Chemoirradiation for Glioblastoma Multiforme: The National Cancer Institute Experience

Purpose

Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established.

Experimental Design

The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging.

Results

At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005.

Conclusions

Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.     

Efficacy and Safety of Bevacizumab for the Treatment of Advanced Hepatocellular Carcinoma: A Systematic Review of Phase II Trials

Background

Hepatocellular carcinoma (HCC) is a common cancer associated with a poor prognosis. Bevacizumab is a monoclonal antibody that binds vascular endothelial growth factor, a mediator of tumor angiogenesis. Bevacizumab is currently under investigation as treatment for HCC. We performed a systematic review of the efficacy and safety of bevacizumab for the treatment of advanced HCC.

Methods

PubMed, the Cochrane Library, and Google Scholar were searched using the terms “bevacizumab AND hepatocellular carcinoma AND (advanced OR unresectable)”. Phase II trials of bevacizumab for the treatment of advanced HCC were included. Outcomes of interest included progression-free and overall survival (PFS and OS), tumor response, and toxicities.

Results

A total of 26 records were identified. Of these, 18 were excluded. Hence, eight trials involving 300 patients were included. Bevacizumab was given as monotherapy (n = 1 trial) or in combination with erlotinib (n = 4 trials), capecitabine (n = 1 trial), capecitabine+oxaliplatin (n = 1 trial), or gemcitabine+oxaliplatin (n = 1 trial). Most trials (five of eight) reported median PFS and OS between 5.3 months and 9.0 months and 5.9 and 13.7 months, respectively. The disease control rate was consistent in five of eight trials, ranging from 51.1% to 76.9%. The response and partial response rates ranged from 0 to 23.7%, but were around 20% in four trials. Only one patient had a complete response. Frequently reported Grade 3/4 toxicities were increased aspartate transaminase/alanine transaminase (13%), fatigue (12%), hypertension (10%), diarrhea (8%), and neutropenia (5%). Thirty patients experienced gastrointestinal bleeding (grade 1/2 = 18, grade 3/4 = 12), typically due to esophageal varices.

Conclusions

Bevacizumab shows promise as an effective and tolerable treatment for advanced HCC. The reported efficacy of bevacizumab appears to compare favorably with that of sorafenib, the only currently approved treatment for unresectable HCC. Phase III trials are warranted to comprehensively examine the efficacy and safety of bevacizumab for treatment of advanced HCC.     

Natural History of Malignant Bone Disease in Hepatocellular Carcinoma: Final Results of a Multicenter Bone Metastasis Survey

Background

Bone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC.

Patients and Methods

Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed.

Results

The median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005), ECOG performance status (p = 0.002) and treatment with bisphosphonate (p = 0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (p = 0.021) and OS (p = 0.001).

Conclusions

This study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.     

SNPs in the TGF-β Signaling Pathway Are Associated with Increased Risk of Brain Metastasis in Patients with Non–Small-Cell Lung Cancer

Purpose

Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is relatively common, but identifying which patients will develop brain metastasis has been problematic. We hypothesized that genotype variants in the TGF-β signaling pathway could be a predictive biomarker of brain metastasis.

Patients and Methods

We genotyped 33 SNPs from 13 genes in the TGF-β signaling pathway and evaluated their associations with brain metastasis risk by using DNA from blood samples from 161 patients with NSCLC. Kaplan-Meier analysis was used to assess brain metastasis risk; Cox hazard analyses were used to evaluate the effects of various patient and disease characteristics on the risk of brain metastasis.

Results

The median age of the 116 men and 45 women in the study was 58 years; 62 (39%) had stage IIIB or IV disease. Within 24 months after initial diagnosis of lung cancer, brain metastasis was found in 60 patients (37%). Of these 60 patients, 16 had presented with BM at diagnosis. Multivariate analysis showed the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with a significantly higher risk of brain metastasis at 24 months follow-up (hazard ratio [HR] 2.540, 95% confidence interval [CI] 1.204–5.359, P = 0.014; and HR 1.885, 95% CI 1.086–3.273, P = 0.024), compared with the GA or CT/CC genotypes, respectively. When we analyzed combined subgroups, these rates showed higher for those having both the GG genotype of SMAD6: rs12913975 and the TT genotype of INHBC: rs4760259 (HR 2.353, 95% CI 1.390–3.985, P = 0.001).

Conclusions

We found the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with risk of brain metastasis in patients with NSCLC. This finding, if confirmed, can help to identify patients at high risk of brain metastasis.     

