Neoadjuvant chemotherapy for muscle-invasive bladder cancer: does variant histology matter?

PURPOSE: The most frequent histology of bladder tumors is urothelial carcinoma. Most are pure urothelial carcinomas (PUC) but up to one-third of the cases present variant histological (VH) features. The aim of this study was to evaluate the role of variant histology in neoadjuvant chemotherapy (NAC) response in patients with urothelial muscle-invasive bladder cancer. METHODS: We retrospectively analyzed data from 77 patients with bladder cancer who performed neoadjuvant chemotherapy at two institutions. RESULTS: Complete pathological response (ypT0) was higher in patients with PUC (38.5%), comparing with VH (12%). Logistic regression analysis demonstrated that variant histology is associated with an 89% lesser likelihood of tumor downstaging, with advanced clinical T stages and positive smoking history as independent predictors. The estimated mean cancer-specific survival was 68.91 months for PUC patients and 50.23 months for VH patients (log rank test, P = 0.024). Multivariate Cox regression analysis demonstrated that VH and clinical T stage were independent predictors of cancer-specific survival, indicating a worse outcome for patients with VH and advanced clinical T stages. CONCLUSIONS: There are only a few retrospective studies evaluating the clinical impact of variant histology tumors, which are mainly managed as PUC. Our results demonstrate that VH is associated with a worse likelihood of tumor downstaging after NAC and a worse cancer-specific survival in bladder cancer patients. There is a need for further studies and genetic analysis to identify the patients most likely to achieve ypT0 status and downstaging after NAC.

Outcomes of laparoscopic salvage radical prostatectomy after primary treatment of prostate cancer.

Introduction: Treatment of radio-recurrent prostate cancer (PC) is managed mainly by androgen deprivation therapy. Nonetheless, selected patients could benefit from local salvage treatment options.In this study we present our series of recurrent PC cases submitted to laparoscopic salvage radical prostatectomy (sRP) at our institution. Material and methods: A total of 29 patients with recurrent PC after primary non-surgical treatment were submitted to laparoscopic sRP at our institution, with a mean follow-up time of 7 years. Results: There were 7 post-operative complications Clavien-Dindo grade ≥2. At the end of the follow-up, 58.6% patients presented biochemical recurrence and five-year recurrence-free survival (RFS) was 50%.Positive lymph nodes, high preoperative prostate-specific antigen (PSA) and TNM stage were correlated with worse RFS. Cox regression analysis demonstrated that stage pT3b was independently associated with worse RFS in comparison with stage pT3a or less.At 12 months, pad-free continence or mild incontinence was observed in 62% of the patients. Conclusions: sRP is a technically challenging surgery, and in our series, we were able to perform this procedure with acceptable operative time and limited blood loss.Post-operative complications, functional results and oncological outcomes were similar to other published studies, being our series, to the best of our knowledge, the one with the longest follow-up, of 7 years.sRP is a feasible local treatment with curative intent for radio-recurrent prostate cancer, with good oncological outcomes and reasonable continence rates in selected patients.

Schwannoma of Seminal Vesicle: A Case Report.

Seminal vesicle neoplasms are extremely rare. Schwannoma is a benign tumor of the peripherical nerve sheath composed of Schwann cells. Most of these tumors are silent and become symptomatic with compression of adjacent organs and nerves. We present a case of a 72-year-old man who presented with a several months history of predominant storage lower urinary tract symptoms and painful ejaculation. Prostate-specific antigen (PSA) was within normal ranges, and imaging documented a retrovesical nodular lesion adjacent to the right seminal vesicle with 5 cm in width. We successfully performed a robotic-assisted laparoscopic surgery to excise the lesion. Anatomopathological analysis revealed a schwannoma.

Undergraduate teaching of urology: Quo vadis?

