Propensity scores with misclassified treatment assignment: a likelihood-based adjustment.

Propensity score methods are widely used in comparative effectiveness research using claims data. In this context, the inaccuracy of procedural or billing codes in claims data frequently misclassifies patients into treatment groups, that is, the treatment assignment ($T$) is often measured with error. In the context of a validation data where treatment assignment is accurate, we show that misclassification of treatment assignment can impact three distinct stages of a propensity score analysis: (i) propensity score estimation; (ii) propensity score implementation; and (iii) outcome analysis conducted conditional on the estimated propensity score and its implementation. We examine how the error in $T$ impacts each stage in the context of three common propensity score implementations: subclassification, matching, and inverse probability of treatment weighting (IPTW). Using validation data, we propose a two-step likelihood-based approach which fully adjusts for treatment misclassification bias under subclassification. This approach relies on two common measurement error-assumptions; non-differential measurement error and transportability of the measurement error model. We use simulation studies to assess the performance of the adjustment under subclassification, and also investigate the method's performance under matching or IPTW. We apply the methods to Medicare Part A hospital claims data to estimate the effect of resection versus biopsy on 1-year mortality among $10\,284$ Medicare beneficiaries diagnosed with brain tumors. The ICD9 billing codes from Medicare Part A inaccurately reflect surgical treatment, but SEER-Medicare validation data are available with more accurate information.

Comparative effectiveness of radiotherapy with vs. without temozolomide in older patients with glioblastoma.

It is unknown whether the addition of temozolomide (TMZ) to radiotherapy (RT) is associated with improved overall survival (OS) among older glioblastoma patients. We performed a retrospective cohort SEER-Medicare analysis of 1652 patients aged ≥65 years with glioblastoma who received ≥10 fractions of RT from 2005 to 2009, or from 1995 to 1999 before TMZ was available. Three cohorts were assembled based on diagnosis year and treatment initiated within 60 days of diagnosis: (1) 2005-2009 and TMZ/RT, (2) 2005-2009 and RT only, or (3) 1995-1999 and RT only. Associations with OS were estimated using Cox proportional hazards models and propensity score analyses; OS was calculated starting 60 days after diagnosis. Pre-specified sensitivity analyses were performed among patients who received long-course RT (≥27 fractions). Median survival estimates were 7.4 (IQR, 3.3-14.7) months for TMZ/RT, 5.9 (IQR, 2.6-12.1) months for RT alone in 2005-2009, and 5.6 (IQR, 2.7-9.6) months for RT alone in 1995-1999. OS at 2 years was 10.1 % for TMZ/RT, 7.1 % for RT in 2005-2009, and 4.7 % for RT in 1995-1999. Adjusted models suggested decreased mortality risk for TMZ/RT compared to RT in 2005-2009 (AHR, 0.86; 95 % CI, 0.76-0.98) and RT in 1995-1999 (AHR, 0.71; 95 % CI, 0.57-0.90). Among patients from 2005 to 2009 who received long-course RT, however, the addition of TMZ did not significantly improve survival (AHR, 0.91; 95 % CI, 0.80-1.04). In summary, among a large cohort of older glioblastoma patients treated in a real-world setting, the addition of TMZ to RT was associated with a small survival gain.

Salvage re-irradiation for recurrent high-grade glioma and comparison to bevacizumab alone.

