Impact of radiation dose on patient-reported acute taste alteration in a prospective observational study cohort in head and neck squamous cell cancer (HNSCC).

PURPOSE: Taste alteration (TA) is a frequent acute side effect of radiation treatment in HNSCC patients. Principal aim of our study was to investigate dosimetric parameters in relation to patient-assessed taste impairment in a prospective cohort treated with intensity-modulated radiotherapy. METHODS: All patients with locally advanced HNSCC and amenable to radical treatment were included. Chemotherapy-induced taste alteration scale (CITAS), EORTC QLQ-C30 and QLQ-HN43 questionnaires at baseline (T0), 3 weeks (T1) and 3 months (T2) after radiotherapy conclusion were used to assess taste impairment. Base of tongue, submandibular glands (SG), parotid glands (PG) and taste buds, along with anterior and medium third of the tongue, were considered as organs at risk and thus delineated according to consensus guidelines. The mean dose to the above-mentioned structures was correlated with patient-reported outcomes. RESULTS: Between September 2019 and November 2020, 33 patients were recruited, 31 of which analyzed. 71% had oropharyngeal carcinoma, mostly HPV-related (60%). All were treated with tomotherapy. 77.4% had concurrent cisplatin. Mean scores of general taste alterations, global health status and dry mouth and sticky saliva were assessed. The mean doses to the anterior third, medium third and base of the tongue were 23.85, 35.50 and 47.67 Gy, respectively. Taste buds received 32.72 Gy; right and left parotid 25 and 23 Gy; right and left submandibular glands 47.8 and 39.4 Gy. At univariate analysis, dysgeusia correlated with SG mean dose (95% CI 0-0.02 p = 0.05) and PG mean dose (95% CI 0-0.02 p = 0.05); dry mouth with mean dose to anterior (95% CI 0.03-1.47 p = 0.04) and medium third (95% CI 0.02-0.93 p = 0.04) of the tongue, to taste buds (95% CI 0.06-0.96 p = 0.03) and to SGs (95% CI 0.06-0.63 p = 0.02); pain mouth with mean dose to taste buds (95% CI 0-0.02 p = 0.04), to SGs (95% CI 0-0.03 p = 0.03) and to base tongue (95% CI 0-0.02 p = 0.02). CONCLUSIONS: Our analysis supports the influence of dose distribution on the development of TA in HNSCC patients. The contribution of dose to taste buds and tongue subvolumes remains unclear and worthy of further investigation.

Suppression of beta 2 adrenergic receptor actions prevent UVB mediated cutaneous squamous cell tumorigenesis through inhibition of VEGF-A induced angiogenesis.

Although beta 2 adrenergic receptors (ß2 ADR) are present in the keratinocytes, their role in cutaneous squamous cell tumorigenesis needs to be ascertained. For the first time, we report here that selective ß2 ADR antagonists by inhibiting ß2 ADR actions significantly retarded the progression of ultraviolet B (UVB) induced premalignant cutaneous squamous cell lesions. These antagonists acted by inhibiting vascular endothelial growth factor-A (VEGF) mediated angiogenesis to prevent UVB radiation-induced squamous cell carcinoma of the skin.

Welding and the risk of head and neck cancer: the ICARE study.

OBJECTIVE: To investigate the association between occupational exposure to welding and the risk of head and neck cancer in a large French population-based case-control study, the Investigation of occupational and environmental CAuses of REspiratory cancers study. METHODS: Analyses were restricted to men (2703 controls and 1588 cases of squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx and larynx). Welding activity and potential confounders were assessed by detailed questionnaires. ORs and CIs (95% CI) were estimated by unconditional logistic regression, adjusted for age, area of residence, tobacco smoking, alcohol consumption and occupational exposure to asbestos. RESULTS: Welding was associated with an increased risk of head and neck cancer overall (OR=1.31, 95% CI 1.03 to 1.67). The association was strongest for laryngeal cancer (OR=1.66, 95% CI 1.15 to 2.38) and the risk increased with the cumulative duration (p-trend <0.01) and the weighted duration (p-trend <0.01) of welding. A cumulative duration and a weighted duration of welding of more than 10 years were also associated with a significantly increased risk of oral cancer (OR=1.82, 95% CI 1.09 to 3.04; OR=2.10, 95% CI 0.99 to 4.45, respectively). A long duration of arc welding was associated with laryngeal cancer, whereas a long duration of spot welding was associated with oral cancer. Welding was not associated with the risk of oropharyngeal and hypopharyngeal cancer. CONCLUSION: Our findings suggest that welding and several welding-related tasks increase the risk of laryngeal cancer and to a lesser extent oral cancer.

