Michele Ghidini

Prognostic Survival Associated With Left-Sided vs Right-Sided Colon Cancer: A Systematic Review and Meta-analysis.

Importance Primary tumor location is emerging as an important prognostic factor owing to distinct biological features. However, the side of origin of colon cancer (CC) still does not represent a prognostic parameter when deciding for adjuvant or palliative chemotherapy. Objective To determine the prognostic role of left vs right-sidedness of primary tumor location in patients with CC. Data Sources We searched PubMed, EMBASE, The Cochrane Library, Web of Science, LILACS, CINAHL, and SCOPUS for prospective or retrospective studies reporting data on overall survival for left-sided colon cancer (LCC) compared with right-sided colon cancer (RCC). Study Selection Studies were selected if: (1) side of CC was reported among variables entered into survival analysis, (2) survival information was available (overall survival [OS] was reported in the article as hazard ratio (HR) according to multivariate analysis, (3) articles were published in the English language. Data Extraction and Synthesis Data were pooled using HRs for OS of LCC vs RCC according to fixed or random-effects models. Subgroup analysis and multivariate random-effects model meta-regression was also implemented adjusting for stage distribution, sample size, race, year of publication, type and quality of studies, and adjuvant chemotherapy. Main Outcomes and Measures HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. In this analysis, all HRs with 95% CIs were pooled to obtain prognostic information on the location of the primary tumor (left vs right location site of CC) independent of other common clinicopathological covariates. Results An analysis was made from the 66 studies conducted. It included 1 437 846 patients with a median follow-up of 65 months. Left sided primary tumor location was associated with a significantly reduced risk of death (HR, 0.82; 95% CI, 0.79-0.84; P < .001) and this was independent of stage, race, adjuvant chemotherapy, year of study, number of participants, and quality of included studies. Conclusions and Relevance Based on these results, CC side should be acknowledged as a criterion for establishing prognosis in all stages of disease. It should be considered when deciding treatment intensity in metastatic settings, and should represent a stratification factor for future adjuvant studies.

Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial

Purpose The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial established perioperative epirubicin, cisplatin, and fluorouracil chemotherapy as a standard of care for patients with resectable esophagogastric cancer. However, identification of patients at risk for relapse remains challenging. We evaluated whether pathologic response and lymph node status after neoadjuvant chemotherapy are prognostic in patients treated in the MAGIC trial. Materials and Methods Pathologic regression was assessed in resection specimens by two independent pathologists using the Mandard tumor regression grading system (TRG). Differences in overall survival (OS) according to TRG were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards method established the relationships among TRG, clinical-pathologic variables, and OS. Results Three hundred thirty resection specimens were analyzed. In chemotherapy-treated patients with a TRG of 1 or 2, median OS was not reached, whereas for patients with a TRG of 3, 4, or 5, median OS was 20.47 months. On univariate analysis, high TRG and lymph node metastases were negatively related to survival (Mandard TRG 3, 4, or 5: hazard ratio [HR], 1.94; 95% CI, 1.11 to 3.39; P = .0209; lymph node metastases: HR, 3.63; 95% CI, 1.88 to 7.0; P < .001). On multivariate analysis, only lymph node status was independently predictive of OS (HR, 3.36; 95% CI, 1.70 to 6.63; P < .001). Conclusion Lymph node metastases and not pathologic response to chemotherapy was the only independent predictor of survival after chemotherapy plus resection in the MAGIC trial. Prospective evaluation of whether omitting postoperative chemotherapy and/or switching to a noncross-resistant regimen in patients with lymph node-positive disease whose tumor did not respond to preoperative epirubicin, cisplatin, and fluorouracil may be appropriate.

FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis

Importance The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial. Objective To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions. Data Sources A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer). Study Selection Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded. Data Extraction and Synthesis Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial. Main Outcomes and Measures Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions. Results Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12). Conclusions and Relevance For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.

Non-Coding RNAs in Primary Liver Cancer

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with poor prognosis and limited therapeutic options. Over the past few years, many studies have evaluated the role of non-coding RNAs (ncRNAs) in hepatocarcinogenesis and tumor progression. ncRNAs were shown to have diagnostic, prognostic, and therapeutic potential in HCC. In this manuscript, we review the latest major discoveries concerning microRNAs and long ncRNAs in HCC pathogenesis, and discuss the potentials and the limitations for their use in clinical practice.

