Androgen receptor expression is a predictive marker in chemotherapy-treated patients with endocrine receptor-positive primary breast cancers

Purpose

The androgen receptor (AR) is intensively discussed as a prognostic and/or predictive marker in breast cancer patients.

Methods

We evaluated the value of AR mRNA expression with the Affymetrix HG-U 133A array in 3 different cohorts: a cohort of breast cancer patients who received adjuvant treatment (cohort A; n = 165), a cohort of untreated breast cancer patients (cohort B; n = 200) and a cohort of chemotherapy-treated breast cancer patients with estrogen receptor (ER)-positive tumors (cohort C; n = 223).

Results

AR mRNA expression was associated with lower grading (Grades 1 and 2) as well as ER and progesterone receptor (PgR) positivity in all cohorts. In the treated cohort (cohort A), low androgen receptor expression was associated with shorter event-free survival (OR 2,34, 95 % CI 1.01–5.43, p = 0.047) which was not seen in the untreated cohort B. Subgroup analysis revealed that shorter survival of patients with low AR mRNA expression was observed mainly in the ER-positive subgroup of patients treated with adjuvant chemotherapy. In the validation cohort C we could confirm a benefit of chemotherapy for the group of tumors with high AR mRNA expression (5-year event-free survival (EFS) 74 % versus 57 %, p = 0.013). In this cohort, low AR mRNA expression was associated with shorter event-free survival also in multivariate analysis (OR 2.86, 95 % CI 1.29–6.35, p = 0.010) adjusted for HER2, ki-67, tumor size, age and tumor grade.

Conclusions

We provide evidence that AR expression is associated with chemotherapy responsiveness in ER-positive patients.     

The effect of bevacizumab on serum soluble FAS/FASL and TRAIL and its receptors (DR4 and DR5) in metastatic colorectal cancer

Purpose

Bevacizumab-based chemotherapy has become the standard of care in metastatic colorectal cancer (MCRC). We aimed to measure the levels of serum soluble FAS, FASL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and its death receptors DR4 and DR5 in MCRC patients and to define prognostic significance of these parameters in response to bevacizumab in these patients.

Patients and methods

The levels of these parameters in serum samples were quantified by a commercially available ELISA kit in 31 MCRC patients before and after 2 cycles of therapy and 25 healthy controls.

Results

Pretreatment sFAS levels in MCRC patients was significantly lower than the levels of controls (p = 0.043). There was no significant difference in sFAS and sFASL levels in MCRC patients before and after bevacizumab-based treatment. There was no significant difference in sFAS/sFASL ratio in MCRC patients before and after treatment and controls. Soluble DR5 levels were significantly higher in pretreatment serum samples compared with controls (p = 0.008). However, pretreatment sTRAIL and sDR4 levels were similar to the levels of controls. There was no significant difference in sTRAIL, sDR4, and sDR5 levels in MCRC patients before and after treatment. When patients were grouped according to treatment response (responders vs. non-responders), post-treatment sFAS/sFASL ratio was significantly lower in responding patients compared with non-responders (p = 0.029). Significant correlations were observed between post-treatment sFASL and sDR4, sFAS and sTRAIL, sTRAIL and sFAS/sFASL ratio, and sFASL and sDR5.

Conclusion

Non-significant changes in apoptotic markers with bevacizumab-based chemotherapy showed that they have no prognostic significance in MCRC patients. Significant change in sFAS/sFASL ratio according to treatment response could be an indicator of chemosensitivity.     

MicroRNA Expression Differentiates Squamous Epithelium from Barrett’s Esophagus and Esophageal Cancer

Background

Current strategies fail to identify most patients with esophageal adenocarcinoma (EAC) before the disease becomes advanced and incurable. Given the dismal prognosis associated with EAC, improvements in detection of early-stage esophageal neoplasia are needed.

Aim

We sought to assess whether differential expression of microRNAs could discriminate between squamous epithelium, Barrett’s esophagus (BE), and EAC.

