Genomic Characterization of Aggressive Breast Cancer in Younger Women.

PURPOSE: Although breast cancer (BC) risk increases with age, BC in younger women is more aggressive with higher mortality compared with older women. We characterize the genomic landscape of BCs in younger women. METHODS: Clinicopathologic, molecular, and genomic differences across age groups (< 40 years, 40-60 years, > 60 years) in female BC patients were investigated in two large cohorts [AACR-GENIE8.1 (n = 11,594) and METABRIC (n = 2509)]. Cox-proportional regression analyzed the prognostic impact of age groups for disease-specific survival (DSS) and recurrence-free survival (RFS) in METABRIC and progression-free survival (PFS) in GENIE cohorts. Chi-squared test was used to assess statistical associations between genomic alterations and age groups. RESULTS: Survival analysis showed that women < 40 years had shorter DSS [hazard ratio (HR): 1.52, p = 0.005], RFS (HR: 1.4, p = 0.006), and PFS (HR: 1.82, p = 0.0003) compared with women 40-60 years, and shorter RFS (HR: 1.5, p = 0.001) and PFS (HR: 2.95, p < 0.0001) compared with women > 60 years. Molecular subtypes in the METABRIC cohort showed women < 40 years were enriched with basal, and HER2+ subtypes, and less enriched with luminal A and B subtype (p < 0.0001). Characterization of genomic alterations in both cohorts demonstrated that BCs in women < 40 years were more enriched with TP53 mutations (FDR < 0.0001), BRCA1 mutations (FDR = 0.01), ERBB2 amplifications (FDR < 0.001), CDK12 amplifications (FDR < 0.001), and PPM1D amplifications (FDR < 0.001). In contrast, BCs in older women (> 60 years) were more enriched with PIK3CA, KMT2C, and CDH1 mutations (FDR < 0.0001). CONCLUSIONS: BCs in young women are associated with shorter survival and more aggressive genomic features, including mutations in TP53 and BRCA1, and amplifications in ERBB2 and CDK12. These findings have the potential to impact clinical trial design and treatment.

Impact of genomic assays on treatment and outcomes in locally advanced breast cancer.

PURPOSE: Genomic profiling in early-stage breast cancer provides prognostic and predictive information. Genomic profiling assays have not been validated in locally advanced breast cancer (LABC). We examined a large cancer registry to evaluate genomic profiling in LABC and its effect on treatment decisions and survival. METHODS: Females with ER+/HER2- LABC who did not receive neoadjuvant therapy were selected from the National Cancer Database 2004-2017. We compared characteristics between patients with and without genomic profiling and with low genomic risk, 21-gene recurrence score ≤ 25 or low-risk 70-gene signature, treated with endocrine therapy ± chemotherapy. Propensity score methods were utilized to account for covariates that may have predicted treatment. Univariable and multivariable survival analyses were performed. RESULTS: Of 18,437 patients with LABC, 1258 (7%) had genomic profiling and 1022 (81%) had low genomic risk results. 562 patients (55%) with low genomic risk received chemotherapy and endocrine therapy (chemoendocrine). Patients who received chemoendocrine therapy were younger, had fewer comorbidities, presented with higher stage disease, had higher grade tumors, more frequently had partial mastectomy, and more often received radiation than those who received endocrine therapy alone. On multivariable analysis, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy (HR 1.77, 95% CI 1.13-2.78, p = 0.013). CONCLUSION: In women with LABC and low genomic risk, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy. This suggests that genomic profiling is not predictive in LABC. Accordingly, genomic profiling should not be routinely utilized to make adjuvant treatment decisions in LABC in the absence of further data which shows a benefit.

Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma.