While salvage re-irradiation is often used for recurrent high-grade glioma (HGG), there have been few comparisons between various re-radiation dose/fractionation schedules or with bevacizumab alone. We analyzed patients with recurrent HGG who received re-irradiation at Dana-Farber Cancer Institute and Brigham and Women's Hospital from 2010 to 2014 (n = 67), as well as those who received bevacizumab alone (n = 177). Cox proportional hazards modeling was used to examine factors associated with overall survival (OS). Propensity score modeling was used to compare survival after re-irradiation vs. bevacizumab alone. Median time from initial diagnosis to re-irradiation was 31.4 months. The most common re-irradiation dose/fractionations used were 6 Gy × 5 (36%), 3.5 Gy × 10 (21%), 2.67 Gy × 15 (15%), and 18-20 Gy × 1 (15%). No early or late toxicities >grade 2 were observed. Median PFS and OS after re-irradiation were 4.8 and 10.7 months, respectively. Number of progressions prior to re-irradiation (adjusted hazard ratio [AHR] 1.6; 95% CI, 1.1-2.3; p = .007), and recurrence in a new brain location (vs. local-only; AHR 7.4; 95% CI, 2.4-23.1; p < .001) were associated with OS; dose/fractionation was not. Compared with bevacizumab alone, re-irradiated patients had a non-significant increase in OS (HR 0.80; 95% CI, 0.53-1.23; P = .31). Among patients with a local-only recurrence, there was a trend towards longer median OS after re-irradiation compared to bevacizumab alone (12.4 vs. 8.0 months; p = .12). Survival after re-irradiation for recurrent HGG appears independent of dose/fractionation and compares favorably with bevacizumab alone.

Model averaged double robust estimation.

Researchers estimating causal effects are increasingly challenged with decisions on how to best control for a potentially high-dimensional set of confounders. Typically, a single propensity score model is chosen and used to adjust for confounding, while the uncertainty surrounding which covariates to include into the propensity score model is often ignored, and failure to include even one important confounder will results in bias. We propose a practical and generalizable approach that overcomes the limitations described above through the use of model averaging. We develop and evaluate this approach in the context of double robust estimation. More specifically, we introduce the model averaged double robust (MA-DR) estimators, which account for model uncertainty in both the propensity score and outcome model through the use of model averaging. The MA-DR estimators are defined as weighted averages of double robust estimators, where each double robust estimator corresponds to a specific choice of the outcome model and the propensity score model. The MA-DR estimators extend the desirable double robustness property by achieving consistency under the much weaker assumption that either the true propensity score model or the true outcome model be within a specified, possibly large, class of models. Using simulation studies, we also assessed small sample properties, and found that MA-DR estimators can reduce mean squared error substantially, particularly when the set of potential confounders is large relative to the sample size. We apply the methodology to estimate the average causal effect of temozolomide plus radiotherapy versus radiotherapy alone on one-year survival in a cohort of 1887 Medicare enrollees who were diagnosed with glioblastoma between June 2005 and December 2009.

Extent of resection and overall survival for patients with atypical and malignant meningioma.

BACKGROUND: The prognosis for patients with atypical and malignant meningioma is guarded; whether the extent of resection is associated with survival-based outcomes in this population remains poorly defined. This study investigated the association between gross total resection (GTR) and all-cause mortality in patients with atypical and malignant meningioma. METHODS: The Surveillance, Epidemiology, and End Results program was used to identify 575 and 64 patients betweens the ages of 18 and 70 years who were diagnosed with atypical and malignant meningioma, respectively, between 2004 and 2009. Multivariate Cox proportional hazards regression was used to assess the adjusted impact of GTR versus subtotal resection on all-cause mortality. RESULTS: Baseline patient characteristics were similar for patients who did undergo GTR and patients who did not undergo GTR. The 5-year overall survival rates were 91.3% (95% confidence interval [CI], 86.2%-94.5%) and 78.2% (95% CI, 70.0%-84.3%) for patients with atypical meningioma who did and did not undergo GTR, respectively, and 64.5% (95% CI, 45.9%-78.1%) and 41.1% (95% CI, 17.9%-63.1%) for patients with malignant meningioma who did and did not undergo GTR, respectively. After adjustments for available, pertinent confounding variables, GTR was associated with lower all-cause mortality in patients with atypical (hazard ratio, 0.39; 95% CI, 0.23-0.67; P < .001) and malignant meningioma (hazard ratio, 0.35; 95% CI, 0.15-0.81; P = .01). CONCLUSIONS: The extent of resection is a powerful predictor of outcome for patients with atypical and malignant meningioma. These data highlight the hazard associated with the presence of gross tumor bulk after surgery and suggest a value for more extensive resections that should be balanced against the additional potential morbidity.

Invasive lobular carcinoma of the breast: local recurrence after breast-conserving therapy by subtype approximation and surgical margin.