Methods

We analyzed microRNA expression in a discovery cohort of human endoscopic biopsy samples from 36 patients representing normal squamous esophagus (n = 11), BE (n = 14), and high-grade dysplasia/EAC (n = 11). RNA was assessed using microarrays representing 847 human microRNAs followed by quantitative real-time polymerase chain reaction (qRT-PCR) verification of nine microRNAs. In a second cohort (n = 18), qRT-PCR validation of five miRNAs was performed. Expression of 59 microRNAs associated with BE/EAC in the literature was assessed in our training cohort. Known esophageal cell lines were used to compare miRNA expression to tissue miRNAs.

Results

After controlling for multiple comparisons, we found 34 miRNAs differentially expressed between squamous esophagus and BE/EAC by microarray analysis. However, miRNA expression did not reliably differentiate non-dysplastic BE from EAC. In the validation cohort, all five microRNAs selected for qRT-PCR validation differentiated between squamous samples and BE/EAC. Microarray results supported 14 of the previously reported microRNAs associated with BE/EAC in the literature. Cell lines did not generally reflect miRNA expression found in vivo.

Conclusions

These data indicate that miRNAs differ between squamous esophageal epithelium and BE/EAC, but do not distinguish between BE and EAC. We suggest prospective evaluation of miRNAs in patients at high risk for EAC.     

Comparison of cetuximab to bevacizumab as the first-line bio-chemotherapy for patients with metastatic colorectal cancer: Superior progression-free survival is restricted to patients with measurable tumors and objective tumor response—a retrospective study

Purpose

We aimed to compare the treatment efficacy of cetuximab versus bevacizumab in combination with either irinotecan-based or oxaliplatin-based regimens (targeted triplet) as the first-line treatment for patients with metastatic colorectal cancer.

Methods

Between April 2005 and March 2012, patients (n = 158) diagnosed with metastatic colorectal cancer after at least four courses of first-line bevacizumab-based (n = 95) or cetuximab-based triplet (n = 63) were retrospectively analyzed. The KRAS genotypes were sequenced for all patients. The Kaplan–Meier method was used for survival analysis, and Cox proportional hazards models were used for univariate and multivariate analyses.

Results

Cetuximab-based triplet was associated with a higher objective response rate (66.0 vs. 47.2 %, p = 0.037) and a higher conversion rate to resectability (39.7 vs. 20.0 %, p = 0.007) compared to bevacizumab-based triplet. Compared with bevacizumab-based triplet, cetuximab-based triplet significantly increased progression-free survival in patients with measurable metastatic colorectal cancer who achieved objective tumor response (responders) (median 13.1 vs. 10.5 months, p = 0.023), but no significant increase was observed for overall survival. After adjustment for group differences in baseline characteristics and combined chemotherapy agents, cetuximab-based triplet remained an independent determinant of progression-free survival in responders as compared with bevacizumab-based triplet. KRAS mutation was not a prognostic factor in patients with metastatic colorectal cancer.

Conclusions

As compared with bevacizumab-based triplet, cetuximab-based triplet as the first-line treatment of metastatic colorectal cancer was associated with better progression-free survival in patients with measurable tumors who achieved objective tumor response to bio-chemotherapy.     

Mitomycin C and capecitabine in pretreated patients with metastatic gastric cancer: a multicenter phase II study

Purpose

We conducted a multicenter phase II study to assess the toxicity and efficacy of a combination of mitomycin C (MMC) and capecitabine in pretreated patients with metastatic or locally advanced gastric cancer.

Methods

Thirty-nine patients (77 % male) between 33 and 78 years (median 66) with pretreated locally advanced or metastatic esophagogastric adenocarcinoma and eastern cooperative oncology group performance status of ≤2, measurable lesions, and adequate organ functions were recruited into the study. Eight patients (21 %) had received more than one prior chemotherapy regimen. Treatment consisted of three-weekly MMC 10 mg/m² day 1 and capecitabine 2,000 mg/m² (day 1–14; repeated day 22).

