Galectin-3 genetic variants are associated with platinum-based chemotherapy response and prognosis in patients with NSCLC

Aim

To explore the association between the galectin-3 genetic polymorphisms and Platinum-based chemotherapy response as well as the prognosis of non-small cell lung cancer (NSCLC).

Method

Three hundred twenty patients with Stage III (A+B) or IV NSCLC were enrolled. A Platinum-based chemotherapy was given to each subjects and therapeutic effect was evaluated. The two galectin-3 genetic polymorphisms, namely, galectin-3 +191 A>C and +292 A>C, were genotyped.

Results

The polymorphic genotypes and the allele frequency of galectin-3 +191 A>C were not significantly different between responders and non-responders to chemotherapy. For galectin-3 +292 A>C, the AA genotype and A allele distribution were significantly higher in responders than in non-responders. Logistic regression analysis showed CC genotype of galectin-3 +292 presented higher risk of being non-responders compared with the AA genotype (OR?=?2.96, 95?% CI: 1.55?C5.47; P?<?0.001). The overall survival in patients with AA genotype of galectin-3 +292 were significantly longer than in those with CC genotype (25.6 vs. 19.5?months, P?=?0.013). The hazard ratio for CC genotype of galectin-3 +292 was 2.43 (95?% CI: 2.03?C3.98, compared with AA carriers, P?=?0.003).

Conclusion

The galectin-3 genetic polymorphisms of galectin-3 +292, rather than galectin-3 +191, were associated with the chemotherapy response and prognosis of NSCLC.     

Risk factors contributing to the development of carboplatin-related delayed hypersensitivity reactions in Japanese patients with gynecologic cancers

Purpose

The rate of hypersensitivity reactions in patients receiving carboplatin (CBDCA) has been reported to increase after multiple doses of the agent. However, risk factors for these onsets have not been well described. In this study, we investigated the contribution of the reported risk factors to the onset of CBDCA-related delayed hypersensitivity reactions.

Methods

We reviewed the records of gynecologic cancer patients receiving CBDCA of more than 7 cycles in Mie University Hospital from March 2006 to July 2009. The patients were divided into two groups on the basis of whether hypersensitivity reactions developed (13 patients) or not (43 patients). Thereafter, the potential influences of the patients?? characteristics on the development of CBDCA-related delayed hypersensitivity reactions were explored using logistic regression analyses.

Results

The median CBDCA-free interval (10?months) in patients with hypersensitivity reactions was significantly higher than that (3?months) in patients without hypersensitivity reactions. Logistic regression analyses revealed a CBDCA-free interval >13?months (odds ratio 22.2, 95% confidence interval 2.57?C192, p?<?0.01) and a maximum dose of CBDCA?>?650?mg (odds ratio 9.52, 95% confidence interval 1.04?C93.9; p?<?0.05) were significantly correlated with the incidence of CBDCA-related delayed hypersensitivity reactions.

Conclusions

Careful attention should be paid to the onset of delayed hypersensitivity reactions for recurrent gynecologic cancer patients receiving CBDCA?>?650?mg after an interval of more than 13?months from the previous CBDCA administration.     

EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma

Background

Frequencies of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) have predominantly been determined in East Asian and North American populations, showing large differences between these populations. The aim of the present study was to determine the frequency of EGFR and KRAS mutations in NSCLC in the West European Dutch population in primary carcinomas and different metastatic locations.

Methods

EGFR (exons 19, 20 and 21) and KRAS (exons 2 and 3) mutation test results of NSCLC samples of patients in 13 hospitals were collected. The tests were performed on paraffin-embedded tissue or cytological material of primary and metastatic lung carcinomas.

Results

EGFR mutations were detected in 71/778 (9.1?%) tested patients; in 66/620 (10.6?%) adenocarcinomas. EGFR mutations were significantly more often detected in female than in male patients (13.4?% vs. 5.5?%, p?<?0.001). KRAS mutations were found in 277 out of 832 (33.3?%) tested patients; in 244/662 (36.9?%) adenocarcinomas. A significantly increased frequency of EGFR mutations was observed in patients with malignant pleural/pericardial effusions (26.5?%; odds ratio (OR) 2.80, 95?% confidence interval (CI) 1.22?C6.41), whereas the frequency of KRAS mutations was significantly decreased (18.8?%; OR 0.35, 95?% CI 0.14?C0.86).