BACKGROUND: The undergraduate teaching of urology is not uniform in the various European medical schools and even absent in some of them, despite the widespread adoption of the Bologna process, which advocates a standardization and harmonization of medical education. Our aim was to evaluate the perception of junior doctors about the undergraduate teaching of Urology and the exposure to the specialty of Urology in undergraduate education in Portuguese medical schools. METHODS: A questionnaire was emailed to all physicians who first enrolled in the Board of Portuguese Doctors in 2017 and 2018. The questionnaire consisted of several questions about specialty exposure, pathology, and basic urological procedures. A database for statistical analysis was created. RESULTS: One hundred and eighty-six answers were considered valid. Although almost all participant physicians attribute considerable importance to Urology specialty, most find their exposure to urological pathology and basic urological procedures to be inappropriate in medical school. Urinary lithiasis and lower urinary tract symptoms are the subjects on which doctors feel most prepared after graduating. Interestingly, 63.4% of doctors consider that the education they had in college was preponderant in choosing their specialty. CONCLUSIONS: The teaching of Urology in Portuguese Medical Schools is considered by junior doctors as inadequate, not reflecting the importance of this specialty in the clinical practice. These results are like those found in other countries. A reflection and consequent change of the teaching paradigm is necessary, namely at the practical teaching level.

RAD52 Functions in Homologous Recombination and Its Importance on Genomic Integrity Maintenance and Cancer Therapy.

Genomes are continually subjected to DNA damage whether they are induced from intrinsic physiological processes or extrinsic agents. Double-stranded breaks (DSBs) are the most injurious type of DNA damage, being induced by ionizing radiation (IR) and cytotoxic agents used in cancer treatment. The failure to repair DSBs can result in aberrant chromosomal abnormalities which lead to cancer development. An intricate network of DNA damage signaling pathways is usually activated to eliminate these damages and to restore genomic stability. These signaling pathways include the activation of cell cycle checkpoints, DNA repair mechanisms, and apoptosis induction, also known as DNA damage response (DDR)-mechanisms. Remarkably, the homologous recombination (HR) is the major DSBs repairing pathway, in which RAD52 gene has a crucial repairing role by promoting the annealing of complementary single-stranded DNA and by stimulating RAD51 recombinase activity. Evidence suggests that variations in RAD52 expression can influence HR activity and, subsequently, influence the predisposition and treatment efficacy of cancer. In this review, we present several reports in which the down or upregulation of RAD52 seems to be associated with different carcinogenic processes. In addition, we discuss RAD52 inhibition in DDR-defective cancers as a possible target to improve cancer therapy efficacy.

CSF-1 and Ang-2 serum levels - prognostic and diagnostic partners in non-small cell lung cancer.

BACKGROUND: Lung cancer is the most incident and lethal form of cancer, with late diagnosis as a major determinant of its bad prognosis. Immunotherapies targeting immune checkpoints improve survival, but positive results encompass only 30%-40% of the patients, possibly due to alternative pathways to immunosuppression, including tumour-associated macrophages (TAM). Colony stimulating factor-1 (CSF-1) is implicated in TAM differentiation and recruitment to tumours and in tumour angiogenesis, through a special setting of Tie-2-expressing macrophages, which respond to angiopoietin-2 (Ang-2). We evaluated the role of serum levels of CSF-1 in non-small cell lung cancer (NSCLC) prognosis and whether these could serve as biomarkers for NSCLC detection, along with Ang-2. PARTICIPANTS AND METHODS: We prospectively studied an unselected cohort of 145 patients with NSCLC and a group of 30 control individuals. Serum levels of Ang-2 and CSF-1 were measured by ELISA prior to treatment. RESULTS: Serum levels of CSF-1 and Ang-2 are positively correlated (p<0.000001). Individuals with high serum levels of CSF-1 have a 17-fold risk for NSCLC presence and patients with combined High Ang-2/CSF-1 serum levels present a 5-fold increased risk of having NSCLC. High Ang-2/CSF-1 phenotype is also associated with worst prognosis in NSCLC. CONCLUSIONS: Combined expression of CSF-1 and Ang-2 seems to contribute to worst prognosis in NSCLC and it is worthy to understand the basis of this unexplored partnership. Moreover, we think CSF-1 could be included as a biomarker in NSCLC screening protocols that can improve the positive predictive value of the current screening modalities, increase overall cost effectiveness and potentially improve lung cancer survival.

TP53 Arg72Pro polymorphism is associated with increased overall survival but not response to therapy in Portuguese/Caucasian patients with advanced cervical cancer.