Results

A median of three cycles of therapy was administered. Grade 3 toxicity occurred in 20 patients (54 %). Main grade 3 adverse events were thrombocytopenia (11 %, n = 4), fatigue (8 %, n = 3), and neuropathy (8 %, n = 3). Two events of grade 4 toxicity were reported (5 %) (dyspnea and elevation of alkaline phosphatase due to bone metastases). Partial remission was noticed in 10.3 % (n = 4), stable disease in 33.3 % (n = 13) adding to a tumor control rate of 43.6 %. The median progression-free and overall survival were 2.8 and 5.6 months, respectively.

Conclusion

The combination of MMC and capecitabine exhibited a favorable tolerability profile in pretreated patients with gastric cancer. The disease control rate compares adequately with that of other phase II and phase III trials for second-line therapy in gastric cancer. This regimen may be considered as an alternative second-line treatment, especially for patients not suitable for or pretreated with taxanes and/or irinotecan.     

Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability

Background

The discovery of practical biomarkers is important to realize personalized medicine for patients with malignant neoplasias, including colorectal cancer (CRC).

Purpose

The aim of this study was to determine reliable prognostic biomarkers by the analysis of patients with resectable colorectal liver metastases (CRLM).

Methods

Genomic DNA was obtained from the CRLM tissues of a cohort of 126 patients with CRLM with curative hepatic resection. The KRAS/BRAF mutation spectrum and microsatellite instability (MSI) status were successfully analyzed in 100 of the 126 CRLM tissues and these findings were examined in relation to the patients’ clinical outcomes.

Results

The cohort of 100 CRLM patients consisted of 46 with synchronous and 54 with metachronous liver metastasis. Overall survival and disease-free survival at 5 years were 57.4 and 24.9 %, respectively. MSI analysis revealed that none of the 100 CRLM specimens showed any evidence of MSI. By KRAS/BRAF mutation analysis, the analyzed CRLM patients were divided into 3 groups; KRAS-mutant (KRAS-Mt; n = 27), BRAF-mutant (BRAF-Mt; n = 3), and wild-types of both genes (Wild-type; n = 70). In the survival analysis, both KRAS-Mt and BRAF-Mt patients showed significantly poorer prognoses compared with Wild-type patients. Furthermore, although the population with the BRAF mutation was small, this mutation had a significant negative impact on disease-free survival.

Conclusions

In this study, all tumors in the cohort of CRLM patients were non-MSI tumors, suggesting MSI cancer in primary CRC would rarely reveal metastatic potential. KRAS and BRAF mutations are suggested to be poor prognostic factors in CRLM. Genetic information has an essential role as a prognostic marker and could contribute to the decisions on treatment strategy for CRLM.     

Impact of anticancer treatment on recurrent obstruction in covered metallic stents for malignant biliary obstruction

Background

In patients with unresectable malignant biliary obstruction (MBO), anticancer treatment is often administered. The impact of anticancer treatment on recurrent biliary obstruction in covered self-expandable metallic stents (SEMS) has not been fully elucidated.

Methods

Data on 279 patients enrolled in a multicenter prospective cohort study of two different covered SEMS for distal MBO, WATCH study (141 partially covered WallFlex stents and 138 partially covered Wallstents) were retrospectively analyzed. The rates and causes of recurrent biliary obstruction (stent occlusion or migration) were compared between anticancer treatment group (n = 173) and best supportive care alone (BSC) group (n = 106). Cumulative time and prognostic factors for recurrent biliary obstruction were analyzed, using a proportional hazards model with death without recurrent biliary obstruction as a competing risk.

Results

The overall rate (43 vs. 25 %, P = 0.002) and the cumulative incidence (16.1 vs. 8.2, 27.9 vs. 18.9 and 44.1 vs. 26.6 % at 3, 6 and 12 months, P = 0.030 by Gray’s test) of recurrent biliary obstruction were significantly higher in anticancer treatment group compared with BSC group. The multivariate analysis revealed anticancer treatment [subdistribution hazard ratio (SHR) 1.93, P = 0.007) as well as the use of a partially covered WallFlex stent (SHR 0.65, P = 0.049) as prognostic factors.