Ablation of Liver X receptors α and ß leads to spontaneous peripheral squamous cell lung cancer in mice.

The etiology of peripheral squamous cell lung cancer (PSCCa) remains unknown. Here, we show that this condition spontaneously develops in mice in which the genes for two oxysterol receptors, Liver X Receptor (LXR) α (Nr1h3) and ß (Nr1h2), are inactivated. By 1 y of age, most of these mice have to be euthanized because of severe dyspnea. Starting at 3 mo, the lungs of LXRα,ß(Dko) mice, but not of LXRα or LXRß single knockout mice, progressively accumulate foam cells, so that by 1 y, the lungs are covered by a "golden coat." There is infiltration of inflammatory cells and progressive accumulation of lipid in the alveolar wall, type 2 pneumocytes, and macrophages. By 14 mo, there are three histological lesions: one resembling adenomatous hyperplasia, one squamous metaplasia, and one squamous cell carcinoma characterized by expression of transformation-related protein (p63), sex determining region Y-box 2 (Sox2), cytokeratin 14 (CK14), and cytokeratin 13 (CK13) and absence of thyroid transcription factor 1 (TTF1), and prosurfactant protein C (pro-SPC). RNA sequencing analysis at 12 mo confirmed a massive increase in markers of M1 macrophages and lymphocytes. The data suggest a previously unidentified etiology of PSCCa: cholesterol dysregulation and M1 macrophage-predominant lung inflammation combined with damage to, and aberrant repair of, lung tissue, particularly the peripheral parenchyma. The results raise the possibility that components of the LXR signaling may be useful targets in the treatment of PSCCa.

Soft palatal melanosis, a simple predictor for neoplasia in the upper aerodigestive tract in Japanese alcoholic men.

Soft palatal melanosis can be detected by visual inspection during routine physical examination or even personally in a mirror. The aim of this study was to evaluate the association between squamous cell neoplasia in the upper aerodigestive tract (UAT) and soft palatal melanosis. We reviewed digitized records of high-quality endoscopic images of the soft palate of 1786 Japanese alcoholic men who underwent endoscopic screening. Soft palatal melanosis was observed in 381 (21.3%) of the subjects (distinct, 6.3%). Older age, an inactive heterozygous aldehyde dehydrogenase-2 genotype, smoking, and a high mean corpuscular volume were positively associated with the presence of soft palatal melanosis. The age-adjusted odds ratio (95% confidence interval) for UAT neoplasia was 1.92 (1.40-2.64) in the group with melanosis and 2.51 (1.55-4.06) in the group with distinct melanosis, compared with the melanosis-free group. A multivariate analysis showed that the presence of soft palatal melanosis was independently associated with a high risk of UAT neoplasia. We calculated the individual number of risk factors out of four easily identifiable and significant factors: age ≥55 years, current/former alcohol flushing, mean corpuscular volume ≥106 fL, and distinct soft palatal melanosis. Compared with the risk-factor-free condition, the odds ratio (95% confidence interval) values of UAT neoplasia for one, two, three, and four risk factors were 1.49 (0.97-2.30), 3.14 (2.02-4.88), 4.80 (2.71-8.51), and 7.80 (2.17-28.1), respectively. The presence of soft palatal melanosis provides a simple new strategy for identifying heavy drinkers with a high risk for UAT neoplasia.

A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation.

Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.

Mold infections in lung transplant recipients.