Conclusions

In the investigated Dutch cohort, patients with malignant pleural/pericardial effusion of lung adenocarcinoma have an increased frequency of EGFR mutations. The overall frequency of EGFR mutations in lung adenocarcinomas in this West European population is within the frequency range of North American and South European populations, whereas KRAS mutation frequency is higher than in any population described to date.     

No evidence for the role of somatic mutations and promoter hypermethylation of FH gene in the tumorigenesis of nonsyndromic uterine leiomyomas

Fumarate hydratase (FH) gene is reported to have specific involvement in syndromic uterine tumors, but its role in nonsyndromic forms is still unclear. Hence, the present study has aimed to screen the role of promoter methylation status and mutations in exon 2 and 7 regions of FH gene in the genesis of nonsyndromic uterine leiomyomas. Leiomyoma and myometrium tissues were collected from 85 hysterectomized uterine specimens. DNA from each of the biopsy was subjected to PCR, methylation-specific restriction assay, and DNA sequencing. In silico analysis was carried out to identify the impact of sequence variants on the protein structure. Chi-square (?? ²) test was used to compare the promoter methylation proportions of leiomyoma and myometrium tissues. No sequence variants were observed in exon 2 region, but three novel heterozygous germ line sequence variants, i.e., c.1010A?>?C, c.1021?G?>?A, and c.1066?T?>?C in exon 7 region of the FH gene were detected in 14/85 (16.5?%) of the cases examined. In silico analysis results showed that c.1010A?>?C and c.1021?G?>?A mutations damage the structure and function of FH, whereas c.1066?T?>?C mutation is mostly tolerant or neutral. No significant difference of FH promoter methylation status between the leiomyoma (11.76?%) and myometrium (5.88?%) tissues was observed (P?=?0.176). Therefore, it is concluded that somatic mutations in FH do not show pronounced effect in nonsyndromic uterine leiomyomas compared to that of their syndromic counterparts. However, higher frequency of FH mutations in leiomyoma cases raises the need to conduct larger number of prospective case-control and family-based studies to assess them as risk markers to nonsyndromic leiomyomas.     

<Emphasis Type="Italic">PRSS1</Emphasis> mutations and the proteinase/antiproteinase imbalance in the pathogenesis of pancreatic cancer

This study aimed to investigate the mutations in the serine protease 1 gene (PRSS1) and the imbalance between trypsin and α1-antitrypsin in patients with pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the sequences of PRSS1 from 65 patients with pancreatic cancer and 260 healthy controls, direct sequencing was performed, and the clinical features were analyzed. In addition, enzyme-linked immunosorbent assay (ELISA) was employed to detect serum trypsin and α1-antitrypsin in pancreatic cancer patients and healthy controls in the same period. Mutations were found at the promoter and exon 3 of the PRSS1 in patients with pancreatic cancer. That is, five patients had c.410 C?>?T mutation causing p.Thr 137 Met, and three patients had c. ?338 T?>?G mutation at the promoter of the PRSS1. In patients with PRSS1 mutations, serum trypsin was 34.5?±?18.3 ng/mL, which was significantly higher than that in normal controls (10.65?±?6.03 ng/mL) and other pancreatic cancer (28.61?±?8.96 ng/mL). What is more, in pancreatic cancer patients, serum α1-antitrypsin was 1.69?±?0.86 g/L, which was comparable to that in normal controls (1.55?±?0.53 g/L), while the ratio of serum trypsin to α1-antitrypsin was 1.46-fold to normal controls. The results presented here have provided a greater insight into the PRSS1 mutations and proteinase-inhibitor interactions occurring in pancreatic cancer.     