Conclusions

Anticancer treatment was a risk factor for recurrent biliary obstruction in covered SEMS for distal MBO. The superiority of a partially covered WallFlex stent was again confirmed in this competing risk analysis; UMIN-CTR: UMIN000002293.     

Prognostic impact of LDH levels in patients with relapsed/refractory seminoma

Purpose

To evaluate the impact of age and LDH levels in patients with relapsed seminoma.

Methods

Data on the 204 seminoma from the International Prognostic Factor Study Group (IPFSG) were analyzed. All patients experienced unequivocal relapse/progression after at least three cisplatin-based chemotherapy cycles. Age and LDH at relapse were assessed in addition to previously identified prognostic factors for all germ cell tumor patients from the database (J Clin Oncol 28:4906, 2010).

Results

The impact of the IPFSG score remained highly significant in multivariate analysis. In addition, LDH ≥1.5 times the upper limit of normal (ULN) was significant in univariate (HR 1.96; CI 1.06–3.61) and multivariate analysis (HR 1.90; CI 1.00–3.62). Age, however, was not significant. Therefore, LDH was incorporated into a modified new IPFSG seminoma score by moving patients to the next unfavorable group for patients with LDH values ≥1.5 × ULN. Three prognostic groups were thus generated, which better subdivided seminoma patients than the original IPFSG score. Progression-free survival at 2 years: “very low risk” (n = 23) 85.7 % (95 % CI 62–95), “low risk” (n = 44) 62.7 % (95 % CI 46–75) and “intermediate risk” (n = 36) 35.1 % (95 % CI 20–51). Overall survival at 3 years: “very low risk” 88.8 % (95 % CI 62–97), “low risk” 71.3 % (95 % CI 55–83) and “intermediate risk” 51.3 % (95 % CI 33–67).

Conclusion

The addition of LDH, but not age, improves the impact of the IPFSG prognostic score in seminoma patients relapsing or progressing after cisplatin-based chemotherapy.     

Clinical impact of radiotherapy for locally advanced pancreatic cancer

Background

Although a randomized controlled trial for locally advanced pancreatic cancer (PC) has demonstrated a survival advantage for treatment with gemcitabine alone, chemoradiotherapy remains the treatment of choice for locally advanced disease in Japan. The aim of this study was to compare the survival benefits associated with gemcitabine and concurrent chemoradiotherapy in locally advanced unresectable PC.

Patients

Seventy-seven patients with locally advanced unresectable PC were retrospectively enrolled from April 2001 to December 2006. All cases were histologically proven, and patients received gemcitabine chemotherapy (n = 30) or concurrent chemoradiotherapy (based on 5-fluorouracil, n = 28, or gemcitabine, n = 19, as a radiosensitizer) at Aichi Cancer Center Hospital.

Results

Patients who received chemoradiotherapy had significantly better performance status than those who had chemotherapy. Tumor response was 0% for chemotherapy and 13% chemoradiotherapy, but survival benefit was similar among patients in the chemotherapy group (overall response (OS) 12 months; progression-free survival (PFS), 3 months) and those in the chemoradiotherapy group (OS, 13 months; PFS, 5 months). Two-year survival was 21% for chemotherapy patients and 19% for chemoradiotherapy patients. Severe toxicities (Grade 3–4 National Cancer Institute-Common Toxicity Criteria, version 3.0) were significantly more frequent for chemoradiotherapy than for chemotherapy.

Conclusions

Gemcitabine chemotherapy showed similar survival benefit compared to 5-fluorouracil- and gemcitabine-based chemoradiotherapy.     

KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer

Background

It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC).

Methods

AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc).

Results

KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (p = 0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p = 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p = 0.10) for the OSc.

Conclusion

This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.     

Effect of prior chemotherapy regimens on the efficacy of endocrine therapy within a German cohort of the TEAM trial

Purpose

Prior chemotherapy may affect the efficacy of endocrine therapy.