Fungal infections continue to produce morbidity and mortality in lung transplant recipients despite the widespread use of antifungal prophylaxis. There has been a decline in Candida infections but Aspergillus species predominate. Other mold pathogens including Fusarium, Scedosporium, and Zygomycetes also cause infections in lung transplant recipients. Furthermore, the widespread use of antifungal prophylaxis has prompted a delay in onset of Aspergillus infection in lung transplant recipients. Pulmonary parenchymal disease has become the most common manifestation of invasive aspergillosis. Among the risk factors pre- or posttransplant Aspergillus colonization is the most important risk factor reported in several retrospective studies. Recently posttransplant colonization has been implicated in the development of bronchiolitis obliterans syndrome. Other factors that have been reported include preceding cytomegalovirus infections, hypogammaglobulinemia, and single-lung transplantation. The risk factors for other mold infections such as Scedosporium, Fusarium, and Zygomycetes are not well studied. The best antimold prophylaxis strategy and choice of drug remains to be elucidated. Most lung transplant centers use either voriconazole or inhaled amphotericin preparations. However, data have emerged regarding the increased risk of squamous cell cancer in lung transplant recipients on voriconazole prophylaxis. Advances in the diagnosis and treatment of invasive aspergillosis have resulted in a significant decrease in mortality.

Development of squamous neoplasia in esophageal iodine-unstained lesions and the alcohol and aldehyde dehydrogenase genotypes of Japanese alcoholic men.

We investigated the development of esophageal neoplasia in biopsy specimens of the distinct iodine-unstained lesions (DIULs) ≥ 5 mm detected in 280 of 2,115 Japanese alcoholic men who underwent screening by esophageal iodine staining. Low-grade intraepithelial neoplasia (LGIN) was diagnosed in 155 of them, high-grade intraepithelial neoplasia (HGIN) in 57, and invasive SCC in 35. The size of the DIULs increased with the degree of neoplasia. Most LGINs were flat and were missed before iodine staining. Some DIULs became a light pink color (PC) about 2 min after staining, and 2.6, 56.1 and 96.0% of the LGIN, HGIN and invasive SCC lesions, respectively, were PC-sign-positive. Multiple DIULs of any size markedly increased the risk of LGIN [adjusted OR (95%CI) = 10.1 (7.12-14.5)], HGIN [27.9 (14.6-53.4)] and invasive SCC [21.6 (10.1-46.4)], and were strongly associated with the presence vs. absence of DIULs ≥ 5 mm [13.3 (9.21-19.1)], inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) vs. ALDH2*1/*1 [2.60 (1.79-3.78)], and less-active alcohol dehydrogenase-1B (ADH1B*1/*1) vs. ADH1B*2 allele [2.61 (1.87-3.64)]. The combination of ALDH2*1/*2 and ADH1B*1/*1 synergistically increased the risk of LGIN [4.53 (2.17-9.47)], HGIN [10.4 (4.34-24.7)] and invasive SCC [21.7 (7.96-59.3)]. Esophageal neoplasia developed at earlier ages in those with ALDH2*1/*2. Biopsy-proven HGIN was diagnosed as invasive SCC in 15 (39.5%) of 38 patients after endoscopic mucosectomy or surgery. In conclusion, large size, non-flat appearance, positive PC sign and multiplicity of DIULs and ALDH2*1/*2 and ADH1B*1/*1 were associated with development of esophageal neoplasia in Japanese alcoholics. Biopsy-proven HGIN should be totally resected for both diagnostic and therapeutic purposes.

Coexistence of adamantinomatous and squamous-papillary type craniopharyngioma: case report and discussion of etiology and pathology.

Craniopharyngiomas are histopathologically classified as adamantinomatous type (AD) and squamous-papillary type (SP). However coexistence of a mixed type seen on histopathologic specimens has not been reported. In this report, a patient diagnosed with mixed type craniopharyngioma is presented and the etiology and pathologic features are discussed.

FDA's regulation of tanning beds: how much heat?