A new nomogram for estimating survival in patients with brain metastases secondary to colorectal cancer

BACKGROUND The prognosis of brain metastases (BM) in colorectal cancer (CRC) is extremely poor, but the incidence is increasing. The performance of existing prognostic classifications such as recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) has never been evaluated in this specific setting. Moreover, the development of nomograms for estimating survival in such patients could be extremely helpful for treating physicians. PATIENTS AND METHODS Between 2000 and 2013, data from 227 patients with BM from CRC were collected at 8 Italian institutions. Overall survival (OS) was estimated with the Kaplan-Meier method and statistical comparison between curves was performed using the log-rank test. The discriminative ability for OS of RPA and GPA was assessed by the Harrell C-index from univariable Cox models. Putative prognostic factors for OS were also studied by multivariable Cox analysis, using the Harrell C index to evaluate the model discriminative ability. After a backward variable selection, a nomogram was developed to predict median survival time from individual patient- and tumor-related characteristics. The nomogram was externally validated on an independent series. RESULTS After a median follow-up of 59 months, fifty percent of patients were still at risk at 5 months. The C index was 0.594 and 0.607 for the RPA and GPA classifications, respectively. The C-index associated with the final multivariable Cox model used for developing the nomogram was 0.643; the favorable prognostic factors for survival were lower age (p=0.061), better Karnofsky performance status (p<0.001), supratentorial site of BM (p<0.001), and lower number of BM (p=0.035). The C index evaluated on the validation series was 0.733, even better than in the development series; also, the calibration of nomogram predictions was good. CONCLUSION The C-index associated to the nomogram model was slightly higher than that obtained for the RPA and GPA classifications. Most importantly, the very satisfactory results of nomogram validation on the external series, make us confident that our instrument may assist in prognostic assessment, treatment decision making, and enrollment into clinical trials.

Clinical development of mTor inhibitors for renal cancer

ABSTRACT Introduction: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90–95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options. Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC. The authors revised the results of the most recent completed clinical trials and provided information about ongoing trials. Expert opinion: mTOR pathway still represents an important driver for RCC management. Combination of everolimus and lenvatinib is considered a category 1 choice with cabozantinib and nivolumab for subsequent therapy in metastatic RCC according to NCCN guidelines v2.2017. These three treatments (levantinib/everolimus, cabozantinib, and nivolumab) all resulted in a superior efficacy compared to everolimus alone. Moreover, mTOR inhibitors, and in particular temsirolimus for poor risk patients, are available choices for treatment in non-clear cell carcinomas together with TKIs.

KRAS mutation in lung metastases from colorectal cancer: prognostic implications

KRAS mutant colorectal cancer (CRC) patients develop lung and brain metastases more frequently than KRAS wild‐type (WT) counterpart. We retrospectively investigated the prognostic role of KRAS, BRAF, and PIK3CA (exon 20) mutations and loss of phosphatase and tensin homolog (PTEN) in surgically resected lung metastases. Lung specimens from 75 metastatic CRC (mCRC) patients treated with one or more metastasectomies with curative intent were analyzed. Sixty‐four percent of patients had KRAS WT lung metastases. PTEN loss‐of‐function was found in 75%. BRAF and PIK3CA exon 20 mutations were not found. Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation. In univariate analysis, median overall survival (OS) for KRAS WT patients was longer, compared to KRAS mutant patients (median 60.9 vs. 36.6 months, P = 0.035). In addition, both progression‐free survival (PFS) and lung disease‐free survival (LDFS) between lung surgery and relapse were not associated with KRAS and PTEN status. In multivariate analysis, the risk of death was significantly increased by KRAS mutational status (OS Hazard ratio (HR) 2.17, 95% IC 1.19–3.96, P = 0.012) and lack of adjuvant chemotherapy (OS HR 0.10, 95% IC 0.01–0.74, P = 0.024). The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors. Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis. Moreover, administration of adjuvant chemotherapy after lung metastasectomy (LM) significantly improved both PFS and OS. KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM. Further larger and prospective studies are necessary to confirm these findings.

Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature

PurposeHER2 gene is a member of the epidermal growth factor receptor (EGFR) family. Across different malignancies, aberrations of HER2 gene commonly correspond to gain-of-function alterations leading to increased receptor signaling.MethodsWe have reviewed the literature currently available on HER2 mutations in human breast cancer (BC) evaluating type and frequency of such mutations. The primary objective was to determine the frequency and the number of patients with HER2-mut in the series analyzed. The secondary objectives were to assess characteristics of mutated cases (ER and HER2 status and stage of disease, type of mutations, and finally the clinical outcome if reported).ResultsWe retrieved 31 published papers, and the pooled rate of HER2 mutations across 12,905 BC patients was calculated. Overall, the frequency of HER2 mutations was 2.7% with most involving the intracellular domain. About 4% of patients were finally mutated. The predictive role was not described. Only 30% of these patients were simultaneously HER2 positive and 63% were ER positive.ConclusionWe have found that the prevalence of HER2 mutations is about 3%. These genic alterations are independently associated with HER2 amplification status, occurring in both ER-positive/HER2-negative diseases or HER2-enriched cancers. Ongoing trials are investigating small molecules tyrosine kinase inhibitors in patients harboring these mutations.

Targeted therapies in gastric cancer treatment: where we are and where we are going.

SummaryGastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma

Background:A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes.Methods:Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT–PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD.Results:The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy.Conclusions:miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.