Methods

The tamoxifen exemestane adjuvant multinational (TEAM) trial compared 5 years of adjuvant exemestane with the sequence of tamoxifen followed by exemestane in postmenopausal women with hormone-receptor-positive breast cancer. A total of 1,502 patients were enrolled in Germany (739 received tamoxifen followed by exemestan and 610 exemestan alone). A retrospective analysis of the German cohort of TEAM was conducted to determine whether prior chemotherapy affected clinical outcome of endocrine therapy.

Results

Overall survival, disease-free survival and distant recurrence were similar between patients who received sequential therapy and those who received exemestane monotherapy, irrespective of prior chemotherapy. Overall survival was not significantly different between patients who had received prior chemotherapy and those who had not (P = 0.2836). Disease-free survival and distant recurrence were significantly better in patients who had not received prior chemotherapy versus those who had (P = 0.0308 and P = 0.0001). In patients receiving sequential therapy, there were no significant differences in overall survival according to prior chemotherapy use (P = 0.1812). However, disease-free survival and distant recurrence were significantly different dependent on prior chemotherapy (P = 0.0143 and P = 0.0053).

Conclusion

In conclusion, there was no difference in overall survival between breast cancer patients who did receive prior chemotherapy before endocrine therapy and those who had not. Patients who had not received prior chemotherapy had significantly improved disease-free survival and less distant recurrence versus those who had received chemotherapy.     

Progression-free survival and post-progression survival in patients with advanced gastric cancer treated with first-line chemotherapy

Purpose

The impact of post-progression survival (PPS) on the overall survival (OS) of patients with advanced gastric cancer (AGC) has not yet been reported in detail. We analyzed prospectively collected data from AGC patients who received first-line chemotherapy including fluoropyrimidine plus platinum.

Methods

We partitioned OS into progression-free survival (PFS) and PPS in each patient and analyzed correlations between OS and either PFS or PPS using the Spearman rank correlation coefficient (ρ).

Results

A total of 291 AGC patients met the inclusion criteria with median PFS, PPS, and OS of 5.3, 8.1, and 14.8 months, respectively. PFS and OS for each patient showed a correlation of ρ = 0.75 [95 % confidence interval (CI) 0.69–0.81]. PPS and OS showed a correlation of ρ = 0.87 (95 % CI 0.84–0.91). According to multivariate analysis, performance status at progression, PFS of first-line chemotherapy, and use of second-line chemotherapy were independently associated with PPS.

Conclusions

These results indicate that both PFS and PPS are correlated with OS in first-line chemotherapy for AGC, suggesting the importance of reporting detailed patient characteristics and treatment course after disease progression in clinical trials of first-line chemotherapy for AGC.     

Characteristics of Small Bowel Tumors Detected by Double Balloon Endoscopy

Background

A few reports suggest that the emergence of double balloon endoscopy (DBE) has likely changed the clinical picture of small bowel tumors (SBTs).

Aim

To further clarify the characteristics of SBTs detected by DBE.

Methods

A retrospective chart review was conducted in 227 patients who had undergone DBE.

Results

The SBT group contained more symptomatic patients than the non-SBT group (90% vs. 49%, P < 0.0005) with a significantly higher rate of gastrointestinal symptoms at presentation (72% vs. 33%, P < 0.005). Twenty patients (8.8%) were eventually diagnosed with SBT, and their indications for DBE were obscure gastrointestinal bleeding (n = 5), abdominal pain (n = 5), abdominal fullness (n = 5), vomiting (n = 2), and diarrhea (n = 1). Tumors were located in the jejunum in 14 patients (70%) and in the ileum in 6 (30%). A final histological diagnosis was assigned to all 20 patients: primary adenocarcinoma (n = 8, 40%), malignant lymphoma (n = 5, 25%), metastatic cancer (n = 4, 20%), gastrointestinal stromal tumor (n = 1, 5%), carcinoid tumor (n = 1, 5%) and inflammatory fibroid polyp (n = 1, 5%). Stenosis or ulceration were the most frequently observed endoscopic findings (n = 13, 65%). All primary adenocarcinomas and three of four (75%) metastatic cancers showed stenosis or ulceration. Three of five (60%) malignant lymphomas showed multiple lymphomatous polyps. All patients but one underwent surgical resection or chemotherapy or both.