Invasive lobular carcinoma (ILC) typically presents at a later stage than invasive ductal carcinoma (IDC) and poses unique radiographic and surgical challenges. However, current principles of breast-conserving therapy (BCT) do not distinguish between histologic subtypes, raising uncertainty about the optimal approach for patients with ILC. We studied 998 BCT patients from 1998-2007, comprised 74 % IDC, 8 % ILC, and 18 % with mixed ILC/IDC. In light of recent guidelines addressing surgical margins, specimens were assessed for margin width and biologic subtype. The Kaplan-Meier method and Cox proportional hazards models were used to analyze effects of patient and disease characteristics on local recurrence (LR). At a median of 119 months, 45 patients had an isolated LR. 10-year LR was 5.5 % for patients with IDC, 4.4 % for ILC, and 1.2 % for mixed histology (p = 0.08). The majority of ILC cases had luminal A biologic subtype (91.1 %), and analysis among all luminal A cases revealed 10-year LR of 2.6 % for IDC, 3.4 % for ILC, and 0 % for mixed tumors (p = 0.12). Patients with ILC were more likely to have initially positive surgical margins (45.0 vs 17.5 %; p < 0.001) resulting in more frequent re-excision (57.1 % vs 40.4 %; p = 0.02), though final margins were similar between ILC and IDC (p = 0.88). No LR was observed among ILC or mixed histology patients with margins <2 mm (n = 28). On multivariate analysis, histologic subtype was not associated with LR (p = 0.52). Modern approaches confer similarly favorable LR rates for ILC, IDC, and mixed histology breast cancers despite inherent histologic differences. Patients with ILC did not require more extensive surgical margins than those with IDC.

Radiotherapy and death from cerebrovascular disease in patients with primary brain tumors.

Radiotherapy is often used in the management of primary brain tumors, but late cerebrovascular risks remain incompletely characterized. We examined the relationship between radiotherapy and the risk of death from cerebrovascular disease (CVD) in this population. We used the Surveillance, Epidemiology, and End Results Program to identify 19,565 patients of any age diagnosed with a primary brain tumor between 1983-2002. Multivariable competing risks analysis and an interaction model were used to determine whether receipt of radiotherapy was associated with an increased risk of CVD-specific death, adjusting for tumor proximity to central arterial circulations of the brain. The median follow up in surviving patients was 12.75 years. Baseline characteristics were similar in patients who did and did not receive radiotherapy. Ten-year CVD-specific mortality in patients with tumors near central arterial circulations who did and did not receive radiotherapy were 0.64 % (95 % CI 0.42-0.93 %) versus 0.16 % (95 % CI 0.055-0.40 %), p = 0.01. After adjustment for demographic, tumor-related, and treatment-related covariates, patients with tumors near central arterial circulations were significantly more likely to experience CVD-specific mortality after radiotherapy (HR 2.81; 95 % CI 1.25-6.31; p = 0.01); no association was observed among patients with more distant tumors (HR 0.77; 95 % CI 0.50-1.16; p = 0.21). The interaction model showed that tumor location was a key predictor of the risk of radiotherapy-associated, CVD-specific mortality (p-interaction = 0.004). Patients receiving radiotherapy for tumors near but not distant from the central vasculature of the brain are at increased risk for death secondary to CVD, which should be considered when counseling patients.

Brachytherapy in the treatment of recurrent aggressive falcine meningiomas.

Recurrent aggressive falcine meningiomas are uncommon tumors that recur despite receiving extensive surgery and radiation therapy (RT). We have utilized brachytherapy as a salvage treatment in two such patients with a unique implantation technique. Both patients had recurrence of WHO Grade II falcine meningiomas despite multiple prior surgical and RT treatments. Radioactive I-125 seeds were made into strands and sutured into a mesh implant, with 1 cm spacing, in a size appropriate to cover the cavity and region of susceptible falcine dura. Following resection the vicryl mesh was implanted and fixed to the margins of the falx. Implantation in this interhemispheric space provides good dose conformality with targeting of at-risk tissue and minimal radiation exposure to normal neural tissues. The patients are recurrence free 31 and 10 months after brachytherapy treatment. Brachytherapy was an effective salvage treatment for the recurrent aggressive falcine meningiomas in our two patients.