Serum levels of surfactant protein D predict the anti-tumor activity of gefitinib in patients with advanced non-small cell lung cancer

Purpose

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has dramatic effects in selective patients with non-small cell lung cancer (NSCLC). A simple non-invasive method for predicting the efficacy of gefitinib is preferable in clinical settings. In this study, we evaluated prospectively whether surfactant protein-A (SP-A) and -D (SP-D) may be new conventional predictors of the efficacy of gefitinib treatment.

Methods

We measured serum SP-A and SP-D levels on days 0 and 29 in 40 patients with advanced NSCLC treated with 250?mg gefitinib daily. Eligibility criteria included performance status ??3, age ??80?years, and stage IIIB?CIV disease. In addition, EGFR mutations were analyzed in 24 patients.

Results

Multivariate analysis showed that favorable progression-free survival (PFS) after gefitinib treatment was associated with adenocarcinoma and high serum SP-D levels before treatment. EGFR mutation analysis of 24 patients showed that 16 patients had exon 19 deletion and/or exon 21 point mutations. EGFR mutations were significantly correlated with response to gefitinib and serum SP-D levels before treatment was significantly high in patients with the EGFR mutations. Serum SP-A levels were not associated with PFS.

Conclusions

The present study showed that measurement of serum SP-D levels before treatment in patients with NSCLC may be a new surrogate marker for predicting the response to gefitinib.     

Tyrosine-kinase mutations in c-KIT and PDGFR-alpha genes of imatinib na?ve adult patients with gastrointestinal stromal tumours (GISTs) of the stomach and small intestine: relation to tumour-biological risk-profile and long-term outcome

Background

The identification of activating mutations in either c-KIT cell surface growth factor receptor or platelet-derived growth factor receptor alpha (PDGFRA) has lead the way for the development of novel agents that selectively inhibit key molecular events in gastrointestinal stromal tumour (GIST) pathogenesis. The aim of this study was to investigate the role of c-KIT and PDGFRA gene mutations in primary resectable, imatinib na?ve GISTs located in the stomach and small intestine.

Methods

All adult patients with GIST located in either stomach or small intestine who underwent surgical resection without prior imatinib (Glivec) treatment were included. DNA extraction and mutational analysis were performed. Mutational analyses were performed for c-KIT (exons 9, 11, 13, and 17) and the PDGFRA genes (exons 12, 14 and 18). Clinical and pathological parameters were analyzed in relation to the mutations in c-KIT and PDGFRA.

Results

A total of 38 patients who underwent surgery for GIST located in either the stomach (n?=?24) or in the small intestines (n?=?14) were included. Mutations were found in 31 of 38 (81.6?%) patients, with 24 (63.2?%) located in c-KIT and 7 (18.4?%) in the PDGRFA exons, respectively. Seven patients (18.4?%) were wildtype (WT). The most common mutation was in c-KIT exon 11. Incidentally found GISTs were significantly smaller (size >5?cm in 15?% for incidental vs. 71?% for symptomatic; OR of 13.4, 95?% CI 2.3?C76.5; P?=?0.001) and had lower mitotic rate (0?% for incidental vs. 44?% of the symptomatic; OR 0.52, 95?% CI 0.36?C0.75; P?=?0.005). Accordingly, the Fletcher grade was significantly better for incidental cases, with most having very low or low risk (85?%) in contrast to 19 of 25 (76?%) symptomatic cases showing moderate to high-risk features (OR 17.4, 95?% CI 2.98?C101.7; P?p?=?0.013).

Conclusions

Long-term survival in resected GISTs of the stomach and small intestine is best determined by Fletcher risk-score. Mitotic activity appears related to tumour size and young age at onset. Mutational status did not influence the clinical or tumour-specific features in this cohort.     

Frequency of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> causative founder variants in ovarian cancer patients in South-East Poland

Background

Causative variants in BRCA1 and BRCA2 are well-established risk factors for breast and ovarian cancer. In Poland, the causative founder variants in the BRCA1 are responsible for a significant proportion of ovarian cancer cases, however, regional differences in the frequencies of various mutations may exist. The spectrum and frequency of BRCA1/2 mutations between ovarian cancer patients have not yet been studied in the region of South-East Poland.

