Impact of viral E2-gene status on outcome after radiotherapy for patients with human papillomavirus 16-positive cancer of the uterine cervix

PURPOSE: Integration of high-risk papillomavirus DNA has been considered an important step in oncogenic progression to cervical carcinoma. Disruption of the human papillomavirus (HPV) genome within the E2 gene is frequently a consequence. This study investigated the influence of episomal viral DNA on outcome in patients with advanced cervical cancer treated with primary radiotherapy. METHODS AND MATERIALS: Paraffin-embedded biopsies of 82 women with locally advanced cervical cancer could be analyzed for HPV infection by multiplex polymerase chain reaction (PCR) by use of SPF1/2 primers. E2-gene intactness of HPV-16-positive samples was analyzed in 3 separate amplification reactions by use of the E2A, E2B, E2C primers. Statistical analyses (Kaplan-Meier method; log-rank test) were performed for overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS), and distant metastases-free survival (DMFS). RESULTS: Sixty-one (75%) of 82 carcinomas were HPV positive, 44 of them for HPV-16 (72%). Seventeen of the 44 HPV-16-positive tumors (39%) had an intact E2 gene. Patients with a HPV-16-positive tumor and an intact E2 gene showed a trend for a better DFS (58% vs. 38%, p = 0.06) compared with those with a disrupted E2 gene. A nonsignificant difference occurred regarding OS (87% vs. 66%, p = 0.16) and DMFS (57% vs. 48%, p = 0.15). CONCLUSION: E2-gene status may be a promising new target, but more studies are required to elucidate the effect of the viral E2 gene on outcome after radiotherapy in HPV-positive tumors.

[Follow-up after malignant tumours of the uterus (cancer of the uterine corpus / cervical cancer)]

Malignant uterine tumours can affect the corpus or the cervix. The endometrial carcinoma with its different histological subtypes counts for most of the malignomas of the uterine body. But the rare category of uterine sarcomas (carcinosarcomas, leiomyosarcomas as well as endometrial stromal sarcomas) also belongs to this group. Cervical cancer presents an own entitity, regarding both histology and therapeutic options. Endometrial cancer is the most common genital malignoma in Northern Europe and North America. Histologically, the endometrial cancer can be subdivided in two groups: type I is hormonal sensitive and well differentiated, type II represents an undifferenciated aggressive tumour with poor prognosis. In general, the patient is elderly. Due to the main symptom - abnormal vaginal bleeding - endometrial cancer is detected in an early stage in about 75% of all patients. First choice in therapy is stage related surgery. Follow-up schemes have not proved yet to improve survival, therefore clear guidelines are missing. National and international groups recommend regular follow-up visits to detect the early vaginal vault relapse which is curable. Cervical cancer is mainly a squamous cell carcinoma and oncogenic Human Papilloma Virus (HPV) associated. Surgery is only indicated up to stage IIA, advanced stages should be treated by radio-chemotherapy. Several studies have shown that follow-up visits can improve survival rates. Intention is the detection of the curable local relapse.

Cancer of the oral cavity and oropharynx

Tumours in the oral cavity and oropharynx differ in presentation and prognosis and the detection of spread of tumour from one subsite to another is essential for the T-staging. This article reviews the anatomy and describes the pattern of spread of different cancers arising in the oral cavity and oropharynx; the imaging findings on computerized tomography and magnetic resonance imaging are also described. Brief mention is made on the role of newer imaging modalities such as [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography, perfusion studies and diffusion-weighted magnetic resonance imaging.