BACKGROUND: Many studies show significantly improved survival after R0 resection compared with R1 resection in pancreatic adenocarcinoma (PAC); however, the effect of neoadjuvant chemoradiation (NACRT) on this association is unknown. OBJECTIVE: The aim of this study was to evaluate the prognostic significance of positive surgical margins (SMs) after NACRT compared with upfront surgery + adjuvant therapy in PAC. METHODS: All cases of surgically resected PAC at a single institution were reviewed from 1996 to 2014; patients treated with palliative intent, metastatic disease, and biliary/ampullary tumors were excluded. The primary endpoint was overall survival (OS). RESULTS: Overall, 300 patients were included; 134 patients received NACRT with concurrent 5-fluorouracil or gemcitabine followed by surgery, and 166 patients received upfront surgery (+ adjuvant chemotherapy in 72% of patients and RT in 65%); 31% of both groups had a positive SM (+SM). The median OS for patients with a +SM or negative SM (-SM) was 26.6 and 31.6 months, respectively for NACRT, and 12.0 and 24.5 months, respectively, for upfront surgery. OS was significantly improved with -SM compared with +SM in both groups (p = 0.006). When resection yielded +SM, NACRT patients had improved OS compared with upfront surgery patients (p < 0.001). On multivariable analysis, +SM in the upfront surgery group (hazard ratio [HR] 2.94, 95% confidence interval [CI] 2.04-4.24; p < 0.001) and older age (HR 1.01, 95% CI 1.00-1.03, per year; p = 0.007) predicted worse OS. +SM in the NACRT group was not associated with worse OS (HR 1.09, 95% CI 0.72-1.65; p = 0.70). CONCLUSION: Patients with a positive margin after NACRT and surgery had longer survival compared with patients with a positive margin after upfront surgery. NACRT should be strongly considered for patients at high risk of R1 resections.

Disparities in Primary Breast Cancer Stage at Presentation Among Hispanic Subgroups.

BACKGROUND: Although the United States (US) Hispanic population consists of diverse communities, prior breast cancer studies often analyze this group in aggregate. Our aim was to identify differences in breast cancer stage at presentation in the US population, with a particular focus on Hispanic subgroups. METHODS: Data from the National Cancer Database (NCDB) from 2004 to 2017 were used to select women with primary breast cancer; individuals were disaggregated by racial and ethnic subgroup and Hispanic country of origin. Ordinal logistic regression was used to create adjusted odds ratios (aORs) with 95% confidence intervals (CIs), with higher odds representing presentation at later-stage breast cancer. Subgroup analysis was conducted based on tumor receptor status. RESULTS: Overall, among 2,282,691 women (5.2% Hispanic), Hispanic women were more likely to live in low-income and low-educational attainment neighborhoods, and were also more likely to be uninsured. Hispanic women were also more likely to present at later-stage primary breast cancer when compared with non-Hispanic White women (aOR 1.19, 95% CI 1.18-1.21; p < 0.01). Stage disparities were demonstrated when populations were disaggregated by country of origin, particularly for Mexican women (aOR 1.55, 95% CI 1.51-1.60; p < 0.01). Disparities worsened among both racial and country of origin subgroups in women with triple-negative disease. CONCLUSION: Later breast cancer stage at presentation was observed among Hispanic populations when disaggregated by racial subgroup and country of origin. Socioeconomic disparities, as well as uncaptured disparities in access and/or differential care, may drive these observed differences. Future studies with disaggregated data are needed to characterize outcomes in Hispanic communities and develop targeted interventions.

Prophylactic Radiotherapy for Prevention of Heterotopic Ossification After Periacetabular Fractures: A Review of Efficacy and Associated Conditions.

Prophylactic radiotherapy (XRT) is a commonly used treatment to decrease heterotopic ossification (HO) in patients with traumatic hip injuries. We conducted a retrospective review of patients at risk for HO who underwent XRT. Of the patients reviewed, 27.3% developed radiographic HO, 11.2% developed symptoms, and 2.0% required resection surgery. Patients were divided into primary (n = 71) and secondary prophylaxis (n = 27) cohorts. In the primary group, 25.0% developed radiographic HO, 5.6% developed symptoms, and 0 required surgery. In the secondary cohort, 33.3% of patients developed new radiographic HO, and 25.9% were symptomatic: four had a Brooker score of 3, and three had a score of 4 (p = 0.03), and 7.4% required surgical resection. (Journal of Surgical Orthopaedic Advances 31(2):113-118, 2022).

Increasing time to treatment initiation for head and neck cancer: an analysis of the National Cancer Database.

BACKGROUND: The objective of this study was to identify trends and predictors of the time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). METHODS: The National Cancer Database (NCDB) was reviewed for the following head and neck cancer sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was defined as the number of days from diagnosis to the initiation of definitive treatment and was measured according to covariates. Significant differences in the median TTI across each covariate were measured using the Kruskal-Wallis test, and the Spearman test was used to measure trends within covariates. For multivariate analysis, a zero-inflated, negative, binomial regression model was used to estimate the expected TTI, which was expressed in the predicted number of days; and the Vuong test was used to identify the predictors of TTI. RESULTS: In total, 274,630 patients were included. Between 1998 and 2011, the median TTI for all patients was 26 days, and it increased from 19 days to 30 days (P < .0001). Treatment with chemoradiation (CRT) (P < .0001), treatment at academic facilities (P < .0001), and stage IV disease (P < .0001) were associated with increased TTI. TTI significantly increased for each disease stage (P < .0001), treatment modality (P < .0001), and facility type (P < .0001) over time. In addition, patients became more likely to transition care between facilities after diagnosis for treatment initiation (P < .0001) over time. On multivariate analysis, treatment at academic facilities (33 days), transitioning care (37 days), and receipt of CRT (39 days) predicted for a longer TTI. CONCLUSIONS: TTI is rising for patients with HNSCC. Those who have advanced-stage disease, receive treatment with CRT, are treated at academic facilities, and who have a transition in care realized the greatest increases in TTI.