Conclusion

DBE is a safe and useful procedure that enables a precise diagnosis of SBTs.     

Single Balloon Enteroscopy (SBE) Assisted Therapeutic Endoscopic Retrograde Cholangiopancreatography (ERCP) in Patients with Roux-en-Y Anastomosis

Background

Endoscopic retrograde cholangiopancreatography (ERCP) in patients with Roux-en-Y anastomosis is a complex challenge. Long length of afferent limb after an acute angle at the jejunojejunostomy and altered location of the biliary orifice make biliary cannulation difficult. Single balloon enteroscopy assisted ERCP (SBE-ERCP) is a promising alternative to conventional approaches.

Aim

The purpose of this study was to assess the efficacy and safety of SBE-ERCP in patients with Roux-en-Y reconstruction at a high volume tertiary referral center.

Methods

This is a retrospective cohort study. All procedures were performed by a single, experienced pancreatobiliary endoscopist. Patient demographics and related clinical data were obtained. The rate of procedure successes and complications were determined.

Results

Fourteen patients (nine women) with a median age of 63 years (range 35–83 years) underwent 22 SBE-ERCP procedures from March 2009 to May 2011. Surgically altered anatomy consisted of Whipple procedure (n = 4), hepaticojejunostomy (n = 9) and partial gastrectomy (n = 1). Indications for SBE-ERCP were obstructive jaundice (n = 10), cholangitis (n = 7), post-PTC internalization (n = 3) and biliary stent extraction/exchange (n = 2). The hepaticojejunostomy site (HJS) was reached in 15 (68 %) procedures. Successful interventions were performed in 11 (73 %) of 15 cases, including balloon dilation of biliary strictures (n = 3), insertion of biliary stents (n = 7), retrieval of biliopancreatic stents (n = 4) and biliary stone extraction (n = 4). The mean procedural time for successful interventions was 97.6 min (range 73–147 min). No procedural complications occurred during the median follow-up of 501 days (range 22–1,242 days).

Conclusion

SBE-ERCP is safe and carries an acceptable success rate in experienced hands.     

Outcomes and predictive factors of prostate cancer patients with extremely high prostate-specific antigen level

Purpose

Prostate-specific antigen (PSA) is a useful biomarker of prostate cancer (PCa). High-risk localized PCa is defined using T stage, Gleason score (GS), and PSA. However, PSA level defining high-risk PCa is at most 20 ng/mL. In PCa patients with high PSA, it is unclear whether PSA itself can be a prognostic factor.

Methods

Of 642 patients who were diagnosed as PCa, 90 patients with PSA > 100 ng/mL were retrospectively analyzed. Patients were divided into three groups according to PSA level: very high (>1,000 ng/mL), moderately high (200–1,000 ng/mL), and slightly high (100–200 ng/mL).

Results

There were no significant differences in overall survival or PCa-specific survival (PCaSS) among the three groups. Regardless of PSA level, high M stage and GS significantly reduced PCaSS. When the risk classification was made using M stage and GS (high risk = M1 and GS ≥ 9, low risk = M0 and GS < 9, and intermediate risk = others), PCaSS was significantly different among high-, intermediate-, and low-risk groups with 5-year survival rates of 58.2, 80.6, and 100 %, respectively. Although there were no differences in treatment performed during the castration-resistant stage, patients undergoing alternative anti-androgen and zoledronic acid treatment had better PCaSS after being castration-resistant.

Conclusions

As PSA could not be a prognostic factor in PCa patients with high PSA > 100 ng/mL, the novel risk classification using M stage and GS may help clinicians to predict PCaSS and to plan follow-up schedules after diagnosis.     