Methods

We examined 158 consecutive unselected cases of ovarian cancer patients from the region of Podkarpacie. We studied 13 Polish causative founder variants in BRCA1 (c.5266dupC, c.4035delA, c.5251C?>?T, c.181 T?>?G, c.676delT, c.68_69delAG, c.3700_3704delGTAAA, c.1687C?>?T, c.3756_3759delGTCT) and in BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT).

Results

A BRCA1 causative founder variants were detected in 10 of the 158 (6.3%) ovarian cancer cases. BRCA2 causative founder variants were not observed. The c.5266dupC mutation was detected in 6 patients, c.181 T?>?G mutation in 3 patients and the c.676delT mutation in 1 patient. The median age of diagnosis of the 10 hereditary ovarian cancers was 55.5 years of age.

Conclusions

The frequency of 13 causative founder variants in Podkarpacie was lower than in other regions of Poland. Testing of three BRCA1 mutations (c.5266dupC, c.181 T?>?G, c.676delT) should be considered a sensitive test panel.

     

Association between cervical dysplasia and human papillomavirus in HIV seropositive women from Johannesburg South Africa

Objective

To examine the association between CD4 counts, HPV infection and the risk of cervical neoplasia among HIV-seropositive women.

Methods

A cross-sectional observational study was conducted among 1,010 HIV-seropositive women using cytology-based Pap smears. HPV DNA testing using Linear Array genotyping assay (Roche) was carried out in a subset of 191 patients. Multivariable-adjusted prevalence ratios (mPR) and 95% confidence intervals (CIs) were estimated with log-binomial regression.

Results

Among 1,010 HIV-seropositive women, the prevalence of AGC/ASCUS, LSIL and HSIL or greater was 8.3, 23.5 and 18.0%, respectively. The risk of cervical lesions was higher with CD4?<?200 cells/mm³ vs. CD4 levels?>?500/mm³. HPV types 16 (41.7%) and HPV 56 (22.2%) were the most common types in HSIL cases. Women with CD4 levels?<?200/mm³ had a higher prevalence of HPV types 16 (p?<?0.01) and 66 (p?=?0.04). No statistical relationship between cervical lesions and HAART use was found.

Conclusion

The burden of HPV infection and HSIL was high and correlated with HIV-induced immunosuppression. HPV 16 was the most common type in HSIL and increased in prevalence with greater immune suppression. Prophylactic HPV 16 vaccination could prevent approximately 40% of HSIL cases. Strengthening screening programs is imperative in this population.     

PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis

Background

PIK3CA mutations in the helical domain (in exon 9) and in the kinase domain (exon 20) cause tumor formation by different means. We aimed to determine the effects of each of these mutations on survival of colon carcinoma patients.

Methods

A large cohort of 685 colon carcinoma patients was tested for PIK3CA mutations in exons 9 and 20 by single nucleotide primer extension (N?=?428) or by real time PCR (N?=?257).

Results

PIK3CA mutation rate was 13%. 66 of 83 (79.5%) were in exon 9 and 17 of 83 (20.5%) in exon 20. In survival analysis, PIK3CA mutations in exon 9 and 20 had different effects on patient outcome. The PIK3CA exon 20 mutation conferred a poorer disease free survival compared to patients with wild type alleles and exon 9 mutations (Log rank p?=?0.04 and p?=?0.03 respectively) and cancer specific survival (Log rank p?=?0.03 and p?=?0.056 respectively) in stage III patients. In stage I and II this negative effect on outcome was not seen.

Conclusions

PIK3CA mutation in exon 20 is a negative prognostic factor in stage III colon cancer patients. Moreover, this negative effect is not present in stage I and II patients.     

Patterns and Biologic Features of p53 Mutation Types in Korean Breast Cancer Patients

Purpose

The p53 gene is one of the most frequently mutated genes in breast cancer. We investigated the patterns and biologic features of p53 gene mutation and evaluated their clinical significance in Korean breast cancer patients.