The Influence of the Patient-Clinician Relationship on Healthcare Outcomes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective

To determine whether the patient-clinician relationship has a beneficial effect on either objective or validated subjective healthcare outcomes.

Design

Systematic review and meta-analysis.

Data Sources

Electronic databases EMBASE and MEDLINE and the reference sections of previous reviews.

Eligibility Criteria for Selecting Studies

Included studies were randomized controlled trials (RCTs) in adult patients in which the patient-clinician relationship was systematically manipulated and healthcare outcomes were either objective (e.g., blood pressure) or validated subjective measures (e.g., pain scores). Studies were excluded if the encounter was a routine physical, or a mental health or substance abuse visit; if the outcome was an intermediate outcome such as patient satisfaction or adherence to treatment; if the patient-clinician relationship was manipulated solely by intervening with patients; or if the duration of the clinical encounter was unequal across conditions.

Results

Thirteen RCTs met eligibility criteria. Observed effect sizes for the individual studies ranged from d = −.23 to .66. Using a random-effects model, the estimate of the overall effect size was small (d = .11), but statistically significant (p = .02).

Conclusions

This systematic review and meta-analysis of RCTs suggests that the patient-clinician relationship has a small, but statistically significant effect on healthcare outcomes. Given that relatively few RCTs met our eligibility criteria, and that the majority of these trials were not specifically designed to test the effect of the patient-clinician relationship on healthcare outcomes, we conclude with a call for more research on this important topic.     

Multi-Targeted Antiangiogenic Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer: Meta-Analyses of 20 Randomized Controlled Trials and Subgroup Analyses

Background

Multi-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied in many randomized controlled trials (RCTs) for treatment of advanced non-small cell lung cancer (NSCLC). We seek to summarize the most up-to-date evidences and perform a timely meta-analysis.

Methods

Electronic databases were searched for eligible studies. We defined the experimental arm as MATKI-containing group and the control arm as MATKI-free group. The extracted data on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS) and overall survival (OS) were pooled. Subgroup and sensitivity analyses were conducted.

Results

Twenty phase II/III RCTs that involved a total of 10834 participants were included. Overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, P = 0.006) and prolonged PFS (HR 0.83, 0.78 to 0.90, P = 0.005) compared to the MATKI-free group. However, no significant improvements in DCR (OR 1.08, 1.00 to 1.17, P = 0.054) or OS (HR 0.97, 0.93 to 1.01, P = 0.106) were observed. Subgroup analyses showed that the benefits were predominantly presented in pooled results of studies enrolling previously-treated patients, studies not limiting to enroll non-squamous NSCLC, and studies using MATKIs in combination with the control regimens as experimental therapies.

Conclusions

This up-to-date meta-analysis showed that MATKIs did increase ORR and prolong PFS, with no significant improvement in DCR and OS. The advantages of MATKIs were most prominent in patients who received a MATKI in combination with standard treatments and in patients who had previously experienced chemotherapy. We suggest further discussion as to the inclusion criteria of future studies on MATKIs regarding histology.     

Prognostic Value of Epidermal Growth Factor Receptor Mutations in Resected Non-Small Cell Lung Cancer: A Systematic Review with Meta-Analysis

Background

The prognostic value of epidermal growth factor receptor (EGFR) mutations in resected non-small cell lung cancer (NSCLC) remains controversial. We performed a systematic review with meta-analysis to assess its role.

Methods

Studies were identified via an electronic search on PubMed, Embase and Cochrane Library databases. Pooled hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis.

Results

There were 16 evaluated studies (n = 3337) in the meta-analysis. The combined HR evaluating EGFR mutations on disease free survival was 0.96 (95% CI [0.79–1.16] P = 0.65). The combined HR evaluating EGFR mutations on overall survival was 0.86 (95% CI [0.72–1.04] P = 0.12). The subgroup analysis based on univariate and multivariate analyses in DFS and OS showed no statistically significant difference. There was also no statistically significant difference in DFS and OS of stage I NSCLC patients.

Conclusion

The systematic review with meta-analysis showed that EGFR mutations were not a prognostic factor in patients with surgically resected non-small cell lung cancer. Well designed prospective study is needed to confirm the result.     

Finger Position Alters the Median Nerve Properties within the Carpal Tunnel: A Pre-Post MRI Comparison Study

Purpose

The purpose of this study was to compare the properties of the median nerve and the flexor retinaculum within the carpal tunnel with Magnetic Resonance Imaging (MRI) under two conditions: (a) fingers extended, and (b) fingers in an isometric squeeze grip.