This paper considers the problem of indoor tanning bed use by teenagers. The paper explores FDA's current authority to regulate tanning lamps as Class I medical devices, concluding that FDA's authority is poorly tailored to affect teenagers' repeated use of these products. An outright ban is unlikely; therefore, the best available options are to regulate access by minors and to amend the warning label requirements to reflect the current state of knowledge about the risks of tanning bed use.

Head and neck squamous cell cancers: need for an organised time-bound surveillance plan.

Optimal care of patients with head and neck squamous cell cancer (HNSCC) involves a pre-determined period of post-treatment follow-up for the detection of recurrent or persistent disease, metastases and second primaries at the earliest opportunity. There is little evidence in literature as to whether the surveillance schemes should be based on patient survival, quality of life or cost-adjusted parameters. This article aims at highlighting some of the issues pertinent to the optimization of surveillance strategies in HNSCC.

Skin cancer prevention education for kidney transplant recipients: a systematic evaluation of Internet sites.

CONTEXT: Repeated patient education about skin cancer prevention is important to self-care after transplant. OBJECTIVE: Examine educational materials for kidney transplant recipients available on the Internet that address sun protection and skin self-examination for early detection of squamous cell carcinoma. DESIGN: Systematic review of Web sites for kidney transplant recipients endorsed by transplant physicians and dermatologists. PARTICIPANTS: An expert panel of 8 dermatologists providing care for kidney transplant recipients and 1 research medical anthropologist. MAIN OUTCOME MEASURES: Reading grade level, inclusion of people with skin of color, sufficient content to support effective sun protection, and description of 4 sun-protection strategies and skin self-examination. Results-Of the 40 sites identified, 11 contained information about sun protection or increased risk of any type of cancer. The Web sites had a ninth-grade median reading level (range, seventh grade to college senior). Interrater reliability for the 25-item assessment tool was assessed by Fleiss' kappa (kappa = 0.87). Skin cancer risk was presented as relevant to those with fair skin. Sites recommended regular use of sunscreen with sun-protection factor of 15 or greater (n=3) to reduce the risk of skin cancer (n=4). Few sites recommended using protective clothing (n=5), seeking shade (n=4), and avoiding deliberate tanning with indoor or outdoor light (n=1). Five sites recommended skin self-examination. CONCLUSION: Because many patients seek self-management information from the Internet, Web sites must provide more thorough educational information about skin cancer prevention and health promotion at a lower reading grade level.

Malignant change in chronic irritation: a case series.

BACKGROUND: Chronic irritation is a known cause of malignant change in humans. It is believed that at least a minimum of five years is needed for the evolution of the illness. OBJECTIVE: To present cases of consecutive squamous cell malignant change in patients with various irritations, and to highlight that these cases are not too uncommon in our environment. METHODS: Case reports of patients with definitive treatments offered. Patients had amputation done after incisional biopsies were done to determine the mitotic status of the lesions. RESULTS: The three patients presented late. All had lower limb affectation. Conservatism was difficult, all of them ending up with amputation of the affected limbs. One of them had inguinal lymph node metastasis after the amputation, signifying advanced disease, but unfortunately had to leave hospital because she could not cope with the financial demands of treatment. CONCLUSION: Malignant change from chronic irritations can occur under five years. Education might help early presentation and improved outcome. Our hospitals should provide for the treatment of these group of patients despite their financial status.

Prevalence and predictors of precancerous cervical lesions among HIV-positive women in Jos, north-central Nigeria.

OBJECTIVE: To determine the prevalence and predictors of precancerous cervical lesions among HIV-positive women in Jos, Nigeria. METHODS: A cross-sectional study was conducted from October 2017 to January 2018 among 326 HIV-positive women. Cervical smears were collected for examination at the AIDS Preventive Initiative of Nigeria clinics of Jos University Teaching Hospital (JUTH) and Bingham University Teaching Hospital (BhUTH), Jos, Nigeria. Demographic characteristics of participants were documented using a structured questionnaire. Data were entered and analyzed using SPSS version 21. RESULTS: Of the 326 participants, precancerous cervical lesions were present in 40 (12.2%) women: 4 (1.2%) had atypical squamous cells of undetermined significance, 19 (5.8%) had low-grade squamous intraepithelial lesions, 1 (0.3%) had atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions, 13 (4.0%) had high-grade squamous intraepithelial lesions, and 3 (0.9%) had high-grade squamous intraepithelial lesions, suspected for invasion. The multivariate logistics regression model showed that parity (odds ratio 3.4, 95% confidence interval 1.3-9.5, P=0.043) was a significant predictor of precancerous cervical lesions. CONCLUSION: The prevalence of precancerous cervical lesions among HIV-infected women is relatively low compared to earlier reported prevalence in an HIV population in Jos. Increasing parity was a significant predictor.