Methods

Patients who underwent p53 gene sequencing were included. Mutational analysis of exon 5 to exon 9 of the p53 gene was carried out using polymerase chain reaction-denaturing high performance liquid chromatography and direct sequencing.

Results

A total of 497 patients were eligible for the present study and p53 gene mutations were detected in 71 cases (14.3%). Mutation of p53 was significantly associated with histologic grading (p<0.001), estrogen receptor and progesterone receptor status (p<0.001), HER2 status (p<0.001), Ki-67 (p=0.028), and tumor size (p=0.004). The most frequent location of p53 mutations was exon 7 and missense mutation was the most common type of mutation. Compared with patients without mutation, there was a statistically significant difference in relapse-free survival of patients with p53 gene mutation and missense mutation (p=0.020, p=0.006, respectively). Only p53 missense mutation was an independent prognostic factor for relapse-free survival in multivariate analysis, with an adjusted hazard ratio of 2.29 (95% confidence interval, 1.08-4.89, p=0.031).

Conclusion

Mutation of the p53 gene was associated with more aggressive clinicopathologic characteristics and p53 missense mutation was an independent negative prognostic factor in Korean breast cancer patients.     

Prognostic factors in patients with advanced biliary tract cancer receiving chemotherapy

Purpose

Prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy are presently not well established. Gallbladder cancer and intra-hepatic cholangiocarcinoma are previously reported prognostic factors of poor prognosis; however, tumor volume has not been analyzed in these previous reports.

Methods

We analyzed 56 consecutive patients with advanced biliary tract cancer who had received gemcitabine and S-1 combination chemotherapy as first-line palliative chemotherapy. Prognostic factors, including the baseline sum longest diameter (BSLD) representing tumor volume in Response Evaluation Criteria in Solid Tumor, were evaluated.

Results

By multivariate analysis, age ??70 (HR 3.01, 95% CI 1.25?C7.31, P?=?0.014) and larger BSLD (HR 1.09, 95% CI 1.01?C1.18, P?=?0.021) were statistically significant independent predictors of poor prognosis. Primary biliary site was not identified as a prognostic factor (P?=?0.728). Median survival times of patients with BSLDs????9.0?cm and BSLDs?>?9.0?cm were 18.7 and 8.8?months, respectively (P?=?0.024).

Conclusions

Age and BSLD were identified as strong prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy. Tumor volume might be more important than primary biliary site for the prognosis of advanced biliary tract cancer.     

Predicting the effects of chemoradiotherapy for squamous cell carcinoma of the esophagus by induction chemotherapy response assessed by positron emission tomography: toward PET-response-guided selection of chemoradiotherapy or esophagectomy

Background

We have developed a treatment protocol for esophageal cancer involving a single course of induction chemotherapy followed by chemoradiotherapy. This study aimed to determine if it was possible to predict the effects of chemoradiotherapy on the basis of the response to induction chemotherapy, assessed by positron emission tomography (PET).

Methods

Sixteen patients with Stage II?CIVA esophageal cancer were treated using this protocol from April 2007 to July 2010. Chemotherapy involved a fluorouracil and platinum-based combination regimen. All patients received PET scans before and 12?C24?days after the beginning of induction chemotherapy. Associations between the response to induction chemotherapy assessed by PET and the effects of chemoradiotherapy were evaluated.

Results

Induction chemotherapy followed by chemoradiotherapy resulted in complete response (CR) in 10 of the 16 patients. The reduction in maximum standardized uptake value (SUV_max) was 58?±?12% in patients with CR (n?=?10), compared with 14?±?16% in patients without CR (n?=?6) (P?<?0.0001). Using a cut-off value of 55% for SUV_max reduction rate, eight of 10 cancers with CR and six of six cancers without CR were correctly identified, providing a sensitivity and specificity of 80 and 100%, respectively. The overall 1-year survival rates for patients with an SUV_max reduction rate >55% (responders) were 100%, compared with 60% for patients with an SUV_max reduction rate ??55% (non-responders), respectively.

Conclusions

The response to a single course of induction therapy assessed by PET was significantly associated with the effects of chemoradiotherapy.     