Methods

Thirty-Four volunteers participated in this experimental study. The flexor retinaculum and median nerve characteristics were measured during both conditions using MRI.

Results

The isometric squeeze grip condition resulted in significant palmar bowing of the flexor retinaculum (t = 7.67, p<.001), a significant flattening-ratio of the median nerve (t = 4.308, p<.001), and no significant decrease in the cross-sectional area of the median nerve (t = 2.508, p = 0.017).

Conclusion

The isometric squeeze grip condition resulted in anatomical deformations within the carpal tunnel, possibly explained by the lumbrical muscles incursion into the carpal tunnel during finger flexion.     

Tissue MicroRNAs as Predictors of Outcome in Patients with Metastatic Colorectal Cancer Treated with First Line Capecitabine and Oxaliplatin with or without Bevacizumab

Purpose

We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC).

Experimental Design

Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs.

Results

In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts.

Conclusions

We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.     

Common and Rare EGFR and KRAS Mutations in a Dutch Non-Small-Cell Lung Cancer Population and Their Clinical Outcome

Introduction

In randomly assigned studies with EGFR TKI only a minor proportion of patients with NSCLC have genetically profiled biopsies. Guidelines provide evidence to perform EGFR and KRAS mutation analysis in non-squamous NSCLC. We explored tumor biopsy quality offered for mutation testing, different mutations distribution, and outcome with EGFR TKI.

Patient and Methods

Clinical data from 8 regional hospitals were studied for patient and tumor characteristics, treatment and overall survival. Biopsies sent to the central laboratory were evaluated for DNA quality and subsequently analyzed for mutations in exons 18–21 of EGFR and exon 2 of KRAS by bidirectional sequence analysis.

Results

Tumors from 442 subsequent patients were analyzed. For 74 patients (17%) tumors were unsuitable for mutation analysis. Thirty-eight patients (10.9%) had EGFR mutations with 79% known activating mutations. One hundred eight patients (30%) had functional KRAS mutations. The mutation spectrum was comparable to the Cosmic database. Following treatment in the first or second line with EGFR TKI median overall survival for patients with EGFR (n = 14), KRAS (n = 14) mutations and wild type EGFR/KRAS (n = 31) was not reached, 20 and 9 months, respectively.

Conclusion

One out of every 6 tumor samples was inadequate for mutation analysis. Patients with EGFR activating mutations treated with EGFR-TKI have the longest survival.     

The Use of Novel Drugs Can Effectively Improve Response,Delay Relapse and Enhance Overall Survival in Multiple Myeloma Patients with Renal Impairment

Background

Renal impairment is a common feature in multiple myeloma and is considered a poor prognostic factor.

Aim

To determine the impact of novel drugs (i.e. bortezomib, lenalidomide and thalidomide) in the treatment of myeloma patients with renal impairment. The primary endpoint was overall survival and secondary endpoints were time to next treatment and response.

Methods

The study population included all patients diagnosed with treatment-demanding multiple myeloma January 2000 to June 2011 at 15 Swedish hospitals. Renal impairment was defined as an estimated glomerular filtration rate under 60 mL/min/1.73 m².

Result

The study population consisted of 1538 patients, of which 680 had renal impairment at diagnosis. The median overall survival in patients with renal impairment was 33 months, which was significantly shorter than 52 months in patients with normal renal function (P<0.001). Novel agents in first line improved overall survival (median 60 months) in non-high-dose treated patients with renal impairment (n = 143) as compared to those treated with conventional cytotoxic drugs (n = 411) (median 27 months) (P<0.001). In the multivariate analysis up front treatment with bortezomib was an independent factor for better overall survival in non-high-dose treated renally impaired patients. High-dose treated renally impaired patients had significantly better median overall survival than non-high-dose ones (74 versus 26 months) and novel drugs did not significantly improve survival further in these patients. Patients with renal impairment had both a shorter median time to next treatment and a lower response rate than those with normal renal function. However, novel drugs and high dose treatment lead to a significantly longer time to next treatment and the use of novel agents significantly improved the response rate of these patients.

Conclusion

High dose treatment and novel drugs, especially bortezomib, can effectively overcome the negative impact of renal impairment in patients with multiple myeloma.     

