Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival

Cervical squamous cell carcinomas are composed histologically of tumour cell islands surrounded by varying amounts of tumour stroma, the amount and composition of which are influenced by local TGF-beta(1). TGF-beta(1) is secreted in an inactive complex with latency-associated peptide (LAP). Both LAP and the extracellular matrix (ECM) protein fibronectin are important ligands for the integrin receptor alpha v beta 6. While alpha v beta 6 is only weakly expressed by normal epithelia, it is up-regulated in different carcinomas where it generally reflects a more aggressive phenotype. In cervical cancer, the expression of alpha v beta 6 has not thus far been investigated. Given the ability of alpha v beta 6 both to activate TGF-beta(1) and to interact with fibronectin, we studied correlations between the expression of these components and disease parameters in a large cohort of cervical cancer specimens. We analysed alpha v beta 6 expression using immunohistochemistry in primary cervical squamous carcinomas of FIGO stage IA to IIB patients and correlated the findings with formerly investigated fibronectin and TGF-beta(1) expression and clinico-pathological parameters. alpha v beta 6 expression was also examined in cervical intra-epithelial neoplasia (CIN) and lymph node metastases. alpha v beta 6 was only weakly expressed in normal epithelium but clearly up-regulated in CIN lesions. In carcinomas, strong expression of alpha v beta 6 in tumour cells correlated with different clinico-pathological parameters and with worse overall and disease-free survival. Furthermore, alpha v beta 6 expression correlated positively with TGF-beta(1) mRNA expression as well as with fibronectin expression. Overexpression of alpha v beta 6 in cervical squamous carcinomas is an unfavourable prognostic factor. This might reflect an increased capacity of alpha v beta 6-expressing tumour cells to migrate in a fibronectin-rich ECM and/or to activate TGF-beta(1) at the tumour/stroma interface, both of which processes may contribute to cervical cancer progression.     

Cell cycle kinetics model of LPS-stimulated spleen cells correlates switch region rearrangements with S phase

The cell cycle kinetics of lipopolysaccharide (LPS)-stimulated spleen cells were measured by acridine orange (AO) staining and flow cytometry. We have devised a computer model to predict the proportions of cells in each cell cycle phase using iteratively varied parameters. The optimum fit between the predicted and observed proportions of cells in various phases of the cell cycle was determined using the minimum sigma chi 2. The model then correlates the variability of intermitotic phase time with the proportion of genomic DNA available for immunoglobulin (Ig) switch region (S mu) rearrangement. This analysis predicts that rearrangements at S mu are cell cycle-dependent events which occur during the first S phase after LPS activation. Molecular analysis of this system confirms these predictions.     

Dissecting the gray zone between follicular lymphoma and marginal zone lymphoma using morphological and genetic features

Nodal marginal zone lymphoma is a poorly defined entity in the World Health Organization classification, based largely on criteria of exclusion and the diagnosis often remains subjective. Follicular lymphoma lacking t(14;18) has similar characteristics which results in a major potential diagnostic overlap which this study aims to dissect. Four subgroups of lymphoma samples (n=56) were analyzed with high-resolution array comparative genome hybridization: nodal marginal zone lymphoma, t(14;18)-negative follicular lymphoma, localized t(14:18)-positive follicular lymphoma and disseminated t(14;18)-positive follicular lymphoma. Gains on chromosomes 7, 8 and 12 were observed in all subgroups. The mean number of aberrations was higher in disseminated t(14;18)-positive follicular lymphoma than in localized t(14:18)-positive follicular lymphoma (P<0.01) and the majority of alterations in localized t(14:18)-positive follicular lymphoma were also found in disseminated t(14;18)-positive follicular lymphoma. Nodal marginal zone lymphoma was marked by 3q gains with amplifications of four genes. A different overall pattern of aberrations was seen in t(14;18)-negative follicular lymphoma compared to t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma is characterized by specific (focal) gains on chromosome 3, as observed in nodal marginal zone lymphoma. Our results support the notion that localized t(14:18)-positive follicular lymphoma represents an early phase of disseminated t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma bears aberrations that are more like those in nodal marginal zone lymphoma, suggesting a relation between these groups.     

