Role of TGF-β in cancer and the potential for therapy and prevention

Transforming growth factor (TGF)-β is a naturally occurring potent inhibitor of cell growth. TGF-β binds first to a Type II (TGFBR2), then a Type I receptor (TGFBR1). TGFBR1 activation results in the phosphorylation of intracellular messengers, the SMADs. Unrestricted cell growth due to decreased growth inhibitory activity is a paramount feature of a defect in TGF-β function. There is growing evidence that common variants of the TGF-β pathway ligand and receptors that alter TGF-β signaling modify cancer risk. Approximately 14% of the general population carry TGFBR1*6A, a variant of the TGFBR1 gene that results in decreased TGF-β-mediated growth inhibition. Recent studies show that overall cancer risk is increased by 70 and 19% among TGFBR1*6A homozygotes and heterozygotes, respectively. This suggests that TGFBR1*6A may contribute to the development of a large proportion of common forms of cancer and may become a target for cancer chemoprevention. While decreased TGF-β signaling increases cancer risk, TGF-β secretion and activated TGF-β signaling enhances the aggressiveness of several types of tumors. The activated TGF-β signaling pathway is emerging as an attractive target in cancer and the authors predict that assessment of functionally relevant variants of this pathway will lead to the identification of individuals with a higher cancer risk and account for some forms of familial cancer susceptibility. In addition, it is predicted that inhibitors of the TGF-β signaling pathway will find their way into cancer clinical trials, leading to delays in tumor progression and improvements in overall survival.     

Chemotherapy treatment for older women with metastatic breast cancer: what is the evidence?

While the over-representation of the elderly in the breast cancer population is projected to dramatically increase within the next two decades, data on chemotherapy for elderly patients with metastatic breast carcinoma (MBC) remain very limited. The aim of the present study is to investigate whether elderly patients included in clinical studies for MBC are representative of the population seen during usual clinical practice. Firstly, a review of the literature was performed identifying 39 publications about chemotherapy for MBC focusing on elderly patients and we examined patient characteristics in each of these publications. Comparison of the age distribution of patients included in these studies with that of a large cohort of consecutive MBC patients aged 65 years who received chemotherapy in our institution over the last ten years (n = 573) indicated that trials tend to include relatively younger patients. Furthermore, criteria to assess external validity of the results are seldom reported. Possible ways to improve the applicability of results such as increasing the minimum age for inclusion and the use of CGA are proposed.     

Uptake of HPV testing and extended cervical cancer screening intervals following cytology alone and Pap/HPV cotesting in women aged 30–65 years

Objective

To evaluate the adoption of HPV testing and recommended extended cervical cancer screening intervals in clinical practice, we described yearly uptake of Pap/HPV cotesting and estimated length of time between normal screens by patient characteristics.

Methods

We examined 55,575 Pap/HPV records from 27,035 women aged 30–65 years from the Johns Hopkins Hospital Pathology Data System between 2006 and 2013. Cotest uptake and median times to next screening test for cotests and cytology only were calculated. Adjusted hazard ratios were estimated using Cox proportional hazards models, with random effects adjustment for clustering within clinic.

Results

Cotest usage increased from <?10% in 2006 to 78% in 2013. The median time to next screening test following normal cytology alone remained constant around 1.5 years. Screening intervals following a dual-negative cotest increased from 1.5 years in 2006/2007 to 2.5 years in 2010, coincident with increases in the proportion of women cotested. Intervals following a dual negative cotest were longer among Medicare patients (3 years) compared with privately insured women (2.5 years), and shorter among black (2 years) compared with white women (2.8 years).

Conclusion

By mid-2013 we observed broad adoption of Pap/HPV cotesting in routine screening in a large academic medical center. Increased screening intervals were observed only among cotested women, while those screened by cytology alone continued to be screened almost annually. The influence of different combinations of race and insurance on screening intervals should be further evaluated to ensure balance of screening risks and benefits in the U.S. population.