Identification of mechanisms that influence the therapeutic response and survival in patients with cancer is important. It is known that the genetic variability of the host, including presence of genetic polymorphisms in genes involved in DNA damage response, serves a crucial role in the prognosis of these patients. The present hospital-based retrospective cohort study aimed to evaluate the influence of TP53 Arg72Pro (rs1042522) polymorphism in the clinical outcome of 260 Caucasian patients diagnosed with cervical cancer and treated with concomitant radiotherapy and chemotherapy. The polymorphism genotyping was assessed using allelic discrimination by quantiative polymerase chain reaction. The results indicate that the TP53 Arg72Pro polymorphism did not significantly impact the response to therapy (P=0.571) nor disease-free survival (P=0.081). However, the polymorphism did influence overall survival, as increased median survival time was observed for patients carrying Arg/Pro genotype when compared with patients with Arg/Arg and Pro/Pro genotypes (126 months vs. 111 months, respectively; P=0.047). To conclude, the present findings suggest that a pharmacogenomic profile based on the genetic background of patients, including the analysis of the TP53 genotypes, may individualize treatment nad assist in the selection of therapies that may improve clinical outcome and lower toxicity for the patients.

Transoral laser microsurgery as standard approach to hypopharyngeal cancer. Survival analysis in a hospital based population / Microcirugía transoral láser con CO2 como una opción válida para el tratamiento del cáncer de hipofaringe en un hospital terciario

Objective: Cancer of the hypopharynx remains one of the most challenging chapters in head and neck oncology. The objective of this study is to ascertain the relevance of a transoral laser approach as a valid functional option for treatment of cancer of the hypopharynx in Portugal, and additionally, to confirm the reproducibility of survival and functional outcomes described in other reference centers. Subjects and methods: The outcomes of 37 out of 60 patients presenting hypopharyngeal carcinoma primarily treated by TLM (transoral laser microsurgery) and neck dissection and or adjuvant treatment when needed, with curative intention in tertiary referral center, were retrospectively evaluated and compared with published results. Results: There were no patients in stage I. Three-year and five-year overall survival (Kaplan-Meier) were 83.5% and 63.5% for stage II (n = 12), 57.1% (only 3-year overall survival evaluable for this stage) for stage III (n = 7), and 53.1% and 39.8% for stage IVa (n = 18), respectively. Five-year local control rates were 90% for stage II and 87.5% for stage IVa, respectively; only three-year local control rates were possible to evaluate for stage III, with a 100% control rate. Five-year total larynx preservation rate was 97.3%. Conclusions: TLM, alone or with neck dissection and adjuvant therapy, is a valid procedure for treatment of hypopharyngeal cancer in different stages. Furthermore, this kind of approach can be replicated in different oncologic centers with similar oncologic and functional results (AU)

Objetivo: El cáncer de hipofaringe continúa siendo uno de los capítulos más difíciles en la oncología de cabeza y cuello. El objetivo del presente estudio es determinar la relevancia del abordaje con microcirugía transoral láser CO2 (MTL) como una opción válida para el tratamiento de cáncer de hipofaringe en un hospital terciario. Adicionalmente, se pretende comparar los datos obtenidos con los de otros centros de referencia en relación a la supervivencia y a los resultados funcionales. Pacientes y Métodos: 37 pacientes de un total de 60 con diagnóstico de carcinoma hipofaríngeo han sido tratados con intención curativa con MTL sola o asociada á disección cervical y terapia adyuvante. Los resultados han sido evaluados retrospectivamente y comparados con los publicados en la literatura. Resultados: No hubo pacientes en estadio I. La supervivencia global a los 3 y 5 años (Kaplan-Meir) fue de 83.5% y 63.5% en el estadio II (n=12); 57.1% en el estadio III (n=7) (en este estadio sólo pudo ser evaluada la supervivencia global a los 3 años) y 53.1% y 39.8% para el estadio IVa (n=18) respectivamente. El porcentaje de control local a los 5 años fue de 90% en el estadio II y de 87.5% en el estadio IVa, respectivamente; en el estadio III, solamente ha sido posible evaluar el control local a los 3 años, que ha sido de 100%. El porcentaje total de preservación laríngea a los 5 años fue de 97.3%. Conclusiones: La MLT, sola o asociada a la disección cervical y terapia adyuvante, es un procedimiento eficiente para el tratamiento del cáncer hipofaringeo en diferentes estadios. Esto confirma que este abordaje es una opción válida y reproducible en diferentes centros oncológicos (AU)

Transoral laser microsurgery as standard approach to hypopharyngeal cancer. Survival analysis in a hospital based population.