Case-control analysis on metformin and cancer of the esophagus

PURPOSE Metformin use has been associated with decreased cancer risks, though data on esophageal cancer are scarce. We explored the relation between use of metformin or other anti-diabetic drugs and the risk of esophageal cancer. METHODS We conducted a case-control analysis in the UK-based general practice research database (GPRD, now clinical practice research datalink, CPRD). Cases were individuals with an incident diagnosis of esophageal cancer between 1994 and 2010 at age 40-89 years. Ten controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Various potential confounders including diabetes mellitus, gastro-esophageal reflux, and use of proton-pump inhibitors were evaluated in univariate models, and the final results were adjusted for BMI and smoking. Results are presented as odds ratios (ORs) with 95 % confidence intervals (CI). RESULTS Long-term use (≥30 prescriptions) of metformin was not associated with a materially altered risk of esophageal cancer (adj. OR 1.23, 95 % CI 0.92-1.65), nor was long-term use of sulfonylureas (adj. OR 0.93, 95 % CI 0.70-1.23), insulin (adj. OR 0.87, 95 % CI 0.60-1.25), or of thiazolidinediones (adj. OR 0.71, 95 % CI 0.37-1.36). CONCLUSION In our population-based study, use of metformin was not associated with an altered risk of esophageal cancer.

Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder

PURPOSE To assess whether Bcl-2, an inhibitor of the apoptotic cascade, can predict response to neoadjuvant chemotherapy in patients with urothelial cancer of the bladder (UCB). METHODS Bcl-2 expression was analyzed in 2 different tissue microarrays (TMAs). One TMA was constructed of primary tumors and their corresponding lymph node (LN) metastases from 152 patients with chemotherapy-naive UCB treated by cystectomy and pelvic lymphadenectomy (chemotherapy-naive TMA cohort). The other TMA was constructed of tumor samples obtained from 55 patients with UCB before neoadjuvant chemotherapy (transurethral resection of the bladder cancer) and after cystectomy with pelvic lymphadenectomy (residual primary tumor [ypT+], n = 38); residual LN metastases [ypN+], n = 24) (prechemotherapy/postchemotherapy TMA cohort). Bcl-2 overexpression was defined as 10% or more cancer cells showing cytoplasmic immunoreactivity. RESULTS In both TMA cohorts, Bcl-2 overexpression was significantly (P<0.05) more frequent in LN metastases than in primary tumors (chemotherapy-naive TMA group: 18/148 [12%] in primary tumors vs. 39/143 [27%] in metastases; postchemotherapy TMA: ypT+7/35 [20%] vs. ypN+11/19 [58%]). In the neoadjuvant setting, patients with Bcl-2 overexpression in transurethral resection of the bladder cancer specimens showed significantly (P = 0.04) higher ypT stages and less regression in their cystectomy specimens than did the control group, and only one-eighth (13%) had complete tumor regression (ypT0 ypN0). In survival analyses, only histopathological parameters added significant prognostic information. CONCLUSIONS Bcl-2 overexpression in chemotherapy-naive primary bladder cancer is related to poor chemotherapy response and might help to select likely nonresponders.

Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.

Trends in incidence of oesophageal and gastric cancer according to morphology and anatomical location, in Switzerland 1982-2011.

QUESTION UNDER STUDY/PRINCIPLES This study aimed to evaluate trends in the incidence of oesophageal and gastric cancer by anatomical location and histology using nationally representative Swiss data. METHODS We included all oesophageal and gastric cancers recorded in 10 Swiss population-based cancer registries 1982-2011. We calculated age-standardised incidence rates (ASIRs) per 100 000 person-years (PY) (European standard) for both cancer sites stratified by sex, language region (German, French-Italian), morphology and anatomical location. To assess time trends, we estimated annual percentage changes (APCs) with 95% confidence intervals (95% CIs). RESULTS ASIR of oesophageal adenocarcinoma increased in both sexes and language regions (p <0.001). The steepest increase occurred in males of the German-speaking region (APC 6.8%, 95% CI 5.8-7.8) with ASIRs of 0.8 per 100,000 PY in 1982-1987 and 3.9 per 100.000 PY in 2007-2011. Incidence of oesophageal squamous cell carcinoma decreased significantly in males of both language regions by around -1.5% per year. In contrast, a slight but significant increase (APC 1.4%, 95% CI 0.3-2.4]) of oesophageal squamous cell carcinoma was observed in females of the German-speaking region. We observed stable rates for cancer of the gastric cardia. The incidence of noncardia gastric cancer decreased substantially in both sexes and language regions (p <0.001). CONCLUSION In Switzerland, the incidence of oesophageal adenocarcinoma has risen whereas incidence of noncardia gastric cancer has decreased substantially as observed in other developed countries.

Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed

Malignant pleural mesothelioma (MPM) is a lethal cancer of the mesothelium with high chemotherapeutic resistance via unknown mechanisms. A prevailing hypothesis states that cancer stem cells (CSCs) persist in tumors causing relapse after chemotherapy, thus, rendering these cells as critical targets responsible for tumor resistance and recurrence. We selected candidate CSC markers based on expansion under hypoxic conditions, a hallmark for the selection of chemoresistant cells; and investigated the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in three MPM cell lines and normal mesothelial cells by quantitative RT-PCR. Furthermore, we evaluated the chemotherapeutic resistance associated with each CSC marker by determining the change in CSC marker-mRNA levels as an index of drug-resistance following treatment with either cisplatin or pemetrexed. We demonstrate the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in both normal and MPM cell lines. Bmi-1+, uPAR+ and ABCG2+ cells show a distinct role in conferring chemoresistance to cisplatin and pemetrexed in the malignant setting. By contrast, these markers have no apparent participation in chemoresistance to drug treatments in normal mesothelial cells. Intriguingly, CD133 revealed chemoresistant properties in both normal mesothelial and malignant pleural mesothelioma cells. This study provides evidence of putative CSCs conferring drug-resistance to cisplatin and pemetrexed in MPM cell lines. Specific targeting of these drug-resistant cells, while considering the functional heterogeneity of the MPM subtypes, may contribute to more focused and effective chemotherapeutic regimens for malignant pleural mesothelioma.

Long-term anticoagulation treatment for acute venous thromboembolism in patients with and without cancer. The SWIss Venous ThromboEmbolism Registry (SWIVTER) II

In patients with acute cancer-associated thrombosis, current consensus guidelines recommend anticoagulation therapy for an indefinite duration or until the cancer is resolved. Among 1,247 patients with acute venous thromboembolism (VTE) enrolled in the prospective Swiss Venous Thromboembolism Registry (SWIVTER) II from 18 hospitals, 315 (25%) had cancer of whom 179 (57%) had metastatic disease, 159 (50%) ongoing or recent chemotherapy, 83 (26%) prior cancer surgery, and 63 (20%) recurrent VTE. Long-term anticoagulation treatment for >12 months was more often planned in patients with versus without cancer (47% vs. 19%; p<0.001), with recurrent cancer-associated versus first cancer-associated VTE (70% vs. 41%; p<0.001), and with metastatic versus non-metastatic cancer (59% vs. 31%; p<0.001). In patients with cancer, recurrent VTE (OR 3.46; 95%CI 1.83-6.53), metastatic disease (OR 3.04; 95%CI 1.86-4.97), and the absence of an acute infection (OR 3.55; 95%CI 1.65-7.65) were independently associated with the intention to maintain anticoagulation for >12 months. In conclusion, long-term anticoagulation treatment for more than 12 months was planned in less than half of the cancer patients with acute VTE. The low rates of long-term anticoagulation in cancer patients with a first episode of VTE and in patients with non-metastatic cancer require particular attention.

MMP-2 and MMP-9 in lymph-node-positive bladder cancer

Matrix metalloproteinases (MMP), particularly MMP-2 and MMP-9, participate in tumour progression and metastasis in various cancers. Their significance in urothelial cancer of the bladder (UCB) is unclear. Expression analysis of MMP-2 and MMP-9 in tissue microarrays (TMA) constructed of corresponding samples from histopathological normal urothelium, tumour centre and invasion front of primary tumours and lymph-node (LN) metastases might help to elucidate their relevance in UCB.