Is smoking an independent risk factor for invasive cervical cancer? A nested case-control study within Nordic biobanks.

The strong correlation between smoking and exposure to oncogenic human papillomaviruses (HPVs) has made it difficult to verify the independent role of smoking in cervical carcinogenesis. Thus, the authors evaluated this role. Five large Nordic serum banks containing samples from more than 1,000,000 subjects were linked with nationwide cancer registries (1973-2003). Serum samples were retrieved from 588 women who developed invasive cervical cancer and 2,861 matched controls. The samples were analyzed for cotinine (a biomarker of tobacco exposure) and antibodies to HPV types 16 and 18, herpes simplex virus type 2, and Chlamydia trachomatis. Smoking was associated with the risk of squamous cell carcinoma (SCC) among HPV16- and/or HPV18-seropositive heavy smokers (odds ratio=2.7, 95% confidence interval: 1.7, 4.3). A similar risk of SCC (odds ratio=3.2, 95% confidence interval: 2.6, 4.0) was found in heavy smokers after adjustment for HPV16/18 antibodies. The point estimates increased with increasing age at diagnosis and increasing cotinine level. This study confirms that smoking is an independent risk factor for cervical cancer/SCC in women infected with oncogenic HPVs. These findings emphasize the importance of cervical cancer prevention among women exposed to tobacco smoke.

MMP-10 (Stromelysin-2) and MMP-21 in human and murine squamous cell cancer.

The squamous cell cancers (SCC) of renal transplant recipients are more aggressive and metastasize earlier than those of the non-immunocompromised population. Matrix metalloproteinases (MMPs) have a central role in tumor initiation, invasion and metastasis. Our aim was to compare the expression of MMPs-10, -12 and -21 in SCCs from immunosuppressed (IS) and control patients and the contribution of MMPs-10 and -21 to SCC development in the FVB/N-Tg(KRT5-Nfkbia)3Rto mouse line. Immunohistochemical analysis of 25 matched pairs of SCCs, nine of Bowen's disease and timed back skin biopsies of mice with selective inhibition of Rel/NF-kappaB signalling were performed. Semiquantitatively assessed stromal MMP-10 expression was higher (P = 0.009) in the control group when compared with IS patients. Tumor cell-derived MMP-10, -12 and -21 expression did not differ between the groups but stromal fibroblasts of the control SCCs tended to express MMP-21 more abundantly. MMP-10 expression was observed already in Bowen's disease while MMP-21 was absent. MMP-10 and -21 were present in inflammatory or stromal cells in ageing mice while dysplastic keratinocytes and invasive cancer were negative. Our results suggest that MMP-10 may be important in the initial stages of SCC progression and induced in the stroma relating to the general host-response reaction to skin cancer. MMP-21 does not associate with invasion of SCC but may be involved in keratinocyte differentiation.

Oral squamous cell cancer in a patient with Lynch syndrome.