Marriage and divorce among young adult cancer survivors

Purpose

We examined marital outcomes among cancer survivors diagnosed during early adulthood from the 2009 Behavioral Risk Factor Surveillance System dataset.

Methods

Eligible participants were ages 20?C39?years. Of the 74,433 eligible, N?=?1,198 self-reported a cancer diagnosis between the ages of 18 and 37, were ??2?years past diagnosis, and did not have non-melanoma skin cancer. The remaining N?=?67,063 were controls. Using generalized linear models adjusted for age, gender, race, and education, we generated relative risks (RR) and 95?% confidence intervals (95?% CI) to examine survivor status on indicators of ever married, currently married, and divorced/separated.

Results

Survivors were slightly older than controls [33.0 (SD?=?3.8) vs. 30.0 (SD?=?4.0); p?<?0.001]. Average time since diagnosis was 7.4?years. Most common diagnoses were cervical (females; 45?%) and non-Hodgkin lymphoma (males; 20?%). Survivors were less likely to be currently married than controls (58?% vs. 64?%; RR?=?0.92, 95?% CI 0.85?C0.99). Among ever married participants, survivors were at an increased risk of divorce/separation than controls (18?% vs. 10?%; RR?=?1.77, 95?% CI 1.43?C2.19). Divorce/separation risk persisted for female survivors (RR 1.83, 95?% CI 1.49?C2.25), survivors ages 20?C29 (RR 2.57, 95?% CI 1.53?C4.34), and survivors ages 30?C39 (RR 1.62, 95?% CI 1.29?C2.04).

Conclusions

The emotional and financial burdens of cancer may lead to marital stress for younger cancer survivors.

Implications for cancer survivors

Young survivors may face a higher risk of divorce; support systems are needed to assist them in the years following diagnosis.     

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

Purpose

The ferret cisplatin emesis model has been used for ~30?years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT₃ receptor antagonists to assess its translational validity.

Methods

A systematic review identified available evidence and was used to perform meta-analyses.

Results

Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n?=?53) used a 10?mg?kg^?1 dose to induce acute emesis, which peaked after 2?h. More recent studies (n?=?11) also used 5?mg?kg^?1, which induced a biphasic response peaking at 12?h and 48?h. Overall, 5-HT₃ receptor antagonists reduced cisplatin (5?mg?kg^?1) emesis by 68% (45?C91%) during the acute phase (day 1) and by 67% (48?C86%) and 53% (38?C68%, all P?<?0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin.

Conclusion

Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT₃ receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret.     

A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

Background

An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.

Methods

We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.

Results

The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.

Conclusions

We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.     

Prognostic value of the Glasgow Prognostic Score for glioblastoma multiforme patients treated with radiotherapy and temozolomide

Introduction

To evaluate the prognostic value of the Glasgow Prognostic Score (GPS), the combination of C-reactive protein (CRP) and albumin, in glioblastoma multiforme (GBM) patients treated with radiotherapy (RT) and concurrent plus adjuvant temozolomide (GPS).

Methods

Data of newly diagnosed GBM patients treated with partial brain RT and concurrent and adjuvant TMZ were retrospectively analyzed. The patients were grouped into three according to the GPS criteria: GPS-0: CRP?<?10 mg/L and albumin?>?35 g/L; GPS-1: CRP?<?10 mg/L and albumin?<?35 g/L or CRP?>?10 mg/L and albumin?>?35 g/L; and GPS-2: CRP?>?10 mg/L and albumin?<?35 g/L. Primary end-point was the association between the GPS groups and the overall survival (OS) outcomes.

Results

A total of 142 patients were analyzed (median age: 58 years, 66.2% male). There were 64 (45.1%), 40 (28.2%), and 38 (26.7%) patients in GPS-0, GPS-1, and GPS-2 groups, respectively. At median 15.7 months follow-up, the respective median and 5-year OS rates for the whole cohort were 16.2 months (95% CI 12.7–19.7) and 9.5%. In multivariate analyses GPS grouping emerged independently associated with the median OS (P?<?0.001) in addition to the extent of surgery (P?=?0.032), Karnofsky performance status (P?=?0.009), and the Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) classification (P?<?0.001). The GPS grouping and the RTOG RPA classification were found to be strongly correlated in prognostic stratification of GBM patients (correlation coefficient: 0.42; P?<?0.001).