Predictive value of sphingosine kinase 1 expression in neoadjuvant treatment of breast cancer

Purpose

Sphingolipids play important roles in apoptosis and cell proliferation. Sphingosine kinase 1 (SphK1) expression has a prognostic impact in primary breast cancer, but its predictive value is currently unknown.

Methods

A total of 112 breast cancer specimens from a prospective neoadjuvant chemotherapy trial (GeparDuo) were studied. Using tissue microarrays of pre-treatment core cut biopsies, we determined the expression of SphK1 by immunohistochemistry. The upper quartile of the cohort according to an immune reactive score of SphK1 was used as cutoff for high expression.

Results

We observed a larger number of samples with high SphK1 expression among ER-negative cancers (36.8 vs. 20.5 % among ER-positive cancers; Fisher test p = 0.073). Eighteen of the 112 patients demonstrated a pathological complete response. A significant predictive value for pathological complete response was observed for ER negativity (p = 0.003), young age (p = 0.037), and high tumor grade (p = 0.049). An increased pCR rate was observed in tumors with high SphK1 expression within the luminal subtype (26.7 vs. 5.8 %; Fisher test p = 0.040). No significant difference in survival was detected according to SphK1 expression.

Conclusions

Our results suggest that SphK1 may be a predictive factor for pCR after neoadjuvant treatment in luminal type breast cancers and warrants further investigation.     

Expression of the calpain system is associated with poor clinical outcome in gastro-oesophageal adenocarcinomas

Background

Surgery is critical in the management of gastro-oesophageal cancer, and the addition of neo-adjuvant chemotherapy has proved to be of benefit. The calpain system has been implicated in tumour progression and response to various anti-cancer therapies, and therefore expression of the system was determined in this tumour type.

Methods

Two cohorts of gastro-oesophageal adenocarcinomas were investigated for calpain-1, calpain-2, calpain-9 and calpastatin expression using conventional immunohistochemistry. 88 patients who received neo-adjuvant chemotherapy and 140 patients who received surgery alone were investigated using a tissue microarray approach.

Results

Calpain-1, calpain-2 and calpastatin expression was associated with adverse cancer-specific survival in the neo-adjuvant cohort (P = 0.004, P = 0.001 and P = 0.012 respectively); which remained significant in multivariate analysis (Hazard ratio (HR) = 0.337; 95 % confidence interval (CI) = 0.140–0.81; P = 0.015, HR = 0.375; 95 % CI = 0.165–0.858; P = 0.020 and HR = 0.481; 95 % CI = 0.257–0.900; P = 0.022 respectively). Calpain-1 and calpastatin expression was also associated with adverse cancer specific survival in the primary surgery cohort (P = 0.001 and P = 0.013 respectively); which remained significant in multivariate analysis (HR = 0.309; 95 % CI = 0.159–0.601; P = 0.001 and HR = 0.418; 95 % CI = 0.205–0.850; P = 0.016 respectively). Calpain-9 expression was not associated with cancer-specific survival in the neo-adjuvant and primary surgery cohorts.

Conclusion

Determining the expression levels of calpain-1, calpain-2 and calpastatin may provide clinically relevant prognostic information for gastro-oesophageal adenocarcinomas; these findings warrant further studies in larger cohorts of patients.     

Vascular Endothelial Growth Factor Levels in Bile Distinguishes Pancreatic Cancer from Other Etiologies of Biliary Stricture: A Pilot Study

Background

Determining the benign or malignant nature of biliary strictures can be challenging. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis.

Objective

The purpose of this study was to investigate whether VEGF levels in bile aspirated during endoscopic retrograde cholangiography (ERCP) can distinguish pancreatic cancer from other causes of biliary stricture.

Methods

Bile was directly aspirated in 53 consecutive patients from March 2012 to October 2012 during ERCP from the common bile duct including 15 with pancreatic cancer, 18 with primary sclerosing cholangitis (PSC), nine with cholangiocarcinoma (CCA), and 11 with benign biliary conditions (sphincter of Oddi and choledocholihiasis). Levels of VEGF in bile were measured. The diagnostic performance was then validated in a second, independent validation cohort of 18 patients (pancreatic cancer n = 10, benign n = 8).