     

Citizenship,length of stay,and screening for breast,cervical, and colorectal cancer in women, 2000–2010

Background

Two factors jointly account for significant gaps in access to health care among immigrants who are present in the U.S.—legal status, and length of residence. The objective of this study is to examine the association between citizenship and length of residence in the U.S. and cancer screening (breast, cervical, and colorectal) among women.

Methods

We analyzed 11 years (2000–2010) of consolidated data from the Medical Expenditure Panel Survey linked with the National Health Interview Survey. Multivariate analyses compared cancer screening among U.S.-born citizens (n?=?58,484), immigrant citizens (n?=?8,404), and immigrant non-citizens (n?=?6,564).

Results

Immigrant non-citizens living in the U.S. for less than 5 years were less likely to receive guideline-concordant breast (OR?=?0.68 [0.53–0.88]), cervical (OR?=?0.65 [0.54–0.78]), and colorectal (OR?=?0.31 [0.19–0.50]) cancer screening compared to U.S.-born citizens. Immigrant citizens and non-citizens living in the U.S. for 5 years or more had higher odds of being screened for breast and cervical cancer compared to U.S.-born citizens; (OR?=?1.26 [1.13–1.41] and OR?=?1.17 [1.06–1.29]) for immigrant citizens, (OR?=?1.28 [1.13–1.45] and OR?=?1.23 [1.09–1.38]) for non-citizens. Immigrant non-citizens living in the U.S. for 5 years or more had lower odds of being screened for colorectal cancer compared to U.S.-born citizens (OR?=?0.76 [0.65–0.90]).

Conclusions

Based on these findings, duration mandates in immigration policy may indirectly influence future pathways to preventive health care and cancer disparities disproportionately affecting immigrant women. We suggest that limits of duration mandates be reevaluated, as they may offer pathways to preventive health care for this vulnerable population, and prevent future cancer disparities.

     

Homeopathy: what is it and is it of value in the care of patients with cancer?

The underlying principles of homeopathy include treating 'like with like' by remedies which are potentized by serial dilution and succussion. These distinguish homeopathy from other forms of alternative or complementary therapy. Conventional scientific wisdom dictates that homeopathy should have no effect above and beyond placebo but experiments on ultra-high dilutions of solutes together with some clinical data suggest the intriguing possibility that it might do in some circumstances. However, most clinical evidence comes from treating relatively minor self-limiting diseases and little comes from treating life-threatening disorders such as cancer. This paper explains the principles of homeopathy and reviews the data on its use in cancer care.     

Can we increase the cervical cancer screening interval with an HPV test for women living with HIV? Results of a cohort study from Maharashtra,India

We are reporting (a) updated incidence of cervical intraepithelial neoplasia (CIN) among women who did not have colposcopic or histopathological disease at baseline and (b) disease outcomes among women treated for CIN and their follow-up HPV status; in a cohort of women living with HIV (WHIV). The median overall follow-up was 3.5 years (IQR 2.8-4.3). The incidence of any CIN and that of CIN 2 or worse disease was 16.7 and 7.0 per 1000 person-years of observation (PYO), respectively. Compared with women who were HPV negative at baseline, women who cleared HPV infection had 23.95 times increased risk of incident CIN 2 or worse lesions (95% CI 2.40-661.07). Women with persistent HPV infection had 138.18 times increased risk of CIN 2 or worse lesions (95% CI 20.30-3300.22). Complete disease regression was observed in 65.6% of the HPV positive women with high-grade CIN and were treated with thermal ablation but HPV persistence was seen in 44.8% of those with high-grade disease. Among those who did not have any disease at baseline and were also HPV negative, about 87% (95% CI 83.79-89.48) women remained HPV negative during consecutive HPV test/s with the median interval of 3.5 years. Long-term surveillance of WHIV treated for any CIN is necessary for the prevention of cervical cancer among them. Our study provides an early indication that the currently recommended screening interval of 3 to 5 years among WHIV may be extended to at least 5 years among HPV negative women. Increasing the screening interval can be cost saving and improve scalability among WHIV to support WHO's cervical cancer elimination initiative.     