Salvage whole brain radiotherapy or stereotactic radiosurgery after initial stereotactic radiosurgery for 1-4 brain metastases.

Patients with limited brain metastases are often candidates for stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Among patients who receive SRS, the likelihood and timing of salvage WBRT or SRS remains unclear. We examined rates of salvage WBRT or SRS among 180 patients with 1-4 newly diagnosed brain metastases who received index SRS from 2008-2013. Competing risks multivariable analysis was used to examine factors associated with time to WBRT. Patients had non-small cell lung (53 %), melanoma (23 %), breast (10 %), renal (6 %), or other (8 %) cancers. Median age was 62 years. Patients received index SRS to 1 (60 %), 2 (21 %), 3 (13 %), or 4 (7 %) brain metastases. Median survival after SRS was 9.7 months (range, 0.3-67.6 months). No further brain-directed radiotherapy was delivered after index SRS in 55 % of patients. Twenty-seven percent of patients ever received salvage WBRT, and 30 % ever received salvage SRS; 12 % of patients received both salvage WBRT and salvage SRS. Median time to salvage WBRT or salvage SRS were 5.6 and 6.1 months, respectively. Age ≤60 years (adjusted hazard ratio [AHR] = 2.80; 95 % CI 1.05-7.51; P = 0.04) and controlled/absent extracranial disease (AHR = 6.76; 95 % CI 1.60-28.7; P = 0.01) were associated with shorter time to salvage WBRT. Isolated brain progression caused death in only 11 % of decedents. In summary, most patients with 1-4 brain metastases receiving SRS never require salvage WBRT or SRS, and the remainder do not require salvage treatment for a median of 6 months.

Incidence, risk factors, and reasons for hospitalization among glioblastoma patients receiving chemoradiation.

Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score ≥ 70. Twenty-six percent of patients underwent gross total resection, 77 % received ≥ 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P < .001). Nearly half of the hospitalizations were due to generalized weakness (17 % of hospitalizations), seizures (16 %), or venous thromboembolism (13 %). On multivariate analysis, age (odds ratio [OR], 1.03; 95 % CI, 1.002-1.060; P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P < .001) were associated with risk of hospitalization. Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival.

Local control after fractionated stereotactic radiation therapy for brain metastases.

Stereotactic radiosurgery (SRS) is frequently used in the management of brain metastases, but concerns over potential toxicity limit applications for larger lesions or those in eloquent areas. Fractionated stereotactic radiation therapy (SRT) is often substituted for SRS in these cases. We retrospectively analyzed the efficacy and toxicity outcomes of patients who received SRT at our institution. Seventy patients with brain metastases treated with SRT from 2006-2012 were analyzed. The rates of local and distant intracranial progression, overall survival, acute toxicity, and radionecrosis were determined. The SRT regimen was 25 Gy in 5 fractions among 87 % of patients. The most common tumor histologies were non-small cell lung cancer (37 %), breast cancer (20 %) and melanoma (20 %), and the median tumor diameter was 1.7 cm (range 0.4-6.4 cm). Median survival after SRT was 10.7 months. Median time to local progression was 17 months, with a local control rate of 68 % at 6 months and 56 % at 1 year. Acute toxicity was seen in 11 patients (16 %), mostly grade 1 or 2 with the most common symptom being mild headache. Symptomatic radiation-induced treatment change was seen on follow-up MRIs in three patients (4.3 %). SRT appears to be a safe and reasonably effective technique to treat brain metastases deemed less suitable for SRS, though dose intensification strategies may further improve local control.

Outcomes in stage I testicular seminoma: a population-based study of 9193 patients.