OBJECTIVE: Cancer of the hypopharynx remains one of the most challenging chapters in head and neck oncology. The objective of this study is to ascertain the relevance of a transoral laser approach as a valid functional option for treatment of cancer of the hypopharynx in Portugal, and additionally, to confirm the reproducibility of survival and functional outcomes described in other reference centers. SUBJECTS AND METHODS: The outcomes of 37 out of 60 patients presenting hypopharyngeal carcinoma primarily treated by TLM (transoral laser microsurgery) and neck dissection and or adjuvant treatment when needed, with curative intention in tertiary referral center, were retrospectively evaluated and compared with published results. RESULTS: There were no patients in stage I. Three-year and five-year overall survival (Kaplan-Meier) were 83.5% and 63.5% for stage II (n=12), 57.1% (only 3-year overall survival evaluable for this stage) for stage III (n=7), and 53.1% and 39.8% for stage IVa (n=18), respectively. Five-year local control rates were 90% for stage II and 87.5% for stage IVa, respectively; only three-year local control rates were possible to evaluate for stage III, with a 100% control rate. Five-year total larynx preservation rate was 97.3%. CONCLUSIONS: TLM, alone or with neck dissection and adjuvant therapy, is a valid procedure for treatment of hypopharyngeal cancer in different stages. Furthermore, this kind of approach can be replicated in different oncologic centers with similar oncologic and functional results.

Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches?

The critical role of angiogenesis in tumor development makes its inhibition a valuable new approach in therapy, rapidly making anti-angiogenesis a major focus in research. While the VEGF/VEGFR pathway is the main target of the approved anti-angiogenic molecules in NSCLC treatment, the results obtained are still modest, especially due to resistance mechanisms. Accumulating scientific data show that vessel co-option is an alternative mechanism to angiogenesis during tumor development in well-vascularized organs such as the lungs, where tumor cells highjack the existing vasculature to obtain its blood supply in a non-angiogenic fashion. This can explain the low/lack of response to current anti-angiogenic strategies. The same principle applies to lung metastases of other primary tumors. The exact mechanisms of vessel co-option need to be further elucidated, but it is known that the co-opted vessels regress by the action of Angiopoietin-2 (Ang-2), a vessel destabilizing cytokine expressed by the endothelial cells of the pre-existing mature vessels. In the absence of VEGF, vessel regression leads to tumor cell loss and hypoxia, with a subsequent switch to a neoangiogenic phenotype by the remaining tumor cells. Unravelling the vessel co-option mechanisms and involved players may be fruitful for numerous reasons, and the particularities of this form of vascularization should be carefully considered when planning anti-angiogenic interventions or designing clinical trials for this purpose. In view of the current knowledge, rationale for therapeutic approaches of dual inhibition of Ang-2 and VEGF are swiftly gaining strength and may serve as a launchpad to more successful NSCLC anti-vascular treatments.

Base excision repair pathway: PARP1 genotypes as modulators of therapy response in cervical cancer patients.

CONTEXT: Genetic polymorphisms in genes of the base excision repair (BER) pathway appear to modulate the therapy response of cancer patients. PARP1 protein recognizes the DNA strand damage and facilitates the subsequent recruitment of BER proteins. Few studies have reported an association between PARP1 Val762Ala polymorphism (rs1136410) and cancer therapy response. OBJECTIVE: The purpose of our study was to determine whether PARP1 Val762Ala polymorphism have prognostic value in patients with cervical cancer. MATERIALS AND METHODS: Two hundred and sixty adult patients, with histologically confirmed cervical cancer, at FIGO-stages IB2-IVA, primarily treated with concurrent chemotherapy (cisplatin) and radiotherapy. Overall survival (OS) and disease-free survival (DFS) were the primary end points of the analysis. The PARP1 Val762Ala genetic variants were analyzed by allelic discrimination by real-time PCR. RESULTS: We observed that peri- and postmenopausal women carrying the C-allele present a statistically significant lower OS and DFS (log-rank test, p = 0.008 and p = 0.006, respectively) among those with early stage cervical cancer. Cox regression analysis confirmed these results, after adjustment for other prognostic factors (for OS: HR, 3.70; 95%CI, 1.32-10.38; p = 0.013 and for DFS: HR, 3.97; 95%CI, 1.59-9.93; p = 0.003). CONCLUSIONS: This is the first study evaluating the effect of PARP1 Val762Ala polymorphism in treatment response in cervical cancer patients. PARP1 genotypes may contribute as an independent prognostic factor in cervical cancer, being useful in predicting the clinical outcome.

Polymorphisms in host immune response associated genes and risk of nasopharyngeal carcinoma development in Portugal.