The transposition advancement flap for repair of postsurgical defects on the upper lip

Skin cancer of the lip is frequent, and reconstruction after Mohs surgery might be challenging mostly when the postsurgical defect has a size of more than 1 cm(2) and is situated adjacent to the philtrum.

Percutaneous endoscopic gastrostomy in head and neck cancer patients: indications, techniques, complications and results

The aim of this study was to review our experience in percutaneous endoscopic gastrostomy (PEG) performed in patients with cancer of the upper aerodigestive tract. Descriptive retrospective study of 142 patients (115 males, 27 females), mean age 62.4 years (25-84 years), with head and neck or esophageal cancer, who underwent PEG tube insertion between January 2006 and December 2008. The studied parameters were indications, success rate, rate and type of complications, and their management. Percutaneous endoscopic gastrostomy was inserted before chemoradiation therapy in 80% and during or after cancer treatment in 20% of the patients. PEG placement was possible in 137 patients (96%). Major complications were observed in 9 (7%) and minor complications in 22 (17%) of the 137 patients. Seven of the 9 patients with a major complication needed revision surgery. The mortality directly related to the procedure was 0.7%. Percutaneous endoscopic gastrostomy tube insertion has a high success rate. In patients with upper aerodigestive tract cancer, PEG should be the first choice for enteral nutrition when sufficient oral intake is not possible. Although apparently easy, the procedure may occasionally lead to severe complications. Therefore, a strict technique and knowledge of clinical signs of possible complications are mandatory.

Elective neck dissection for carcinomas of the oral cavity: occult metastases, neck recurrences, and adjuvant treatment of pathologically positive necks

BACKGROUND: Supraomohyoid neck dissection (SOHND) is currently performed in patients with carcinoma of the oral cavity with clinically negative neck. Most investigators consider SOHND as a staging procedure. METHODS: Records of 100 patients with cancer of the oral cavity and clinically negative neck undergoing SOHND were reviewed. The rate and significance of occult metastases are evaluated, the neck recurrences are analyzed and the indication of adjuvant radiation of pN+ necks is discussed. RESULTS: In 34 of 1814 of analyzed lymph nodes, metastatic disease was detected as follows: 30 macrometastases and 4 micrometastases. In 13 of 34 metastases (38%), extracapsular spread was observed. Twenty of 100 patients (20%) had to be upstaged. In 9 of 87 (10%) patients without local recurrence and with a minimal follow-up of 24 months, 5 ipsilateral (4 within the dissection field) and 5 contralateral neck recurrences were observed. Regional recurrence developed in 4% and 35% of patients with pN0 and pN+ necks, respectively. CONCLUSIONS: In 20% of patients with oral cavity tumors and pN0 neck, occult metastases were disclosed. Neck recurrences developed significantly more often in patients with pN+ than in those with pN0 necks. To evaluate the exact indication for an adjuvant treatment of patients with cN0/pN+ necks, prospective studies should be performed.

Composite skin grafts for basal cell carcinoma defects of the nose

Basal cell carcinoma is the most frequent cutaneous cancer of the nose and is characterized by its local spreading and exceptionally rare tendency to metastasize. Since a significant advantage has been seen in surgery compared to other treatments, surgical excision ensuring the highest chance of cure is frequently employed. Excision defects of the nose may be covered with either local flap or a full-thickness skin graft. In resurfacing such defects following excision of basal cell carcinomas, we favor the technique of composite-skin grafting which involves the harvesting of composite-skin graft including the epidermis, dermis and superficial layers of subcutaneous tissue to obtain the required thickness in the recipient site. This technique was used for defects remaining after the excision of basal cell carcinomas in a series of 15 patients. The areas involved were lateral nasal region (5 cases), nasal tip (4 cases), dorsum (3 cases), alar lobule (2 cases), and soft triangle (1 case). The mean follow-up was 14.2 months. The color, texture and thickness of the composite-skin graft harvested from the preauricular site and the neck compare favorably with the skin of the nose region. Satisfactory results, both clinically and in patient appreciation, have been obtained in both the reconstruction site and the appearance of the donor site in all patients.