BACKGROUND: Few studies have quantified temporal patterns of cause-specific mortality in contemporary cohorts of men with early-stage seminoma. Given that several management strategies can be applied in these patients, each resulting in excellent long-term survival, it is important to evaluate associated long-term sequelae. In particular, data describing long-term risks of cardiovascular disease (CVD) are conflicting. METHODS: We identified 9193 men diagnosed with stage I seminoma (ages 15-70 years) in the population-based SEER registries (1973-2001). We calculated survival estimates, standardized mortality ratios (SMRs), and adjusted hazard rates (AHRs). RESULTS: During 121,037 person-years of follow-up (median, 12.3 years), 915 deaths (SMR, 1.23; 95% CI, 1.16-1.32) were reported, with significant excesses for suicide (n = 39; SMR, 1.45; 95% CI, 1.06-1.98), infection (n = 58; SMR, 2.32; 95% CI, 1.80-3.00), and second malignant neoplasms (SMNs; n = 291; SMR, 1.81; 95% CI, 1.61-2.03), but not CVD (n = 201; SMR, 0.91; 95% CI, 0.80-1.05). After radiotherapy (78% patients), CVD deaths were not increased (n = 158; SMR, 0.89; 95% CI, 0.76-1.04), in contrast to SMN deaths (n = 246; SMR, 1.89; 95% CI, 1.67-2.14). SMN mortality was higher among patients administered radiotherapy than among those not given radiotherapy (AHR, 1.36; 95% CI, 0.99-1.88; P = .059), with a cumulative 15-year risk of 2.64% (95% CI, 2.19-3.16). Suicide, although rare, accounted for 1 in 230 deaths. CONCLUSIONS: Modern radiotherapy as applied in this large population-based study is not associated with excess CVD mortality. Although increased all-cause mortality exists, cumulative SMN risk is considerably smaller than reported in historical series, but additional follow-up will be required to characterize long-term trends. The increased risk of suicide, previously unreported in men with stage I seminoma, requires confirmation.

Margin status and the risk of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy.

We sought to assess whether a close surgical margin (>0 and <2 mm) after breast-conserving therapy (BCT) confers an increased risk of local recurrence (LR) compared with a widely negative margin (≥2 mm). We studied 906 women with early-stage invasive breast cancer treated with BCT between January 1998 and October 2006; 91 % received adjuvant systemic therapy. Margins were coded as: (1) widely negative (n = 729), (2) close (n = 85), or (3) close (n = 84)/positive (n = 8) but having no additional tissue to remove according to the surgeon. Cumulative incidence of LR and distant failure (DF) were calculated using the Kaplan-Meier method. Gray's competing-risk regression assessed the effect of margin status on LR and Cox proportional hazards regression assessed the effect on DF, controlling for biologic subtype, age, and number of positive lymph nodes (LNs). Three hundred seventy-seven patients (41.6 %) underwent surgical re-excision, of which 63.5 % had no residual disease. With a median follow-up of 87.5 months, the 5-year cumulative incidence of LR was 2.5 %. The 5-year cumulative incidence of LR by margin status was 2.3 % (95 % CI 1.4-3.8 %) for widely negative, 0 % for close, and 6.4 % (95 % CI 2.7-14.6 %) for no additional tissue, p = 0.3. On multivariate analysis, margin status was not associated with LR; however, triple-negative subtype (AHR 3.7; 95 % CI 1.6-8.8; p = 0.003) and increasing number of positive LNs (AHR 1.6; 95 % CI 1.1-2.3; p = 0.025) were associated. In an era of routine adjuvant systemic therapy, close surgical margins and maximally resected close/positive margins were not associated with an increased risk of LR compared to widely negative margins. Additional studies are needed to confirm this finding.

Pathologic characteristics of second breast cancers after breast conservation for ductal carcinoma in situ.