Results

A total of 53 consecutive patients were recruited. The median bile VEGF levels were significantly elevated in patients with pancreatic cancer (1.9 ng/ml (interquartile range [IQR] 0.7, 2.2) compared to those with benign biliary conditions (0.3 ng/ml [IQR 0.2, 0.6]; p < 0.001), PSC (0.7 ng/ml [IQR 0.5, 0.9]; p = 0.02) or CCA (0.4 ng/ml [IQR 0.1, 0.5]; p < 0.001). A VEGF cut-off value of 0.5 ng/ml distinguished pancreatic cancer from CCA with a sensitivity and specificity of 93.3 and 88.9 %, respectively, and area under curve (AUC) of 0.93, and from benign conditions with a sensitivity and specificity of 93.3 and 72.7 %, respectively, with AUC of 0.89. The diagnostic accuracy of biliary VEGF was confirmed in the second independent validation cohort.

Conclusions

This study suggests that measurement of biliary VEGF-1 levels distinguishes patients with pancreatic cancer from other etiologies of biliary stricture. This may be particularly relevant in approaching patients with indeterminate biliary stricture.     

Causes of death in HIV-infected patients from the Cologne–Bonn cohort

Purpose

Causes of death in human immunodeficiency virus (HIV)-infected subjects have changed in countries with high resources over the last several years. Acquired immunodeficiency syndrome (AIDS)-related diseases have become less prevalent, whereas deaths due to non-AIDS causes are increasing. The aim of the present study was to analyse causes of death in the Cologne–Bonn cohort.

Methods

Causes of death from the Cologne–Bonn cohort between 2004 and 2010 were systematically recorded using the CoDe algorithm (The Coding Causes of Death in HIV Project).

Results

In 3,165 patients followed from 2004 to 2010, 182 deaths occurred (5.7 %, 153 males, 29 females). The median age at the time of death was 47 years (range 24–85 years). The most frequent causes of death were AIDS-defining events (n = 60, 33 %), with non-Hodgkin lymphoma (NHL) (n = 29, 16 %) and infections (n = 20, 11 %) being the leading entities in this category. Non-AIDS malignancies accounted for 16 % (n = 29), non-HIV-related infections for 10 % (n = 18), cardiovascular diseases for 7 % (n = 14), suicide or accident for 4 % (n = 7) and liver diseases for 3 % (n = 5) of deaths (unknown n = 47, 26 %). Although the majority of patients (92.5 %) was on antiretroviral therapy (ART), only 50 % were virologically suppressed (HIV-RNA <50 copies/mL) and 44 % had a decreased CD4+ count (<200/μL) at their last visit before death.

Conclusion

One-third of the causes of death in our cohort between 2004 and 2010 was AIDS-related. Since most of these deaths occur with severe immune suppression, they can possibly be prevented by the early diagnosis and treatment of HIV infection. Care providers must be aware of an increased risk for a broad range of diseases in HIV-infected patients and should apply appropriate preventive measures.     

Prognostic value of ERCC1 in head and neck carcinoma treated with definitive or adjuvant radiotherapy

Purpose

To evaluate the prognostic significance of excision repair cross-complementation group 1 (ERCC1) expression in head and neck carcinoma patients treated with definitive radiotherapy (DR) or adjuvant radiotherapy (AR).

Methods

ERCC1 expression was assessed by immunohistochemical staining. A total of 48 patients were assessed.

Results

High ERCC1 expression was found in 23 patients (48 %). More ERCC1-positive tumours were detected in patients treated with DR than in patients treated with AR (73 vs. 36 %, respectively, p = 0.03). ERCC1 expression had no impact on overall survival neither in the whole cohort of patients (p = 0.16) nor in each particular treatment group (AR p = 0.98; DR p = 0.21).

Conclusions

ERCC1 expression had no predictive value in head and neck carcinoma patients treated with DR or AR. There might be difference in ERCC1 positivity that comes out of whether the assessment is done on biopsy or surgical specimens.