BACKGROUND: Host genetic susceptibility markers in immune response associated genes may contribute to identify individuals with high risk of developing viral infection and viral-associated cancers. We aimed to characterize different polymorphisms in immune response associated genes and evaluate its association with nasopharyngeal carcinoma (NPC) development. METHODS: We have developed a hospital-based case-control study selecting 134 patients with NPC (cases) and 732 healthy individuals (controls) from the Northern Region of Portugal. Eight single nucleotide polymorphisms (SNP) were selected: -56C>T IFNGR1 (rs2234711), +4854G>T IL1A (rs17561), +3954C>T IL1B (rs1143634), +1902A>G IL4RA (rs1801275), -1082G>A IL10 (rs1800896), +2018T>C IL1RN (rs419598), HLA-A locus A>T (rs2530388), HCGA9 locus A>T (rs6457110). All polymorphisms were analysed by real-time methodology using TaqMan(®) SNP Genotyping Assays. RESULTS: The overall analysis revealed no statistical significant differences between genotypes distributions in all of studied polymorphisms (p>0.05). However, the results for HCGA9 rs6457110 polymorphism showed a tendency for an increased risk of NPC development among TT carriers with an almost of 2-fold increased risk (OR=1.86; 95%CI 1.00-3.65). CONCLUSIONS: This is the first study to characterize these polymorphisms in NPC patients in Portugal. Our study indicates that HCGA9 rs6457110 polymorphism might represent a risk marker for NPC development in our population and that other SNPs should be further studied in larger populations to clarify the evidences. This data reinforces the need for more studies, especially in NPC low-prevalent populations.

Combined Ang-2 and VEGF serum levels: holding hands as a new integral biomarker in non-small-cell lung cancers.

AIM: Evaluate if serum levels of VEGF and Ang-2 are correlated in non-small-cell lung cancers (NSCLCs) and its implications in the diagnostic and prognostic of the disease. PATIENTS & METHODS: Unselected cohort of 145 NSCLC patients and 30 control individuals. The serum levels of Ang-2 and VEGF of each patient were measured by ELISA prior to treatment. RESULTS & CONCLUSIONS: Serum levels of Ang-2 and VEGF are correlated (p < 0.0001). High serum levels of Ang-2 and VEGF isolated and both combined (high(Ang-2/VEGF)) correlate with likelihood of presenting NSCLC (p = 0.016; p = 0.003; p < 0.0001, respectively). Serum levels of Ang-2 and high(Ang-2/VEGF) but not VEGF alone are independent prognostic factors (p = 0.001; p = 0.619; p = 0.005). High(Ang-2/VEGF) serum levels could be exploited as a new valuable integral biomarker in NSCLC.

IL-6 polymorphism in non-small cell lung cancer: a prognostic value?

Lung cancer was found to be the most commonly diagnosed cancer, as well as the primary cause of cancer-related mortality for males worldwide and the second leading cause of cancer-related deaths for women. Cytokines are fundamental for several biological processes-associated malignant tumors. The IL-6 is a cytokine involved in the regulation of cellular functions including processes associated with cancer, such as proliferation, apoptosis, angiogenesis, and differentiation. Furthermore, IL-6 is a potent pleiotropic inflammatory cytokine that is considered a key growth-promoting and antiapoptotic factor. The polymorphism-174G/C SNP is a G to C transition in the -174 position of the promoter region of the IL-6 gene. The aim of our study was to evaluate the influence of -174G/C polymorphism in clinical outcome of non-small cell cancer (NSCLC) patients. DNA was extracted from peripheral blood of 424 patients diagnosed with cytologically or histologically NSCLC. The characterization of IL-6 -174G/C genotypes was performed by PCR-RFLP (NlaIII). IL-6 polymorphism's genotypes were divided according to functional activity, so the G carriers (CG/GG) is the high-producer IL-6, and CC genotype is the low-producer IL-6. Regarding survival, we verify that patients with genotypes carrying the G allele (CG/GG) had a statistically significant diminished survival when compared with patients with CC genotype (62.79 and 42.31 months, respectively; P = 0.032). In the promoter region of the IL-6 gene, polymorphic variants were located and may be responsible for alterations in transcription that consequently affect serum levels of the cytokine. With our study, we demonstrated that genetic variant (-174G/G and G/C) can be responsible for changes in prognosis of NSCLC patients.

Transoral laser microsurgery for laryngeal carcinoma: Survival analysis in a hospital-based population.