Conclusions

The GPS appeared to be useful in prognostic stratification of GBM patients into three groups with significantly different survival durations resembling the RTOG RPA classification.

     

DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity

Background

Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy.

Methods

About 65 patients with HNC (59?±?9?years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59?±?10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage.

Results

Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia?+?sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P?=?0.790).

Conclusions

Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.     

Evaluation of the efficacy and usability of NCI’s Facing Forward booklet in the cancer community setting

Introduction

The NCI developed the print-based educational brochure, Facing Forward, to fill a gap in helping cancer patients meet the challenges of transitioning from active treatment to survivorship; however, little research has been conducted on its efficacy.

Purpose

The aims of this study were to evaluate the efficacy of Facing Forward in promoting the uptake of recommended behaviors (e.g., ways to manage physical changes) and to explore its usability.

Methods

At the last treatment appointment, early-stage breast, prostate, colorectal, and thoracic cancer patients (N?=?340) recruited from community clinical oncology practices and an academic medical center completed a baseline assessment and were randomized to receive either Facing Forward (n?=?175) or an attention control booklet about the NCI’s Cancer Information Service (n?=?165). Patients completed follow-up assessments at 8 weeks and 6 months post-baseline.

Results

The reported uptake of recommended stress management behaviors was greater among intervention than control participants at both 8 weeks post-baseline (p?=?0.016) and 6 months post-baseline (p?=?0.017). At 8 weeks post-baseline, the intervention control group difference was greater among African-American than Caucasian participants (p?<?0.03) and significant only among the former (p?<?0.003); attendance at a cancer support group was also greater among the intervention than control group participants (p?<?0.02). There were no significant intervention control group differences in the reported uptake of recommended behaviors in three other categories (p?>?0.025). Intervention participants rated Facing Forward as understandable and helpful and indicated a high level of intention to try the behaviors recommended.

Conclusions

Facing Forward can enhance early-stage survivors’ reported ability to manage stress and increase support group use during the reentry period.

Implications for Cancer Survivors

Facing Forward can help survivors meet the challenges of the reentry period.     

Measured body mass index in adolescence and the incidence of pancreatic cancer in a cohort of 720,000 Jewish men

Purpose

The increasing prevalence of adolescent obesity affects adult health. We investigated the association of adolescent overweight with pancreatic cancer incidence in a cohort of 720,927 Jewish Israeli men.

Methods

Body mass index (BMI) was measured during a general health examination at ages 16?C19 between the years 1967 and 1995. Overweight was defined as BMI????85th percentile of the reference US-CDC distribution in adolescence. Pancreatic cancer was identified by linkage with the Israel National Cancer Registry up to 2006.

Results

The mean follow-up period was 23.3?±?8.0?years. During 16.8 million person-years, 98 cases of pancreatic cancer were detected. Using Cox proportional hazards modeling, overweight in adolescence predicted an increased risk of pancreatic cancer [hazard ratio (HR)?=?2.09; 95% confidence interval (CI): 1.26?C3.50, p?=?0.005]. Compared with adolescents with ??normal?? range BMI Z-scores (?1 to +1), adolescents with Z-scores?>?1 showed significantly increased risk [HR, 2.28 (95% CI: 1.43?C3.64), p?=?0.001]. Lower education level (10 or less years of schooling vs. 11?C12?years) was also associated with increased risk of pancreatic cancer [HR 1.90 (95% CI: 1.27?C2.86, p?=?0.002)], whereas height, country of origin and immigration status were not.

Conclusions

Adolescent overweight is substantially associated with pancreatic cancer incidence in young to middle-aged adults. Applying our point estimates to the 16.8% prevalence of excess weight in Israeli adolescents in the past decade suggests a population fraction of 15.5% (95% CI: 4.2?C29.6%) for pancreatic cancer attributable to adolescent overweight in Israel.