Low Serum 25-Hydroxyvitamin D Concentrations Are Associated with Increased Risk for Melanoma and Unfavourable Prognosis

Background

Low vitamin D status (serum 25(OH)D concentration) is associated with increased incidence and unfavourable outcome of various types of cancer. However, there are limited data on influence of serum 25(OH)D on risk and prognosis of malignant melanoma.

Methods

Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients (n = 324) and healthy controls (n = 141). We tested the hypothesis that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS).

Results

Median serum 25(OH)D concentrations were significantly lower (p = 0.004) in melanoma patients (median = 13.6 ng/ml) as compared to controls (median = 15.6 ng/ml). Primary tumors of patients with low serum 25(OH)D concentrations (<10 ng/ml) had significantly (p = 0.006) greater Breslow thickness (median: 1.9 mm) as compared to patients with higher levels (>20 ng/ml; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049).

Conclusions

Our data support the concept that serum 25(OH)D concentrations are associated with risk and prognosis of melanoma. Whether normalizing serum 25(OH)D concentrations in these patients improves outcomes will require testing in future clinical trials.     

Melanoma Patients with Unknown Primary Site or Nodal Recurrence after Initial Diagnosis Have a Favourable Survival Compared to Those with Synchronous Lymph Node Metastasis and Primary Tumour

Background

A direct comparison of prognosis between patients with regional lymph node metastases (LNM) detected synchronously with the primary melanoma (primary LNM), patients who developed their first LNM subsequently (secondary LNM) and those with initial LNM in melanoma with unknown primary site (MUP) is missing thus far.

Patients and Methods

Survival of 498 patients was calculated from the time point of the first macroscopic LNM using Kaplan Meier and multivariate Cox hazard regression analysis.

Results

Patients with secondary LNM (HR = 0.67; p = 0.009) and those with initial LNM in MUP (HR = 0.45; p = 0.008) had a better prognosis compared to patients with primary LNM (median survival time 52 and 65 vs. 24 months, respectively). A high number of involved nodes, the presence of in-transit/satellite metastases and male gender had an additional independent unfavourable effect.

Conclusions

Survival of patients with LNM in MUP and with secondary LNM is similar and considerably more favourable compared to those with primary LNM. This difference needs to be considered during patient counselling and for stratification purposes in clinical trials. The assumption of an immune privilege of patients with MUP which is responsible for rejection of the primary melanoma, and results in a favourable prognosis is not supported by our data.     

Treatment Adherence and Health Outcomes in MSM with HIV/AIDS: Patients Enrolled in “One-Stop” and Standard Care Clinics in Wuhan China

Background

Conducted in Wuhan China, this study examined follow-up and health markers in HIV patients receiving care in two treatment settings. Participants, all men who have sex with men, were followed for18–24 months.

Method

Patients in a “one-stop” service (ACC; N = 89) vs those in standard care clinics (CDC; N = 243) were compared on HIV treatment and retention in care outcomes.

Results

Among patients with CD4 cell count ≦350 cells/µL, the proportion receiving cART did not differ across clinic groups. The ACC was favored across five other indicators: proportion receiving tests for CD4 cell count at the six-month interval (98.2% vs. 79.4%, 95% CI 13.3–24.3, p = 0.000), proportion with HIV suppression for patients receiving cART for 6 months (86.5% vs. 57.1%, 95% CI 14.1–44.7, p = 0.000), proportion with CD4 cell recovery for patients receiving cART for 12 months (55.8% vs. 22.2%, 95% CI 18.5–48.6, p = 0.000), median time from HIV confirmation to first test for CD4 cell count (7 days, 95% CI 4–8 vs. 10 days, 95% CI 9–12, log-rank p = 0.000) and median time from first CD4 cell count ≦350 cells/µL to cART initiation (26 days, 95% CI 16–37 vs. 41.5 days, 95% CI 35–46, log-rank p = 0.031). Clinic groups did not differ on any biomedical indicator at baseline, and no baseline biomedical or demographic variables remained significant in the multivariate analysis. Nonetheless, post-hoc analyses suggest the possibility of self-selection bias.

Conclusions

Study findings lend preliminary support to a one-stop patient-centered care model that may be useful across various HIV care settings.     

Culture Conversion Rate at 2 Months of Treatment According to Diagnostic Methods among Patients with Culture-Positive Pulmonary Tuberculosis

Introduction

The culture-negative conversion rate of sputum after 2 months of treatment in patients with pulmonary tuberculosis (TB) is used as a reliable surrogate marker for relapse after completion of treatment. We hypothesized that culture conversion of sputum at 2 months of anti-TB treatment and the time to culture conversion are different among pulmonary TB patients who are diagnosed using different methods.