BACKGROUND: The number of women diagnosed with ductal carcinoma in situ (DCIS) is increasing. Although many eventually develop a second breast cancer (SBC), little is known about the characteristics of SBCs. The authors described the characteristics of SBC and examined associations between the pathologic features of SBC and index DCIS cases. METHODS: Women were identified in the National Comprehensive Cancer Network Outcomes Database who were diagnosed with DCIS from 1997 to 2008 and underwent lumpectomy and who subsequently developed SBC (including DCIS or invasive disease that occurred in the ipsilateral or contralateral breast). The Fisher exact test and the Spearman test were used to examine associations between the pathologic characteristics of SBC and index DCIS cases. RESULTS: Among 2636 women who underwent lumpectomy for DCIS, 150 (5.7%) experienced an SBC after a median of 55.5 months of follow-up. Of these 150 women, 105 (70%) received adjuvant radiotherapy, and 50 (33.3%) received tamoxifen for their index DCIS. SBCs were ipsilateral in 54.7% of women and invasive in 50.7% of women. Among the index DCIS cases, 60.6% were estrogen receptor (ER)-positive, and 54% were high grade, whereas 77.5% of SBCs were ER-positive, and 48.2% were high grade. Tumor grade (P = .003) and ER status (P = .02) were associated significantly between index DCIS and SBC, whereas tumor size was not (P = .87). CONCLUSIONS: After breast conservation for DCIS, SBC in either breast exhibited pathologic characteristics similar to the index DCIS, suggesting that women with DCIS may be at risk for developing subsequent breast cancers of a similar phenotype.

Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer.

BACKGROUND: Neoadjuvant chemotherapy before chemoradiation therapy (CRT) may improve outcomes for patients with locally advanced pancreatic cancer, but optimal management remains controversial, and prior reports have limited follow-up. METHODS: Seventy consecutive patients with unresectable (n = 46) or borderline resectable (n = 24) locally advanced pancreatic cancer were treated with CRT from 2005 to 2009. Patients typically received 50.4 grays in 28 fractions (91%) with concurrent 5-fluorouracil (84%) or capecitabine (14%). Forty patients received CRT alone, and 30 patients received neoadjuvant chemotherapy before CRT for a median of 4 months, typically gemcitabine (93%). All patients without progression after neoadjuvant chemotherapy were offered CRT. RESULTS: Median follow-up was 14.2 months (range, 3-57 months). Fifty-three percent of patients in the CRT group versus 83% in the neoadjuvant chemotherapy before CRT group had unresectable tumors at diagnosis; after completion of CRT, 20% of patients in both groups underwent resection. Compared with CRT alone, the neoadjuvant chemotherapy before CRT group demonstrated improved median overall survival (OS; 18.7 vs 12.4 months; P = .02) and progression-free survival (11.4 vs 6.7 months; P = .02). On multivariate analysis, receipt of neoadjuvant chemotherapy (adjusted hazard ratio [HR], 0.49; 95% CI, 0.28-0.87; P = .02) and surgical resection (adjusted HR, 0.38; 95% CI, 0.17-0.85; P = .02) were associated with increased OS. CONCLUSIONS: Gemcitabine-based neoadjuvant chemotherapy confers a significant OS advantage by allowing the selection of patients who will derive greatest benefit from CRT. Median survival with this approach was similar to that seen with surgical resection.

Brain metastases after breast-conserving therapy and systemic therapy: incidence and characteristics by biologic subtype.

The characteristics of brain metastases (BM) that develop after breast-conserving therapy (BCT) for early-stage breast cancer (BC) remain incompletely defined. We examined 1,434 consecutive patients with stage I/II invasive BC who received BCT from 1997 to 2006, 91 % of whom received adjuvant systemic therapy, according to BC subtype. Median follow-up was 85 months. Overall 5-year cumulative incidence of BM was 1.7 %; 0.1 % for luminal A, 3.3 % for luminal B, 3.2 % for luminal-HER2, 3.7 % for HER2, and 7.4 % for triple negative (TN). Women who developed BM were more likely at BC diagnosis to be younger (P < .0001) and have node-positive (P < .0001), grade 3 (P < .0001), hormone receptor-negative (P = .006), and HER2-positive (P = .01) tumors. Median time from BC diagnosis to BM was 51.4 months (range, 7.6-108 months), which was longer among luminal versus non-luminal subtypes (P = .0002; median, 61.4 vs. 34.5 months). Thirty-four percent of patients who developed distant metastases (DM) eventually developed BM. Median time from DM to BM was 12.8 months but varied by subtype, including 7.4 months for TN, 9.6 months for luminal B, and 27.1 months for HER2. Eighty-one percent of all BM patients presented with neurologic symptoms. Median number of BM at diagnosis was two, and median BM size was 15 mm, with TN (27 mm) and luminal B (16 mm) exhibiting the largest median sizes. In conclusion, the risk of BM after BCT varies significantly by subtype. Given the large size and symptomatic presentation among luminal B and TN subtypes, earlier BM detection might improve quality of life or increase eligibility for non-invasive treatments including stereotactic radiosurgery. Women with DM from these two BC subtypes have a high incidence of BM with a short latency, suggesting an ideal target population for trials evaluating the utility of MRI screening.