Excess breast cancer risk in first degree relatives of CHEK211100delC positive familial breast cancer cases

AimThe CHEK211100delC mutation confers a relative risk of two for breast cancer (BC) in the general population. This study aims to explore the excess cancer risk due to the CHEK211100delC mutation within a familial non-BRCA1/2 breast cancer setting.Patients and MethodsCancer incidences were compared between first degree relatives of 107 familial breast cancer patients positive for the CHEK211100delC mutation (CHEK2 positive families) and first degree relatives of 314 familial breast cancer patients without the CHEK211100delC mutation (CHEK2 negative families). All families were derived from the same pool of familial non-BRCA1/2 breast cancer families (n = 2554). Medical information of 2188 first degree relatives of these families was analysed for cancer risk. CHEK211100delC status of relatives was unknown.ResultsIncreased breast cancer risk (hazard ratio (HR) 2.0 (95% confidence interval (CI): 1.4–2.7), p < 0.001) was observed in sisters of CHEK211100delC positive index cases compared to sisters of CHEK211100delC negative index cases. HR was 1.6 (95% CI: 1.0–2.4) for mothers of CHEK2 positive versus negative index cases (p = 0.041). For second primary breast cancers HR was increased in CHEK211100delC positive index cases (HR 2.1, 95% CI: 1.3–3.3, p = 0.003) and their sisters (HR 2.6, 95% CI: 1.1–6.1, p = 0.025).ConclusionThere is an excess breast cancer risk in first degree relatives of CHEK211100delC positive non-BRCA1/2 familial breast cancer patients compared to non-CHEK211100delC familial breast cancer relatives.Genotyping for the CHEK211100delC mutation in a familial breast cancer setting contributes to optimal clinical surveillance in countries in which this mutation is prevalent. Carriers and female relatives are eligible for stringent breast surveillance programs.     

Multimodal surgical guidance towards the sentinel node in vulvar cancer

Introduction

Conventional sentinel node (SN) mapping is performed by injecting a radiocolloid followed by lymphoscintigraphy (and SPECT/CT imaging). An extra intraoperative injection with blue dye can then allow for optical identification of the SN. In order to improve the current clinical standard, the hybrid tracer indocyanine green (ICG)-^99mTc-nanocolloid was introduced, a tracer that is both radioactive and fluorescent. This feasibility study aimed to evaluate the value of a multimodal-based SN biopsy in vulvar cancer.

Materials and methods

Fifteen patients with vulvar cancer (29 groins) scheduled for SN biopsy were peritumorally injected with ICG-^99mTc-nanocolloid followed by lymphoscintigraphy and SPECT/CT imaging to identify the SNs. In thirteen patients, shortly before the start of the operation, blue dye was intradermally injected around the lesion. SNs were harvested using a combination of radiotracing, fluorescence imaging, and optical blue dye detection. A portable gamma camera was used before and after SN excision to confirm excision of the preoperatively defined SNs.

Results

Preoperative lymphoscintigraphy and SPECT/CT imaging visualized drainage to 39 SNs in 28 groins. During the operation, 98% (ex vivo 100%) of the SNs were radioactive. With fluorescence imaging 96% of the SNs (ex vivo 100%) could be visualized. Only 65% of the SNs had stained blue at the time of excision.

Conclusion

ICG-^99mTc-nanocolloid can be used for preoperative SN identification and enables multimodal (radioactive and fluorescent) surgical guidance in patients with vulvar cancer. The addition of fluorescence-based optical guidance offers more effective SN visualization compared to blue dye.     

Combined adaptive servo-ventilation and automatic positive airway pressure (anticyclic modulated ventilation) in co-existing obstructive and central sleep apnea syndrome and periodic breathing

BackgroundThe co-existence of obstructive and central sleep apnea/hypopnea syndrome (OSAS) and periodic breathing is common in patients with and without underlying heart diseases. While automatic continuous positive airway pressure (APAP) has proven to effectively treat OSAS, the adaptive servo-ventilation (ASV) sufficiently improves periodic breathing. This is the first trial on a device which combines both treatment modes.MethodsPilot study on a two-week treatment in patients with co-existing obstructive and central and periodic breathing disturbances during sleep. Twelve consecutive patients (9 male, 3 female, age 56.9 ± 10.6 years, BMI 32.4 ± 5.5 kg/m²) were treated with a new algorithm which combines APAP and ASV (also called anticyclic modulated ventilation (ACMV), SOMNOventCR^®, Weinmann, Hamburg, Germany). Seven suffered from arterial hypertension, coronary heart disease and mitral regurgitation, none from congestive heart failure.ResultsThe total apnea–hypopnea index (AHI) improved from 43.8 ± 24.0/h to 2.1 ± 2.4 (p < 0.01), the obstructive AHI from 12.8 ± 14.3/h to 0.3 ± 0.6/h (p < 0.01) and the central AHI from 31.0 ± 17.5/h to 1.7 ± 2.0/h (p < 0.01). Moreover, there was a significant improvement in the total number of arousals, respiratory induced arousals, oxygen saturation and sleep profile.ConclusionThe algorithm combining automatic continuous positive airway pressure (CPAP) and ASV normalizes all types of co-existing obstructive and central apnea/hypopnea and periodic breathing.     