Methods

Culture-confirmed pulmonary TB patients who were diagnosed between 1 January, 2011 and 31 December, 2012 were classified into three groups based on the diagnostic method that prompted treatment initiation: positive acid-fast bacilli (AFB) staining of sputum (smear-positive group), negative AFB staining, but Mycobacterium tuberculosis was cultured from sputum (culture-positive group), and positive AFB staining, positive polymerase chain reaction (PCR) for M. tuberculosis, or culture of M. tuberculosis from a bronchoscopic specimen (bronchoscopy group). Rates of negative mycobacterial culture conversion at 2 months of anti-TB treatment and the time to negative culture conversion of sputum were compared among the three groups.

Results

A total of 203 patients with culture-confirmed pulmonary TB were included in the final analysis. TB patients in the culture-positive group (94.1%) and the bronchoscopy group (97.6%) showed a higher culture conversion rate at 2 months of treatment than those in the smear-positive group (78.7%, P = 0.001). Additionally, the time to culture conversion was longer in the smear-positive group (median, 40 days) than in the culture-positive (median, 19 days; P = 0.009) and bronchoscopy groups (median, 29 days; P = 0.004).

Conclusions

The higher culture conversion rate at 2 months and the shorter time to culture conversion among pulmonary TB patients with a negative AFB smear suggests the feasibility of shortening treatment duration and isolation in these patients.     

Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study

Background

In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates.

Methodology/Principal Findings

KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p = 0.0038; HR: 1.40; 95% CI:1.12–1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p = 0.0002; HR: 1.55; 95% CI: 1.23–1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p = 0.0054; OR: 1.77; 95% CI: 1.18–2.64).

Conclusions/Significance

This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses.     

Prognostic Significance of B-Cells and pSTAT3 in Patients with Ovarian Cancer

Background

Several previous studies have identified a strong association between T-cell infiltration and clinical outcome in ovarian cancer. The role of B-cells remains controversial, however.

Methods

Forty-nine paraffin-embedded omental specimens derived from patients with high grade epithelial ovarian cancer were assessed. Immunohistochemical analyses were performed to characterize expression of CD19⁺ B-cells and pSTAT3 as high (>50% positively staining cells [PSCs]) or low (<50% PSCs). The Kaplan-Meier method with log-rank test was used to determine the association between clinicopathologic parameters and overall survival (OS). A multi-variate Cox proportional hazards regression analysis including nature of debulking (primary vs secondary), histology, tumor grade, receipt of prior chemotherapy, B-cell infiltration and pSTAT3 expression was performed.

Results

Median OS was 160.6 months in those patients with low B-cell expression vs 47.3 months in those with high B-cell expression (P = 0.0015). Similarly, median OS was improved in those patients with low pSTAT3 expression (160.6 vs 47.9 months, P = 0.02). In a multivariate model to predict survival, only the degree of B-cell infiltration and clinical stage were retained. pSTAT3 expression did not enter the final model, possibly be due to a high positive correlation with B-cell infiltration (r = 0.82, P<0.0001).

Conclusions

Increased B-cell infiltration and pSTAT3 expression in omental tissue are associated with poorer survival.     

Icotinib Is an Active Treatment of Non-Small-Cell Lung Cancer: A Retrospective Study

Background

Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with preclinical and clinical activity in non-small cell lung cancer (NSCLC). This retrospective analysis was performed to assess the efficacy of icotinib on patients with non-small-cell lung cancer (NSCLC).

Methods

82 consecutive patients treated with icotinib as first (n = 24) or second/third line (n = 58) treatment at three hospitals in Nanjing were enrolled into our retrospective research. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the tumor responses and the progression-free survival (PFS) and overall survival (OS) was evaluated by the Kaplan-Meier method.

Results

Median PFS was 4.0 months (95% CI 2.311–5.689). Median OS was 11.0 months (95% CI 8.537–13.463) in this cohort. Median PFS for first and second/third line were 7.0 months (95% CI 2.151–11.8) and 3.0 months (95% CI 1.042–4.958), respectively. Median OS for first and second/third line were 13.0 months (95% CI 10.305–15.695) and 10.0 months (95% CI 7.295–12.70), respectively. In patients with EGFR mutation (n = 19), icotinib significantly reduced the risk of progression (HR 0.36, 95% CI 0.18–0.70, p = 0.003) and death (HR 0.10, 95% CI 0.02–0.42, p = 0.002) compared with those EGFR status unknown (n = 63). The most common adverse events were acne-like rash (39.0%) and diarrhea (20.7%).