To what extent is women’s economic situation associated with cancer screening uptake when nationwide screening exists? A study of breast and cervical cancer screening in France in 2010

Purpose

In France, larger social inequalities are reported for cervical cancer screening, based on individual practice, than for breast cancer screening for which organized screening exists. Our aim was to investigate the association between women’s economic situation and breast and cervical cancer screening.

Methods

We used data from a large French national health survey conducted in 2010. The economic situation was assessed using the number of adverse economic conditions respondents were facing, based on three variables (low income, lacking food, and perceived financial difficulties). Logistic regressions were adjusted for socioeconomic and sociodemographic characteristics, healthcare use and insurance, and health behaviors.

Results

Mammography was less frequent among women experiencing two or more adverse economic conditions, whereas Pap smear was less frequent among women experiencing at least one adverse economic condition. For both screenings, higher rates were observed among women who lived in the Paris region. Sociodemographic indicators and health behaviors were associated with Pap smear, whereas healthcare use and insurance characteristics were associated with mammography.

Conclusions

The women’s economic situation is an important determinant of breast and cervical cancer screening in France in 2010. Alleviating economic barriers to female cancers screening should be a priority in future programs implementation.     

How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer,treatment rates and adverse obstetric outcomes in Australia,a high vaccination coverage country

Primary HPV screening enables earlier diagnosis of cervical lesions compared to cytology, however, its effect on the risk of treatment and adverse obstetric outcomes has not been extensively investigated. We estimated the cumulative lifetime risk (CLR) of cervical cancer and excisional treatment, and change in adverse obstetric outcomes in HPV unvaccinated women and cohorts offered vaccination (>70% coverage in 12–13 years) for the Australian cervical screening program. Two‐yearly cytology screening (ages 18–69 years) was compared to 5‐yearly primary HPV screening with partial genotyping for HPV16/18 (ages 25–74 years). A dynamic model of HPV transmission, vaccination, cervical screening and treatment for precancerous lesions was coupled with an individual‐based simulation of obstetric complications. For cytology screening, the CLR of cervical cancer diagnosis, death and treatment was estimated to be 0.649%, 0.198% and 13.4% without vaccination and 0.182%, 0.056% and 6.8%, in vaccinated women, respectively. For HPV screening, relative reductions of 33% and 22% in cancer risk for unvaccinated and vaccinated women are predicted, respectively, compared to cytology. Without the implementation of vaccination, a 4% increase in treatment risk for HPV versus cytology screening would have been expected, implying a possible increase in pre‐term delivery (PTD) and low birth weight (LBW) events of 19 to 35 and 14 to 37, respectively, per 100,000 unvaccinated women. However, in vaccinated women, treatment risk will decrease by 13%, potentially leading to 4 to 41 fewer PTD events and from 2 more to 52 fewer LBW events per 100,000 vaccinated women. In unvaccinated women in cohorts offered vaccination as 12–13 year olds, no change to lifetime treatment risk is expected with HPV screening. In unvaccinated women in cohorts offered vaccination as 12–13 year olds, no change to lifetime treatment risk is expected with HPV screening. HPV screening starting at age 25 in populations with high vaccination coverage, is therefore expected to both improve the benefits (further decrease risk of cervical cancer) and reduce the harms (reduce treatments and possible obstetric complications) associated with cervical cancer screening.     

Is adherence to diet,physical activity,and body weight cancer prevention recommendations associated with colorectal cancer incidence in African American women?

Purpose

The purpose of this study was to evaluate whether adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations was associated with colorectal cancer incidence in the Black Women’s Health Study (BWHS).

Methods

In this ongoing prospective cohort of African American women (analytic cohort n = 49,103), 354 incident colorectal cancers were diagnosed between baseline (1995) and 2011. Adherence scores for seven WCRF/AICR recommendations (adherent = 1 point, non-adherent level 1 = 0.5 points, non-adherent level 2 = 0 points) were created using questionnaire data and summed to an overall adherence score (maximum = 7). Recommendation adherence and colorectal cancer incidence were evaluated using baseline and time-varying data in Cox regression models.

Results

At baseline, 8.5 % of women adhered >4 recommendations. In time-varying analyses, the HR was 0.98 (95 % CI 0.84–1.15) per 0.5 point higher score and 0.51 (95 % CI 0.23–1.10) for adherence to >4 compared to <3 recommendations. Adherence to individual recommendations was not associated with colorectal cancer risk. Results were similar in models that considered baseline exposures only.

Conclusions

Adherence to cancer prevention recommendations was low and not associated with colorectal cancer risk among women in the BWHS. Research in diverse populations is essential to evaluate the validity of existing recommendations, and assess whether there are alternative recommendations that are more beneficial for cancer prevention in specific populations.

     

Racial/ethnic and socioeconomic disparities in mortality among women diagnosed with cervical cancer in New York City, 1995–2006

Background  

Though cervical cancer rates have declined due to Pap screening, racial and socioeconomic disparities in cervical cancer incidence and mortality persist. This study assesses the relative impact of race/ethnicity and neighborhood poverty on cervical cancer incidence and mortality in New York City (NYC).     

How can the overtreatment rate of "see and treat" approach be reduced in women with high-grade squamous intraepithelial lesion on cervical cytology?

Background: The aim of this study was to determine the incidence and predictors of overtreatment in "see and treat" approach using loop electrosurgical excision procedure (LEEP) in women with high-grade squamous intraepithelial lesion (HSIL) on cervical cytology. The overtreatment was considered when LEEP specimens contained no cervical pathology. Between January 2001 and April 2006, 446 women with HSIL on Pap smear underwent colposcopy followed by LEEP at Chiang Mai University Hospital. Mean age of these patients was 45.6 years with a range of 25-78 years. One hundred and twenty-one (27.1%) women were menopausal. Unsatisfactory colposcopy was observed in 357 (80.0%) women. Of 446 women, histologically-confirmed HSIL, invasive cancer, low-grade squamous intraepithelial lesions, and adenocarcinoma in situ were detected in 330 (74.0%), 76 (17.0%), 9 (2.0%), and 5 (1.1%), respectively. The overtreatment rate on LEEP specimens was noted in 26 women or 5.8% (95% confidence interval [CI] = 3.8 to 8.4) of 446 women. By multivariate analysis, postmenopausal status was the only significant independent predictor of overtreatment with an adjusted odds ratio of 2.89 (95% CI = 1.30 to 6.43, P = 0.009). When postmenopausal women were excluded from analysis, the overtreatment rate was reduced to only 4.0%. In conclusion, "see and treat" approach appears to be an appropriate strategy in managing women with HSIL cytology. The overtreatment rate could be reduced when such policy is limited for premenopausal women.     

Active surveillance for favorable risk prostate cancer: what are the results, and how safe is it?

Active surveillance for favorable risk prostate cancer has become increasingly popular in populations in which prostate cancer screening is widespread because of evidence that prostate cancer screening results in the detection of disease that is not clinically significant in many patients (ie, untreated, would not pose a threat to health). The approach is supported by data showing that patients who fall into the category of clinically insignificant disease can be identified with reasonable accuracy and that patients who are initially classified as low risk who reclassify over time as higher risk and are treated radically are still cured in most cases. This means (1) identifying patients who have a low likelihood of disease progression during their lifetime based on clinical and pathologic features of the disease and patient age and comorbidity, (2) close monitoring over time, (3) reasonable criteria for intervention that will both identify more aggressive disease in a timely fashion and not result in excessive treatment, and (4) meeting the communication challenge to reduce the psychological burden of living with untreated cancer. The results of active surveillance, the criteria for patient selection, and the appropriate triggers for intervention are reviewed.     

RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis,IL-1α release,and efficient paracrine dendritic cell activation

Previous studies have shown that cervical cancer cells only release low levels of pro-inflammatory cytokines owing to infection with human papillomaviruses. This results in low immunogenicity of the cancer cells. The viral dsRNA analog PolyIC has been suggested as a promising adjuvant for cervical cancer immunotherapy. However, little is known about the molecular requirements resulting in successful immune activation. Here, we demonstrate that stimulation of cervical cancer cells with PolyIC induced necroptotic cell death, which was strictly dependent on the expression of the receptor-interacting protein kinase RIPK3. Necroptotic cancer cells released interleukin-1α (IL-1α), which was required for powerful activation of dendritic cells (DC) to produce IL-12, a cytokine critical for anti-tumor responses. Again both, IL-1α release and DC activation, were strictly dependent on RIPK3 expression in the tumor cells. Of note, our in situ analyses revealed heterogeneous RIPK3 expression patterns in cervical squamous cell carcinomas and adenocarcinomas. In summary, our study identified a novel RIPK3-dependent mechanism that explains how PolyIC-treatment of cervical cancer cells leads to potent DC activation. Our findings suggest that the RIPK3 expression status in cervical cancer cells might critically influence the outcome of PolyIC-based immunotherapeutic approaches and should therefore be assessed prior to immunotherapy.     

Concordance with the World Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention and colorectal cancer risk in Morocco: A large,population-based case–control study

The present study aimed to investigate associations between adherence to the recommendations on cancer prevention from the WCRF/AICR and colorectal cancer (CRC) risk in Morocco. Incident CRC cases (n = 1,516) and controls (n = 1,516) matched on age, sex and center, were recruited between September 2009 and February 2017 at five major hospitals located in Morocco. In-person interviews were conducted to assess habitual diet using a validated Food Frequency Questionnaire, physical activity and anthropometric measurements. Adherence to the WCRF/AIRC Recommendations was ranged from 0 (no adherence) to 6 (maximal adherence) and incorporating six WCRF/AICR components (food groups, physical activity and BMI). Multivariable odd ratios (OR_A) and 95% confidence intervals (CI) were calculated using conditional multivariate logistic regression models, with low adherence as referent, adjusting for potential confounding factors. Compared to those with the lowest adherence score, individuals in the highest WCRF/AICR score category had a statistically significant reduced risk for colon cancer (OR_A = 0.63, 95% CI 0.53–0.76); rectal cancer (OR_A = 0.52, 95% CI 0.43–0.63) and CRC overall (OR_A = 0.58, 95% CI 0.51–0.66). For individual score components, when comparing the lowest with the highest adherence category, CRC risk was significantly lower in the highest adherence category for body fatness (OR_A = 0.73; 95% CI 0.62–0.85), physical activity (OR_A = 0.70; 95% CI 0.60–0.82), plant foods (OR_A = 0.50; 95% CI 0.39–0.63) and red/processed meat (OR_A = 0.81; 95% CI 0.71–0.92). Our analysis indicated that greater adherence to the WCRF/AICR recommendations for cancer prevention may lower CRC risk in Morocco.     

What is the prevalence of symptomatic or asymptomatic femoral head osteonecrosis in patients previously treated with chemoradiation? A magnetic resonance study of anal cancer patients

It is generally assumed that femoral head osteonecrosis (FHO) is a serious but rare complication of pelvic radiotherapy. A review of the literature carried out by the authors indicates a prevalence of 4/763 (95% confidence interval 0.1%-1.3%). A recent publication has suggested that the prevalence of symptomatic FHO may be much greater than previously assumed as a result of sensitization of bone to radiation by concomitant treatment with chemotherapy. Magnetic resonance imaging (MRI) is currently the most sensitive modality for detecting and confirming symptomatic or asymptomatic FHO of any aetiology. The aim of this study therefore was to assess the prevalence of symptomatic and asymptomatic FHO in patients previously treated for anal cancer by chemoradiation (CRT). The hips of 34 currently disease-free individuals (11 men and 23 women; median age 67 years, range 32-86) were scanned using a coronal T1-weighted sequence. The images were assessed for evidence of FHO. The median time of scanning after the end of CRT was 35 months (range 6-107). No cases (0/34) of symptomatic or asymptomatic FHO were detected in these patients. Given the established sensitivity of MRI in the detection of FHO, it is concluded that changes indicative of osteonecrosis were uncommon after CRT in the current cohort of patients. Recent evidence from the literature suggests, however, that elderly females are at greatest risk of developing FHO after CRT.