Intra-articular Corticosteroid Injection for the Treatment of Idiopathic Adhesive Capsulitis of the Shoulder

Treatment for idiopathic adhesive capsulitis or frozen shoulder of the shoulder is controversial. The hypothesis of the study is that intra-articular corticosteroid injection in the early stages of idiopathic adhesive capsulitis will lead to a razpid resolution of stiffness and symptoms. This is a retrospective cohort study of only patients with stage 1 or stage 2 adhesive capsulitis. The diagnosis was made by history and physical examination and only when other causes of pain and motion loss were eliminated. Stage 1 adhesive capsulitis was defined as significant improvement in pain and normalization of motion following intra-articular injection. Stage 2 included patients who had significant improvement in pain and partial improvement in motion following injection. Seven patients with stage 1 and 53 patients with stage 2 comprised the baseline cohort. The mean age was 52 years (range: 30 to 78); 46 patients were female and nine patients had diabetes mellitus. Patients completed a physical examination as well as a shoulder rating questionnaire for symptoms and disability. Criteria for resolution were defined as forward flexion and external rotation to within 15° of the contralateral side and internal rotation to within three spinal levels of the contralateral side. Forty-four of the patients out of 60 met the criteria for recovery at a mean of 6.7 months. The mode and median time to recovery was 3 months. The mean score at final follow-up for 41 patients using the shoulder-rating questionnaire of L’Insalata was 90 (range 52–100). The mean time to recovery for the stage 1 patients was 6 weeks (range: 2 weeks to 3 months), and it was 7 months for stage 2 patients (range: 2 weeks to 2 years). Glenohumeral corticosteroid injection for early adhesive capsulitis may have allowed patients to recover motion at a median time of 3 months. In many cases, the patients had improvement prior to the 3-month mark; however, that was the routine time for follow-up. Patients with stage 1 disease tended to resolve more rapidly than stage 2 patients. Prompt recognition of stage 1 and stage 2 idiopathic adhesive capsulitis and early injection of corticosteroid with local anesthesia may be both diagnostic and therapeutic. This project was funded by philanthropic support of Marcia Kapp.     

Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma

Genetic variation of the antigen processing machinery (APM) components TAP2, LMP7, and ERAP1 is related to cervical carcinoma risk, although the relation with expression and clinical outcome remains unknown. We have investigated the occurrence of APM component single nucleotide polymorphisms (SNPs) in cervical carcinoma. Twelve nonsynonymous, coding SNPs in the TAP1, TAP2, LMP2, LMP7, and ERAP1 genes were genotyped in 75 cervical carcinoma patients with known APM component and HLA class I expression levels. Individual genotype distributions were assessed for association with APM component expression, various histopathological parameters and survival. Genotype distributions at the ERAP1‐56 and ERAP1‐127 loci were significantly associated with overall survival (OS); haplotype construction spanning these two SNPs revealed that the combination of a major allele at ERAP1‐56 and a minor allele at ERAP1‐127 was significantly associated with survival, homozygosity for this haplotype being associated with decreased OS (5‐year survival 50% vs. 70 and 81% for complete absence or heterozygosity for this haplotype, respectively; P = 0.021). Heterozygosity for this haplotype was an independent predictor for better OS in multivariate analysis (HR = 0.219; P = 0.014). These data indicate that genetic variation in APM component genes, particularly ERAP1, is an important contributing factor in cervical carcinogenesis, progressive tumor growth and survival. The location of the ERAP1‐127 SNP in the peptidase M1 domain of the ERAP1 aminopeptidase suggests the possibility of direct functional consequences of variation at this locus. © 2009 Wiley‐Liss, Inc.     

Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance

BACKGROUND & AIMS: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers. METHODS: Mutation analysis was performed in 20 families with a germline mutation in MSH6. We compared the cancer risks between MSH6 and MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors. RESULTS: A total of 146 MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in MSH6 than in MLH1 or MSH2 mutation carriers (P = 0.002). In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in MSH6 mutation carriers, but the difference was not significant (P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in MSH6. CONCLUSIONS: We recommend starting colonoscopic surveillance in female MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for MSH6 mutation analysis.