Impact of Low-dose Chest CT Screening on the Association Between Rurality and Lung Cancer Outcomes.

INTRODUCTION: Lung cancer mortality is higher among rural United States populations compared with nonrural ones. Little is known about screening low-dose chest computed tomography (LDCT) outcomes in rural settings. MATERIALS AND METHODS: This retrospective cohort study examined all patients (n=1805) who underwent screening LDCT in a prospective registry from March 1, 2015, through December 31, 2019, in a majority-rural health care system. We assessed the proportion of early-stage lung cancers (American Joint Committee on Cancer stage I-II) diagnosed among LDCT-screened patients, and analyzed overall survival after early-stage lung cancer diagnosis according to residency location. RESULTS: The screening cohort had a median age of 63 and median 40-pack-year smoking history; 62.4% had a rural residence, 51.2% were female, and 62.7% completed only 1 LDCT scan. Thirty-eight patients were diagnosed with lung cancer (2.1% of the cohort), of which 65.8% were early-stage. On multivariable analysis, rural (vs nonrural) residency was not associated with a lung cancer diagnosis (adjusted hazard ratio 1.59; 95% CI, 0.74-3.40; P =0.24). At a median follow-up of 37.1 months (range, 3.3 to 67.2 months), 88.2% of rural versus 87.5% of nonrural patients with screen-diagnosed early-stage lung cancer were alive ( P =0.93). CONCLUSIONS: In a majority-rural United States population undergoing LDCT, most screen-detected lung cancers were early-stage. There were no significant differences observed between rural and nonrural patients in lung cancer diagnosis rate or early-stage lung cancer survival. Increased implementation of LDCT might blunt the historical association between rural United States populations and worse lung cancer outcomes.

Risk of death from prostate cancer after radical prostatectomy or brachytherapy in men with low or intermediate risk disease.

PURPOSE: Radical prostatectomy and brachytherapy are widely used treatments for favorable risk prostate cancer. We estimated the risk of prostate cancer specific mortality following radical prostatectomy or brachytherapy in men with low or intermediate risk prostate cancer using prospectively collected data. MATERIALS AND METHODS: The study cohort comprised 5,760 men with low risk prostate cancer (prostate specific antigen 10 ng/ml or less, clinical category T1c or 2a and Gleason score 6 or less), and 3,079 with intermediate risk prostate cancer (prostate specific antigen 10 to 20 ng/ml, clinical category T2b or T2c, or Gleason score 7). Competing risks multivariable regression was performed to assess the risk of prostate cancer specific mortality after radical prostatectomy or brachytherapy, adjusting for age, year of treatment, cardiovascular comorbidity and known prostate cancer prognostic factors. RESULTS: After a median followup of 4.2 years (IQR 2.0-7.4) for low risk and 4.8 years (IQR 2.2-8.1) for intermediate risk men, there was no significant difference in the risk of prostate cancer specific mortality among low risk (adjusted hazard ratio 1.62, 95% CI 0.59-4.45, p = 0.35) or intermediate risk men (AHR 2.30, 95% CI 0.95-5.58, p = 0.07) treated with brachytherapy compared with radical prostatectomy. The only factor associated with an increased risk of prostate cancer specific mortality (AHR 1.05, 95% CI 1.01-1.10, p = 0.03) was increasing age at treatment in intermediate risk men. CONCLUSIONS: The risk of prostate cancer specific mortality in men with low or intermediate risk prostate cancer was not significantly different following radical prostatectomy vs brachytherapy.

Brain metastases.

An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood-tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve.

Radiation-induced caspase-8 mediates p53-independent apoptosis in glioma cells.

Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation.