Estimate of global human papillomavirus vaccination coverage: analysis of country-level indicators.

BACKGROUND: Mortality rates from cervical cancer demonstrate deep inequality in health between richer and poorer populations. Over 310 000 women died of this preventable disease in 2018, mostly in low-income and middle-income countries (LMICs) where screening and treatment are beyond the capacity of health systems. Immunisation against human papillomavirus (HPV) offers a primary prevention strategy, but rates of vaccination uptake are unclear. Understanding coverage levels and factors affecting uptake can inform immunisation strategies. OBJECTIVES: The aim of this study is to evaluate the status of HPV vaccination coverage from nationally reported indicators and to estimate global coverage in a single year cohort of vaccine-eligible girls. DESIGN: This study provides quantitative population-level estimates of important global health indicators. Using data from the Global Cancer Observatory and WHO/UNICEF, incidence of and mortality from cervical cancer and HPV vaccination coverage are described for countries, categorised by income group. Characteristics of LMICs achieving high coverage are explored using selected development indicators from World Bank sources. Global HPV immunisation coverage is calculated and its impact on cervical cancer mortality estimated. RESULTS: Incidence and mortality for cervical cancer correlate with poverty. Whilst all WHO member states report high infant measles vaccination rates, fewer than half report on HPV vaccination. Even amongst high-income countries, coverage varies widely. In upper-middle-income countries, there is a trend for higher coverage with increased health spending per capita. Four LMICs report good coverage levels, all associated with external funding. Global HPV immunisation coverage for 2018 is estimated at 12.2%. Of the global cohort of 61 million 15-year-old girls in 2018, 7000 are likely to die from cervical cancer, almost all in LMICs. CONCLUSIONS: Countries in all income groups must devise strategies to achieve and maintain higher levels of HPV immunisation. For all but the richest, affordability remains a barrier.

Current challenges and future perspectives of radiotherapy for locally advanced breast cancer.

PURPOSE OF REVIEW: To discuss current issues in the field of radiation oncology for locally advanced breast cancer (LABC). RECENT FINDINGS: Large randomized studies involving nodal irradiation have recently been completed. The incremental benefit of treating the internal mammary nodes (IMNs) remains controversial. A randomized study specifically evaluating internal mammary node radiation (IMNR) failed to demonstrate significant benefit. A high impact, population-based study detected a proportional increase in major coronary events with increasing radiation dose. Advanced treatment techniques should be employed to reduce cardiac exposure. In patients with stage IV breast cancer (BCa), there is increasing evidence to suggest that locoregional treatments may improve overall survival (OS). Radiotherapy alone, without surgery, may provide equivalent local control and OS in patients with distant metastasis. High-dose stereotactic radiation regimens can be used to treat breast tumors with good local control rates in as few as three visits.BCa biomarkers are predictive of locoregional recurrence risk and should be used to guide radiotherapy in conjunction with standard staging. Clinically validated genetic profiling can measure tumor radiosensitivity and also help to predict normal tissue toxicity. SUMMARY: We are entering an era of personalized radiotherapy for LABC. Radiation treatments must be tailored to each individual patient's risk and intrinsic tumor biology.

Evaluation of neoadjuvant chemotherapy response in women with locally advanced breast cancer using ultrasound elastography.

PURPOSE: Ultrasound elastography is a new imaging technique that can be used to assess tissue stiffness. The aim of this study was to investigate the potential of ultrasound elastography for monitoring treatment response of locally advanced breast cancer patients undergoing neoadjuvant therapy. METHODS: Fifteen women receiving neoadjuvant chemotherapy had the affected breast scanned before, 1, 4, and 8 weeks following therapy initiation, and then before surgery. Changes in elastographic parameters related to tissue biomechanical properties were then determined and compared to clinical and pathologic tumor response after mastectomy. RESULTS: Patients who responded to therapy demonstrated a significant decrease (P < .05) in strain ratios and strain differences 4 weeks after treatment initiation compared to non-responding patients. Mean strain ratio and mean strain difference for responders was 81 ± 3% and 1 ± 17% for static regions of interest (ROIs) and 81 ± 3% and 6 ± 18% for dynamic ROIs, respectively. In contrast, these parameters were 102±2%, 110±17%, 101±4%, and 109±30% for non-responding patients, respectively. Strain ratio using static ROIs was found to be the best predictor of treatment response, with 100% sensitivity and 100% specificity obtained 4 weeks after starting treatment. CONCLUSIONS: These results suggest that ultrasound elastography can be potentially used as an early predictor of tumor therapy response in breast cancer patients.

Quantitative ultrasound evaluation of tumor cell death response in locally advanced breast cancer patients receiving chemotherapy.

PURPOSE: Quantitative ultrasound techniques have been recently shown to be capable of detecting cell death through studies conducted on in vitro and in vivo models. This study investigates for the first time the potential of early detection of tumor cell death in response to clinical cancer therapy administration in patients using quantitative ultrasound spectroscopic methods. EXPERIMENTAL DESIGN: Patients (n = 24) with locally advanced breast cancer received neoadjuvant chemotherapy treatments. Ultrasound data were collected before treatment onset and at 4 times during treatment (weeks 1, 4, and 8, and preoperatively). Quantitative ultrasound parameters were evaluated for clinically responsive and nonresponding patients. RESULTS: Results indicated that quantitative ultrasound parameters showed significant changes for patients who responded to treatment, and no similar alteration was observed in treatment-refractory patients. Such differences between clinically and pathologically determined responding and nonresponding patients were statistically significant (P < 0.05) after 4 weeks of chemotherapy. Responding patients showed changes in parameters related to cell death with, on average, an increase in mid-band fit and 0-MHz intercept of 9.1 ± 1.2 dBr and 8.9 ± 1.9 dBr, respectively, whereas spectral slope was invariant. Linear discriminant analysis revealed a sensitivity of 100% and a specificity of 83.3% for distinguishing nonresponding patients by the fourth week into a course of chemotherapy lasting several months. CONCLUSION: This study reports for the first time that quantitative ultrasound spectroscopic methods can be applied clinically to evaluate cancer treatment responses noninvasively. The results form a basis for monitoring chemotherapy effects and facilitating the personalization of cancer treatment.

Diffuse optical spectroscopy evaluation of treatment response in women with locally advanced breast cancer receiving neoadjuvant chemotherapy.

The aim of this study was to investigate the potential of diffuse optical spectroscopy for monitoring of patients with locally advanced breast cancer (LABC) undergoing neoadjuvant chemotherapy. Fifteen women receiving treatment for LABC had the affected breast scanned before; 1 week, 4 weeks, and 8 weeks after treatment initiation; and before surgery. Optical properties related to tissue microstructure and biochemical composition were obtained. Clinical and pathologic tumor response was evaluated using whole-mount pathology after mastectomy. Patients who responded to treatment demonstrated an initial increase followed by a drop in optical parameters measured in the whole breast, whereas nonresponding patients demonstrated only a drop in the same parameters 1 week after treatment initiation. Responding patients demonstrated a significant increase of 17% ± 7%, 8% ± 8%, 10% ± 7%, 11% ± 11%, and 16% ± 15% in deoxygenated hemoglobin, oxygenated hemoglobin, total hemoglobin concentrations, water percentage, and tissue optical index, 1 week after treatment initiation, respectively. In contrast, nonresponding patients had a decrease of 14% ± 9%, 18% ± 7%, 17% ± 7%, 29% ± 7%, and 32% ± 9% in their corresponding optical parameters. Deoxygenated hemoglobin concentration (with 100% sensitivity, 83% specificity) and water percentage (with 75% sensitivity, 100% specificity) were found to be the best predictors of treatment response at 1 week after starting treatment. The results of this study suggest that optical parameters can be potentially used to predict and monitor patients' responses to neoadjuvant chemotherapy and can form a basis for the customization of treatments in which inefficacious treatments can be switched to more efficacious therapies.

Modern palliative radiation treatment: do complexity and workload contribute to medical errors?

PURPOSE: To examine whether treatment workload and complexity associated with palliative radiation therapy contribute to medical errors. METHODS AND MATERIALS: In the setting of a large academic health sciences center, patient scheduling and record and verification systems were used to identify patients starting radiation therapy. All records of radiation treatment courses delivered during a 3-month period were retrieved and divided into radical and palliative intent. "Same day consultation, planning and treatment" was used as a proxy for workload and "previous treatment" and "multiple sites" as surrogates for complexity. In addition, all planning and treatment discrepancies (errors and "near-misses") recorded during the same time frame were reviewed and analyzed. RESULTS: There were 365 new patients treated with 485 courses of palliative radiation therapy. Of those patients, 128 (35%) were same-day consultation, simulation, and treatment patients; 166 (45%) patients had previous treatment; and 94 (26%) patients had treatment to multiple sites. Four near-misses and 4 errors occurred during the audit period, giving an error per course rate of 0.82%. In comparison, there were 10 near-misses and 5 errors associated with 1100 courses of radical treatment during the audit period. This translated into an error rate of 0.45% per course. An association was found between workload and complexity and increased palliative therapy error rates. CONCLUSIONS: Increased complexity and workload may have an impact on palliative radiation treatment discrepancies. This information may help guide the necessary recommendations for process improvement for patients who require palliative radiation therapy.

Accelerated hypofractionated radiotherapy for early-stage non-small-cell lung cancer: long-term results.

PURPOSE: To retrospectively review the results of a single-institution series of accelerated hypofractionated radiotherapy for early-stage non-small-cell lung cancer (NSCLC) in patients who are medically inoperable or who refuse surgery. METHODS AND MATERIALS: Peripherally located T1 to T3 N0 M0 tumors were treated with 48 to 60 Gy in 12 to 15 fractions between 1996 and 2007. No elective nodal irradiation was delivered. Patient, tumor, and treatment information was abstracted from the medical records. RESULTS: A total of 124 tumors were treated in 118 patients (56 male and 62 female). Median age at diagnosis was 76.3 years (range, 49-90 years). In all, 113 patients (95.8%) were not surgical candidates because of medical comorbidities. The 2- and 5-year overall survival (OS) rates were 51.0% and 23.3%, respectively, and the 2- and 5-year cause-specific survival (CSS) rates were 67.6% and 59.8%, respectively. The 2- and 5-year actuarial local control (LC) rates were 76.2% and 70.1%, respectively. Univariate analysis revealed that tumor size less than 3 cm compared with greater than 3 cm resulted in significantly improved OS (40.0% vs. 5.0% at 5 years; p = 0.0002), CSS (69.7% vs. 45.1% at 5 years; p = 0.0461), and a trend toward better LC (82.5% vs. 66.9% at 2 years, 76.6% vs. 60.8% at 5 years; p = 0.0685). Treatment was well tolerated and there were no treatment delays because of acute toxicity. CONCLUSIONS: Accelerated hypofractionated radiotherapy with 48 to 60 Gy using fractions of 4 Gy per day provides very good results for small tumors in medically inoperable patients with early-stage NSCLC.

Functional imaging using diffuse optical spectroscopy of neoadjuvant chemotherapy response in women with locally advanced breast cancer.

PURPOSE: Functional imaging with tomographic near-infrared diffuse optical spectroscopy (DOS) can measure tissue concentration of deoxyhemoglobin (Hb), oxyhemoglobin (HbO2), percent water (%water), and scattering power (SP). In this study, we evaluated tumor DOS parameters and described their relationship to clinical and pathologic outcome in patients undergoing neoadjuvant therapy for locally advanced breast cancer. EXPERIMENTAL DESIGN: Ten patients were enrolled and intended to undergo five scans each. Scans were taken up to 3 days before treatment and at 1, 4, and 8 weeks after neoadjuvant treatment before surgery. Changes in volume of interest weighted tissue Hb, HbO2, %water, and SP corresponding to the tumor were compared with clinical and pathologic response. RESULTS: All patients' tumor volumes of interest were significantly different compared with background tissue for all parameters. Five patients had a good pathologic response. Four patients were considered nonresponders. One patient initially did not respond to chemotherapy but, after a change in chemotherapy, had a good response. In the five patients with a good response, the mean drop in Hb, HbO2, %water, and SP from baseline to the 4-week scan was 67.6% (SD = 20.8), 58.9% (SD = 20.3), 51.2% (SD = 28.3), and 52.6% (SD = 26.4), respectively. In contrast, the four nonresponders had a mean drop of 17.7% (SD = 9.8), 18.0% (SD = 20.8), 15.4% (SD = 11.7), and 12.6% (SD = 10.2) for Hb, HbO2, %water, and SP, respectively. CONCLUSIONS: Responders and nonresponders were significantly different for all functional parameters at the 4-week scan, except for %water, which approached significance. Thus, DOS could be used as an early detector of tumor response.

Biological Markers Predictive of Invasive Recurrence in DCIS.

DCIS is a heterogeneous group of non-invasive cancers of the breast characterized by various degrees of differentiation and unpredictable propensity for transformation into invasive carcinoma. We examined the expression and prognostic value of 9 biological markers with a potential role in tumor progression in 133 patients with pure DCIS treated with breast conserving surgery alone, between 1982-2000. Histology was reviewed and immunohistochemical staining was performed. Pearson correlation coefficient was used to determine the associations between markers and histopathological features. Univariate and multivariate analysis examined associations between time to recurrence and clinicopathologic features and biological markers.Median age at diagnosis was 55 years (25-85). With a median follow up of 8.91 years, 41/133 patients recurred (21 as invasive recurrence). In this cohort 13.5% had low, 43% intermediate and 42% high nuclear grade. Comedo necrosis was found in 65% of cases. Expression of ER (62.4%), PR (55.6%), HER2/neu (31.6%), MIB1 (39.8%), p53 (22.6%), p21 (39.8%), Cyclin D1 (95.5%) calgranulin (20.5%), psoriasin (12%), was found in DCIS. HER2/neu was overexpressed in 45% that recurred as DCIS and 42.9% that recurred as invasive cancer, and only in 26.1% in cases that never recurred. On univariate analysis, HER2/neu overexpression was the only marker associated with an increased risk for any recurrence (p = 0.044). The hazard ratio for recurrence for HER2/neu positive DCIS was 1.927 (confidence interval 1.016-3.653) compared to HER2 negative DCIS. On multivariate analysis, HER2/neu overexpression remained the only independent variable significantly associated with any recurrence (p = 0.014) and with invasive recurrence (p = 0.044).This data suggest that HER2/neu testing may become an important parameter in the management of DCIS and the treatment of cases with positive HER2/neu status could be modified accordingly, similar to the current approach for HER2/neu positive invasive disease.

Invasive cervical cancer: a failure of screening.

BACKGROUND: Cervical screening is an effective prevention measure. It is unclear whether cervical cancer results from non-participation in screening or from failures in detection by screening. Analysis of the screening history of patients with cervix cancer may contribute to understanding failures in prevention. METHODS: A cohort of patients presenting during 1 year was identified. Dates and results of cervical smears in the 4 years prior to presentation were extracted from a screening database. Patients were grouped as follows: 'No screening'--no Pap records; 'Pre-diagnostic'--one or more Pap tests within 6 months of presentation; 'Sporadic screening'--one Pap test between 6 and 48 months prior to presentation; and 'Regular screening'--at least two Pap tests 6-48 months before presentation. RESULTS: 225 patients were identified (median age: 48 years, range 25-107). Eighty- eight had no records of screening; a further 66 were categorized as pre-diagnostic. These two groups (68% of incident cases) were considered not to have participated in routine screening. A further 15% had sporadic screening tests, but only 37 patients (16%) had evidence of regular screening. Clinically, 53, 41 and 6% presented with early, locally advanced and metastatic disease, respectively. Older patients (>50 years) were more likely to present with advanced disease (61 vs 37% at least Stage II). CONCLUSIONS: These results suggest that the failure to prevent invasive cervix cancer in this population can largely be attributed to failures in recruitment for screening.

Significance of multifocality in ductal carcinoma in situ: outcomes of women treated with breast-conserving therapy.

PURPOSE: There is concern that women with multifocal ductal carcinoma in situ (DCIS; confined to one quadrant) who are treated with breast-conserving surgery face a high risk of local recurrence; therefore, many are treated with mastectomy. The objective of this study is to evaluate the significance of multifocality and the outcomes of women with multifocal DCIS treated with breast-conserving therapy. METHODS: The records of patients treated with breast-conserving surgery for DCIS between 1982 and 2000 were reviewed. Multivariate analyses were performed to evaluate the effects of multifocality and other prognostic factors on the rate of local recurrence. RESULTS: Of 615 cases of DCIS reviewed, 310 (41%) received breast-conserving surgery and 305 (40%) received breast-conserving surgery plus radiation (n = 260 with multifocality, n = 314 without multifocality, and n = 31 focality unreported). On multivariate analysis, multifocality (hazard ratio [HR] = 1.80; 95% CI, 1.15 to 2.80; P = .01), radiation treatment (HR = 0.46; 95% CI, 0.29 to 0.74; P = .001), margin width 4 mm or smaller (HR = 1.74; 95% CI, 1.03 to 2.92; P = .04), and high nuclear grade (HR = 1.65; 95% CI, 1.02 to 2.65; P = .04) were associated with risk of local recurrence. The detrimental effect of multifocality was limited to women who did not receive radiotherapy; the local recurrence-free survival rate at 10 years was 59% for women with multifocal disease and 80% for women without multifocality (P = .02). Among women treated with breast-conserving surgery plus radiation, there was no difference in 10-year local recurrence-free survival (80% v 87%; P = .35). There was no association between multifocality and the development of invasive recurrence. CONCLUSION: Multifocality is a significant predictor of local recurrence in women who receive breast-conserving surgery for DCIS without radiotherapy; however, low recurrence rates can be achieved if adjuvant radiation is administered.

Prognostic and predictive molecular markers in DCIS: a review.

Eighteen percent of all new breast cancers detected on screening mammography are ductal carcinoma in situ (DCIS), a preinvasive lesion that is highly curable. However, some women with DCIS will develop life-threatening invasive breast cancer. Because the determinants of invasive recurrence are unknown, all women with DCIS require the same treatment (usually with surgery and radiation). Therefore, there is a need to identify biologic markers and create a profile that will provide prognostic information that is more accurate than the currently used van Nuys Index to predict invasive recurrence. In the present review, we examined the many biologic markers studied in breast cancer, describe their main biologic role and their expression in DCIS, and review the various studies regarding their ability to serve as prognostic factors in breast cancer with an emphasis on predicting invasive recurrence in patients with DCIS. This review covers established markers, namely, ER, PR and HER2/neu, that are used routinely to make treatment decisions as well as investigative biologic factors involved in cell proliferation, cell cycle regulation, extracellular molecules, factors involved in extracellular matrix degradation, and angiogenesis. However, controversies exist regarding the value of these prognostic factors, their interrelationship, and their advantages over morphologic evaluation.