Conclusions

Icotinib is active in the treatment of patients with NSCLC both in first or second/third line, especially in those patients harbouring EGFR mutations, with an acceptable adverse event profile.     

Distinct Clinical Outcomes of Non-Small Cell Lung Cancer Patients with Epidermal Growth Factor Receptor (EGFR) Mutations Treated with EGFR Tyrosine Kinase Inhibitors: Non-Responders versus Responders

Introduction

Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been associated with favorable progression free survival (PFS) in patients with non-small cell lung cancers (NSCLC) harboring EGFR mutations. However, a subset of this population doesn''t respond to EGFR-TKI treatment. Therefore, the present study aimed to elucidate survival outcome in NSCLC EGFR-mutant patients who were treated with EGFR TKIs.

Methods

Among the 580 consecutive NSCLC patients who were treated at our facility between 2008 and 2012, a total of 124 treatment-naïve, advanced NSCLC, EGFR-mutant patients treated with EGFR TKIs were identified and grouped into non-responders and responders for analyses.

Results

Of 124 patients, 104 (84%) responded to treatment, and 20 (16%) did not; and the overall median PFS was 9.0 months. Notably, the PFS, overall survival (OS) and survival rates were significantly unfavorable in non-responders (1.8 vs. 10.3 months, hazard ratio (HR) = 29.2, 95% confidence interval (CI), 13.48–63.26, P<0.0001; 9.4 vs. 17.3 months, HR = 2.74, 95% CI, 1.52–4.94, P = 0.0008; and 58% vs. 82% in 6, 37% vs. 60% in 12, and 19 vs. 40% at 24 months, respectively). In multivariate analysis, treatment efficacy strongly affected PFS and OS, independent of covariates (HR = 47.22, 95% CI, 17.88–124.73, P<0.001 and HR = 2.74, 95% CI, 1.43–5.24, P = 0.002, respectively). However, none of the covariates except of the presence of EGFR exon 19 deletion in the tumors was significantly associated with better treatment efficacy.

Conclusions

A subset of NSCLC EGFR-mutant patients displayed unfavorable survival despite EGFR TKI administration. This observation reinforces the urgent need for biomarkers effectively predicting the non-responders and for drug development overcoming primary resistance to EGFR TKIs. In addition, optimal therapeutic strategies to prolong the survival of non-responders need to be investigated.     

Association between Irrigation Fluids,Washout Volumes and Risk of Local Recurrence of Anterior Resection for Rectal Cancer: A Meta-Analysis of 427 Cases and 492 Controls

Background

Rectal washout can prevent local recurrence after anterior resection of rectal cancer. Few studies have focused particularly on the association between irrigation fluids volume or agents and the risk of local recurrence after anterior resection of rectal cancer.

Objective

To estimate the association between irrigation fluids types, volumes of rectal washout and risk of local recurrence after anterior resection for cancer.

Data Sources

Relevant studies were identified by a search of Medline, Embase, Wiley Online Library, China National Knowledge Infrastructure, Cochrane Oral Health Group Specialized Register, Wanfang databases and Google Website from their inception until October 18,2013.

Study Selection

Studies reporting the association between rectal washout types and volumes and risk of local recurrence after anterior resection for cancer were included.

Interventions

Eligible studies used rectal washout. Control groups were defined as no washout.

Study Appraisal and Synthesis Methods

Random-effects model were used to obtain summary estimates of RR and 95% CI, with Stata version 11 and RevMan 5.2.5 softwares used. The quality of report was appraised in reference to the MINORS item.

Results

Of the 919 rectal cancer patients in 8 included studies, a total of 61(6.64%) cases of local recurrence were reported, with a pooled RR 0.51 (95%CI = 0.28–0.92, P = 0.03). The RRs 0.37 and 0.39 in normal saline and washout volume (≥1500 ml normal saline) subgroup, respectively, indicated that rectal washout with normal saline, or ≥1500 ml in volume could significantly reduce local recurrence (LR) rate (95% CI = 0.17–0.79, P = 0.01; 95% CI = 0.18–0.87, P = 0.02) after anterior resection for cancer.

Limitation

The included studies were non-randomized observational studies, with diversity of study designs.

Conclusion

Rectal washout with normal saline alone can reduce the risk of local recurrence in patients with resectable rectal cancer, and 1.5 liters rectal washout in volume is recommended.