joint probabilities were: 2L 74.3%, 3L 47.0%, and 4L 21.6%. A total of 298 (71.5%) of 417 patients had a clinical benefit with 1L; 134 (48.6%) of 276 with 2L; 50 (35.2%) of 142 with 3L; and 12 (25.0%) of 48 with 4L. Taking all these data together, 31% of the patients who experienced early progression at 1L had the chance to have a clinical benefit with any further lines. CONCLUSION: Our study demonstrated that of 4 patients submitted to a 1L, about 3 will receive a 2L, about 2 a 3L, and nearly 1 a 4L. Later lines could be beneficial even though earlier ones were not.

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis.

PURPOSE: The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R2). RESULTS: Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. CONCLUSION: Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

Bioequivalence of Branded and Generic Oxaliplatin: From Preclinical Assessment to Clinical Incidence of Hypersensitivity Reactions.

BACKGROUND: Generic anticancer drugs represent an opportunity in terms of cost savings but there are some concerns about their tolerability. The safety profiles of generic versus branded oxaliplatin formulations have never been studied in detail. PATIENTS AND METHODS: We tested in vitro concentrations, stability and efficacy of branded versus generic oxaliplatin formulations, then we retrospectively collected data about hypersensitivity reactions (HSR) of 427 colorectal cancer patients treated with oxaliplatin-based regimens. RESULTS: No significant difference in oxaliplatin concentration or time-dependent antiproliferative activity between branded and generic oxaliplatin was detected. The incidence of HSR was 12.1% (33/273 patients) in those treated with branded and 9.8% (15/154 patients) in those treated with generic oxaliplatin (p=0.46). The occurrence of grade III-IV HSRs and severe HSRs leading to oxaliplatin discontinuation were comparable. CONCLUSION: No difference between generic and branded formulations of oxaliplatin were demonstrated in preclinical nor in clinical settings. Generic oxaliplatin can be considered a safe alternative to branded formulation.

Unusual paraneoplastic neurological syndrome secondary to a well differentiated pancreatic neuroendocrine tumor: a case report and review of the literature.

BACKGROUND: Paraneoplastic neurological syndrome (PNS) is a heterogeneous group of disorders affecting any part of the nervous system, in a patient affected by cancer. PNS is estimated to occur in 0.01 to 8% of cancer patients, with higher incidence in those with small cell lung cancer, gynecological tumours or hematological disease. Paraneoplastic cerebellar degeneration (PCD) is the most common PNS, but it has never been reported in patients with pancreatic well-differentiated neuroendocrine tumours. CASE PRESENTATION: A 61-year-old man presented with an unusual PNS and absence of circulating neural auto-antibodies. Subsequently, contrast-enhanced computed tomography revealed a large pancreatic mass, together with multiple liver metastases, histologically diagnosed as a well-differentiated neuroendocrine tumor. Initial treatment with long-acting somatostatin analogue (octreotide LAR) and prednisone achieved a biochemical response (reduction of chromogranin A level) and a radiological disease control, but patient experienced only a brief improvement of neurological symptoms. Seven months after the onset of the symptoms, he died from neurological impairment. CONCLUSIONS: PNS can be associated with metastatic non-functioning well-differentiated pancreatic neuroendocrine tumors. These tumors may be unresponsive to treatment with somatostatin analogues and an early neurological treatment should be considered for the optimal management of these uncommon cases.

YKL-40/c-Met expression in rectal cancer biopsies predicts tumor regression following neoadjuvant chemoradiotherapy: a multi-institutional study.

BACKGROUND: Neoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors. MATERIAL AND METHODS: A multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria. RESULTS: A significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, p< 0.01 and p = 0.006, respectively). Thirty of the 32 biopsies co-expressing both markers had partial or absent tumor response (TRG 2-5), strengthening their positive predictive value (94%). The exclusive predictive role of YKL-40 and c-Met was confirmed using a multivariate analysis (p = 0.004 and p = 0.007 for YKL-40 and c-Met, respectively). TRG was the sole morphological parameter associated with poor outcome. CONCLUSION: c-Met and YKL-40 expression is a reliable predictor of partial/absent response to neoadjuvant CRT in rectal cancer. Targeted therapy protocols could take advantage of prior evaluations of c-MET and YKL-40 expression levels to increase therapeutic efficacy.

Stromal contribution to the colorectal cancer transcriptome.

Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis showed that the mRNA levels of SSM genes were mostly due to stromal expression. Transcriptional signatures built to specifically report the abundance of cancer-associated fibroblasts (CAFs), leukocytes or endothelial cells all had significantly higher expression in human CRC samples of the SSM subtype. High expression of the CAF signature was associated with poor prognosis in untreated CRC, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stromal component.

Pilot clinical trial on the efficacy of prophylactic use of vitamin K1-based cream (Vigorskin) to prevent cetuximab-induced skin rash in patients with metastatic colorectal cancer.

BACKGROUND: Cetuximab is an effective option for the treatment of metastatic colorectal cancer in the first and subsequent lines of treatment; among its side effects, acneiform skin rash is one of the major causes of treatment delay, reduction, or interruption, with a negative effect on quality of life. No effective strategy to prevent skin rash induced by epidermal growth factor receptor inhibitors is available; however, encouraging results have come from vitamin K1, phytomenadione, applied as a topical formulation. Available studies have been conducted in heterogeneous populations and are mainly focused on the use of vitamin K1-based cream for the treatment, rather than the prophylaxis, of acneiform rash. PATIENTS AND METHODS: Forty-one consecutive patients from a single center all affected by metastatic colorectal cancer and receiving cetuximab, alone or combined with chemotherapy, applied vitamin K1-based cream to prevent the occurrence of acneiform skin rash. The cream was applied twice a day on the face and trunk from the first day of administration of cetuximab. RESULTS: The application of the cream was well tolerated. No grade 4 rash was reported. The proportion of grade 3 skin rash in the first 8 weeks of treatment in this population was 15%, at the lower limit of values reported in the literature, and the proportion of patients with grade 2 rash was reduced (22.5%). CONCLUSION: This experience confirms available data in a homogeneous population, suggesting a possible benefit of topical vitamin K1 as prophylaxis for cetuximab-induced skin rash in patients with metastatic colorectal cancer.