BACKGROUND: Although already established for treatment for early-stage laryngeal cancers, transoral laser microsurgery indications for more advanced tumors are not unanimous. Additionally, no outcomes concerning the Portuguese population are currently accessible. METHODS: Outcomes of 248 patients presenting laryngeal carcinoma primarily treated by transoral laser microsurgery with curative intention in tertiary referral center were retrospectively evaluated and compared with concerning literature. RESULTS: For supraglottic tumors (23 stage I-II and 20 stage III-IV), 5-year disease-specific survival (DSS) was, respectively, 88.4% and 72.7%, and the total larynx-preservation rate was 90.7%. For glottic cancer (165 stage I-II and 40 stage III-IV), 5-year DSS was, respectively, 96.5% and 90.8% and the larynx preservation rate was 88.3%. CONCLUSION: Transoral laser microsurgery, alone or with neck dissection and adjuvant therapy, is an efficient procedure for treatment of laryngeal cancer in different stages. To the best of our knowledge, this is the first study reporting transoral laser microsurgery outcomes in the Portuguese population.

Circulating Ang-2 mRNA expression levels: looking ahead to a new prognostic factor for NSCLC [corrected].

Non-small cell lung cancer (NSCLC) is the most common cancer and the leading cause of death from cancer worldwide. Antiangiogenic strategies directed towards tumor stroma are becoming gold standard in NSCLC treatment and researchers have been searching for biomarkers to identify patients for whom therapy with antiangiogenic inhibitors may be most beneficial and the importance of these as prognostic factors in NSCLC. The purpose of this study was to evaluate the prognostic value of circulating Ang-2 mRNA levels prior to treatment in NSCLC patients. The mRNA levels were determined by quantitative real-time PCR in the peripheral blood of 92 NSCLC patients. Our results demonstrate that patients with high circulating Ang-2 mRNA levels have diminished overall survival when compared to those with low mRNA levels (20.3 months vs 34.3 months, respectively; Log Rank Test, p = 0.016), when considering all NSCLC stages and this difference is even bigger when considering only patients with stage IV (15.9 months vs 31.3 months, respectively; Log Rank Test, p = 0.036). Moreover, circulating Ang-2 mRNA levels independently determine overall survival, and the concordance (c) index analysis showed that the definition of a nomogram that contains information regarding tumor stage, patients' smoking status and circulating Ang-2 mRNA levels present an increased capacity to predict overall survival in NSCLC patients (c-index 0.798). These results suggest that this nomogram could serve as a unique and practical tool to determine prognosis in NSCLC, not relying on the availability of adequate surgical or biopsy specimens of NSCLC. Attending to our results, the circulating Ang-2 mRNA levels should also be included in the design of preclinical studies and clinical trials involving antiangiogenic drugs targeting Ang-2, to guide adequate patient stratification and dose selection and increasing the likelihood of benefit to a level that is acceptable to patients and clinicians.

Tumour necrosis factor alpha 308 G/A is a risk marker for the progression from high-grade lesions to invasive cervical cancer.

Tumour necrosis factor alpha (TNF-α) is a strong pro-inflammatory cytokine with important functions on immune response to viral infections. A single nucleotide polymorphism on the -308 position of the promoter region of TNFA gene characterised by a G > A transition has been associated with different TNF-α levels and therefore with differential susceptibility for the development several diseases. A cross-sectional case-control study was performed with 509 women with cancer from the northern region of Portugal, including 205 healthy women and 337 women with different cervical lesions including invasive cervical. The -308G > A polymorphism genotyping was performed with TaqMan® SNP Genotyping Assay and studied for its association with cervical cancer development. This study showed increased frequency of the -308A allele in women with any cervical lesions. Statistical analysis revealed that -308A carriers are associated with an almost 2-fold increased risk for invasive cervical cancer development (p = 0.005; odds ratio (OR) = 1.87). Similar results were found when comparing the risk of progression between preinvasive lesions and invasive cervical cancer development (p = 0.002; OR = 2.41). Our results reveal that -308 TNFA AA individuals are at increased risk of invasive cervical cancer development and more important, that the risk is significantly increased for the progression from premalignant lesion to invasive cancer. Considering previous data and this study, this polymorphism confirms to be a significant marker in our population.

Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients treated with first-line chemotherapy: implication of a CYP3A4 activity profile.