For patients with Lynch Syndrome (LS) (formerly known as hereditary nonpolyposis colorectal cancer or HNPCC), inheritance of one of several mutated mismatch repair genes (MMR) results in an increased risk for a variety of malignancies including colon, rectal, endometrial, urinary tract, gastric, small bowel and others [1]. Confirmation of increased risk of particular malignancies for patients harboring an MMR germline mutation has typically been the result of population studies of families tracked for the development of the possible associated cancer. When cancer results from inheritance of a particular mutated MMR gene, the malignancy has a characteristic fingerprint referred to as microsatellite instability-high (MSI-H), which results from deficient expression of the inherited MMR gene product (dMMR). Therefore, if sporadic tumors of a particular tissue of origin are only rarely dMMR, identifying a tumor as dMMR in a known LS family member suggests that, in that particular family, inheritance of the mutated MMR gene does predispose to that malignancy. Here we describe a patient diagnosed with a germline mutation in the MMR gene MSH6 who developed an oral pharynx cancer. Oral pharynx cancers are not known to be associated with LS. By confirming that the tumor was not dMMR and not MSI-H, it was concluded that his oral pharynx cancer was sporadic, rather than LS-related, and other family members carrying the mutated MSH6 are unlikely to be at above-average risk for the development of oral cancers, as a result of the LS. In additional, he would not be eligible for the so-called FDA agnostic approved immunotherapy which is endorsed for dMMR or MSI-H tumors [2].

The spectrum of human immunodeficiency virus-associated cancers in a South African black population: results from a case-control study, 1995-2004.

The effect of the evolving HIV epidemic on cancer has been sparsely documented in Africa. We report results on the risk of cancer associated with HIV-1 infection using data from an ongoing study. A case-control analysis was used to estimate the relative risk (odds ratio, OR) of cancer types known to be AIDS defining: Kaposi's sarcoma (n = 333), non-Hodgkin lymphoma (NHL, n = 223) and cancers of the cervix (n = 1,586), and 11 cancer types possibly associated with HIV infection: Hodgkin lymphoma (n = 154), cancers of other anogenital organs (n = 157), squamous cell cancer of the skin (SCC, n = 70), oral cavity and pharynx (n = 319), liver (n = 83), stomach (n = 142), leukemia (n = 323), melanoma (n = 53), sarcomas other than Kaposi's (n = 93), myeloma (n = 189) and lung cancer (n = 363). The comparison group comprised 3,717 subjects with all other cancer types and 682 subjects with vascular disease. ORs were adjusted for age, sex (except cervical cancer), year of diagnosis, education and number of sexual partners. Significantly increased risks associated with HIV-1 infection were found for HIV/AIDS associated Kaposi's sarcoma (OR = 47.1, 95% CI = 31.9-69.8), NHL (OR = 5.9, 95% CI = 4.3-8.1) and cancer of the cervix (OR = 1.6, 95% CI = 1.3-2.0); Hodgkin's disease (OR = 1.6, 95% CI = 1.0-2.7), cancers of anogenital organs other than the cervix (OR = 2.2; 95% CI = 1.4-3.3) and SCC (OR = 2.6, 95% CI = 1.4-4.9) were also significantly increased. No significant associations were found between HIV and any of the other cancers examined. Risks for HIV-related cancers are consistent with previous studies in Africa, and are lower when compared to those observed in developed countries.

Evidence for benefits from treating cervical ectopy: literature review.

CONTEXT AND PURPOSE: Uterine cervical ectopy (cervical erosion) is today considered to be a physiological condition, but there still seems to be a strong tendency towards treating it. The purpose of this study was to review the medical literature for evidence regarding benefits from treating cervical ectopy. METHODS: The following databases were reviewed: Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica Database (Embase), Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs) and Cochrane Library databases. In addition, six medical textbooks were consulted. RESULTS: The review showed that: 1) there is probably an association between ectopy and higher risk of Chlamydia trachomatis, human papillomavirus and human immunodeficiency virus infection; 4) there is probably an association between ectopy and cervical intraepithelial neoplasia; 5) there is an association between ectopy and mucous discharge and nocturia; and 6) there is no evidence of an association between ectopy and cervical cancer, or of protection against cervical cancer associated with ectopy treatment. CONCLUSIONS: 1) No data were found in the medical literature to support routine treatment for ectopy; 2) Treatment could be recommended for symptom relief, but more symptoms are attributed to ectopy than could be demonstrated in a controlled study; 3) Further studies to test the hypothesis of protection against cervical cancer associated with treatment are necessary.