CYP3A4 is a key enzyme involved in the metabolism of numerous compounds, such as paclitaxel, and its activity shows an extensive inter-individual variation which can influence treatment response. The study's purpose was to investigate the potential predictive role of a CYP3A4 profile (CYP3A4*1B, rs2740574 and CYP3A4*22, rs35599367) in serous ovarian cancer patients treated with first-line chemotherapy (paclitaxel and cisplatin or carboplatin), after cytoreductive surgery. CYP3A4*1B and CYP3A4*22 genotypes were determined by Nested PCR-RFLP and Taqman® Allelic Discrimination, respectively. We observed that the mean survival rates were statistically different according the patients CYP3A4 genotypes. The group of patients carrying the CYP3A4*1B G allele present a decreased mean survival rate when compared with AA genotype patients (103.93 and 134.44 months, respectively, p = 0.010). This result is consistent after multivariate Cox regression analysis (HR, 2.15; 95% CI, 1.03-4.52; p = 0.043). The combination of CYP3A4*1B and CYP3A4*22 polymorphisms result in the definition of a CYP3A4 activity profile: the group of patients with a higher CYP3A4 activity profile had significantly diminished survival when compared with patients with a lower CYP3A4 activity profile (101.06 and 134.44 months, respectively, p = 0.012). Multivariate Cox regression analysis revealed a diminished overall survival time for patients with CYP3A4 high activity profile (HR, 2.29; 95% CI, 1.05-5.02; p = 0.038). The definition of a CYP3A4 activity profile resulted in the increase of prediction ability, using Harrels's concordance indexes (C-index from 0.617 to 0.626). To conclude, our results demonstrate an association between CYP3A4*1B and a diminished overall survival of patients with serous ovarian cancer. The definition of a CYP3A4 activity profile proved to be benefic and the CYP3A4 high activity profile was associated with a lower overall survival. We consider that the definition of a CYP3A4 activity profile might be useful as molecular marker for predicting the clinical outcome of serous ovarian cancer patients.

IL-1RN VNTR polymorphism as a susceptibility marker for nasopharyngeal carcinoma in Portugal.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare malignancy in Western countries that is widely associated with the infection by Epstein-Barr virus (EBV). Several studies have showed that a common allele (allele 2) of the 86-bp variable number of tandem repeats (VNTR) polymorphism within intron 2 of the interleukin 1 receptor antagonist (IL-1RN) gene is associated with several disorders, including viral-associated cancers. METHODS: We have developed a hospital-based case-control study to characterise the role of the IL-1RN 86-bp VNTR polymorphism in the development of NPC with 112 patients with the disease and 433 healthy individuals from the northern region of Portugal. IL-1RN genotypes were combined according to the number of repeats: allele 2 (A2), the short allele that corresponds to two repeats, and L, the long allele that corresponds to three or more repeats. RESULTS: Our study revealed that 31.2% of NPC patients were IL-1RN A2*A2, compared with 9.7% observed in the control group. The statistical analysis revealed that IL-1RN*A2 homozygosity for the A2 allele was associated with a fourfold increased risk for NPC development (p<0.001). Additionally, cumulative hazard analysis revealed that estimated median age of onset of NPC is significantly (p<0.001) different for A2*A2 homozygous versus non-A2*A2 (57.0 vs. 74.0, respectively). CONCLUSIONS: This is the first study to evaluate the role of the IL-1RN VNTR in NPC development in Portugal. Our study indicates IL-1RN*A2 homozygosity as a significant risk marker in our population and that it should be further investigated for the potential role in the definition of a susceptibility profile for NPC onset.

DNA repair and cytotoxic drugs: the potential role of RAD51 in clinical outcome of non-small-cell lung cancer patients.

Many of the cytotoxic drugs used in the treatment of non-small-cell lung carcinoma patients can interfere with DNA activity and the definition of an individual DNA repair profile could be a key strategy to achieve better response to chemotherapeutic treatment. Although DNA repair mechanisms are important factors in the prevention of carcinogenesis, these molecular pathways are also involved in therapy response. RAD51 is a crucial element in DNA repair by homologous recombination and has been shown to interfere with the prognosis of patients treated with chemoradiotherapy. There is increasing evidence that genetic polymorphisms in repair enzymes can influence DNA repair capacity and, consequently, affect chemotherapy efficacy. We conducted this review to show the possible influence of the RAD51 genetic variants in damage repair capacity and treatment response in non-small-cell lung carcinoma patients.