Impact of obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for localized prostate cancer.

BACKGROUND: Previous publications have demonstrated conflicting results regarding body mass index (BMI) and prostate cancer (CaP) outcomes after definitive radiotherapy (RT) before the dose escalation era. The goal of the current study was to determine whether increasing BMI was associated with outcomes in men with localized CaP who were treated with dose-escalated RT. METHODS: The authors identified patients with localized (T1b-T4N0M0) CaP who were treated with definitive intensity-modulated RT and image-guided RT from 2001 through 2010. BMI was analyzed as a continuous variable. Adjusting for confounders, multivariable competing risk and Cox proportional hazards regression models were used to assess the association between BMI and the risk of biochemical failure (BF), distant metastases (DM), cause-specific mortality (CSM), and overall mortality. RESULTS: Of the 1442 patients identified, approximately 20% had a BMI <25 kg/m(2) , 48% had a BMI of 25 to 29.9 kg/m(2) , 23% had a BMI of 30 to 34.9 kg/m(2) , 6% had a BMI of 35 to 39.9 kg/m(2) , and 4% had a BMI of ≥40 kg/m(2) . The median follow-up was 47.6 months (range, 1-145 months), with a median age of 68 years (range, 36-89 years). The median dose was 78 grays (range, 76-80 grays) and 30% of patients received androgen deprivation therapy. Increasing BMI was found to be inversely associated with age (P<.001) and pretreatment prostate-specific antigen level (P = .018). On multivariable analysis, increasing BMI was associated with an increased risk of BF (hazard ratio [HR], 1.03; 95% confidence interval [95% CI], 1.00-1.07 [P = .042]), DM (HR, 1.07; 95% CI, 1.02-1.11 [P = .004]), CSM (HR, 1.15; 95% CI, 1.07-1.23 [P<.001]), and overall mortality (HR, 1.05; 95% CI, 1.02-1.08 [P = .004]). CONCLUSIONS: For patients with CaP receiving dose-escalated intensity-modulated RT with daily image-guidance, increasing BMI appears to be associated with an increased risk of BF, DM, CSM, and overall mortality.

Post-Mastectomy Implant Complications in the Hispanic Breast Cancer Patient Population.

BACKGROUND/AIM: The purpose was to analyze the impact of post-mastectomy radiation therapy (PMRT) on implant-based breast reconstruction (IBR) in self-identified Hispanic patients compared to non-Hispanic counterparts. PATIENTS AND METHODS: We retrospectively reviewed patients who underwent IBR between January 1, 2017 and December 31, 2019 at a single hospital system. Patients were cisgender women, assigned female at birth, 18 years or older, and underwent mastectomy with immediate IBR +/- PMRT. We compared characteristics between Hispanic and non-Hispanic patients, assessing capsular contracture and implant loss rates. Multivariable analysis was performed to identify factors associated with complications. RESULTS: A total of 317 patients underwent mastectomy and reconstruction. Of these patients, 302 underwent a total of 467 mastectomies with IBR, and these 467 procedures were included in the analysis of complications. Complications occurred in 175 breasts (37.5%), regardless of PMRT. Seventy-two of the 302 patients (24%) received PMRT to one breast. The overall rates of capsular contracture, implant loss, and overall complications did not vary significantly between Hispanic and non-Hispanic patients (p=0.866, 0.974, and 0.761, respectively). When comparing only irradiated patients, there was a trend towards increased implant loss and overall complication rates in Hispanic versus non-Hispanic patients (p=0.107 and 0.113, respectively). Following PMRT the rate of any complication was 71% in Hispanic women and 53% in non-Hispanic women. CONCLUSION: Our study illuminates a trend towards higher complication rates after PMRT in Hispanic versus non-Hispanic patients. Further studies are needed to understand why Hispanic patients may have more side effects from radiation therapy.

Erring Characteristics of Deformable Image Registration-Based Auto-Propagation for Internal Target Volume in Radiotherapy of Locally Advanced Non-Small Cell Lung Cancer.

Purpose: Respiratory motion of locally advanced non-small cell lung cancer (LA-NSCLC) adds to the challenge of targeting the disease with radiotherapy (RT). One technique used frequently to alleviate this challenge is an internal gross tumor volume (IGTV) generated from manual contours on a single respiratory phase of the 4DCT via the aid of deformable image registration (DIR)-based auto-propagation. Through assessing the accuracy of DIR-based auto-propagation for generating IGTVs, this study aimed to identify erring characteristics associated with the process to enhance RT targeting in LA-NSCLC. Methods: 4DCTs of 19 patients with LA-NSCLC were acquired using retrospective gating with 10 respiratory phases (RPs). Ground-truth IGTVs (GT-IGTVs) were obtained through manual segmentation and union of gross tumor volumes (GTVs) in all 10 phases. IGTV auto-propagation was carried out using two distinct DIR algorithms for the manually contoured GTV from each of the 10 phases, resulting in 10 separate IGTVs for each patient per each algorithm. Differences between the auto-propagated IGTVs (AP-IGTVs) and their corresponding GT-IGTVs were assessed using Dice coefficient (DICE), maximum symmetric surface distance (MSSD), average symmetric surface distance (ASSD), and percent volume difference (PVD) and further examined in relation to anatomical tumor location, RP, and deformation index (DI) that measures the degree of deformation during auto-propagation. Furthermore, dosimetric implications due to the analyzed differences between the AP-IGTVs and GT-IGTVs were assessed. Results: Findings were largely consistent between the two algorithms: DICE, MSSD, ASSD, and PVD showed no significant differences between the 10 RPs used for propagation (Kruskal-Wallis test, ps > 0.90); MSSD and ASSD differed significantly by tumor location in the central-peripheral and superior-inferior dimensions (ps < 0.0001) while only in the central-peripheral dimension for PVD (p < 0.001); DICE, MSSD, and ASSD significantly correlated with the DI (Spearman's rank correlation test, ps < 0.0001). Dosimetric assessment demonstrated that 79% of the radiotherapy plans created by targeting planning target volumes (PTVs) derived from the AP-IGTVs failed prescription constraints for their corresponding ground-truth PTVs. Conclusion: In LA-NSCLC, errors in DIR-based IGTV propagation present to varying degrees and manifest dependences on DI and anatomical tumor location, indicating the need for personalized consideration in designing RT internal target volume.

Primary Versus Secondary Radiotherapy for Heterotopic Ossification Prevention About the Elbow.

OBJECTIVES: To examine the efficacy and safety of radiotherapy for the prevention of heterotopic ossification (HO) about the elbow. DESIGN: Retrospective chart review. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Two hundred and twenty-nine patients who received prophylactic radiotherapy (XRT) over a 15-year period were identified. Patients were included if they received XRT to the elbow joint and had at least 12 weeks of follow-up after XRT. Fifty-four patients were ultimately included. INTERVENTION: All patients were treated with a single dose of 7 Gy. Ninety-eight percentage of patients received XRT within 24 hours after surgery, and all patients received XRT within 72 hours after surgery. MAIN OUTCOMES MEASUREMENTS: The primary study measures evaluated were the presence or absence of clinically symptomatic HO and the presence of radiographic HO after XRT to the elbow joint. RESULTS: Eighteen patients were treated with XRT after a traumatic injury requiring surgery (primary prophylaxis), and 36 were treated with XRT after excision surgery to remove HO which had already formed (secondary prophylaxis). In the primary cohort, 16.7% developed symptomatic HO after XRT and 11.1% required surgery to resect the heterotopic bone. In the secondary cohort, 11.1% developed symptomatic HO after surgery and XRT and 5.5% required resection surgery. No secondary malignancies were identified. CONCLUSIONS: Our findings suggest that XRT for elbow HO may be safe and effective for both primary and secondary HO. XRT for HO was not shown to be associated with radiation-induced sarcoma in this series, at least in the short term. Further study in a large patient population with extended follow-up is required to better characterize populations at high risk for development of HO and secondary malignancy. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Low-level shRNA cytotoxicity can contribute to MYC-induced hepatocellular carcinoma in adult mice.

Short hairpin RNAs (shRNAs) have emerged as a novel therapeutic modality, but there is increasing concern over nonspecific effects in vivo. Here, we used viral vectors to express shRNAs against endogenous p53 in livers of conditional MYC-transgenic mice. As expected, the shRNAs silenced hepatic p53 and accelerated liver tumorigenesis when MYC was concurrently expressed. Surprisingly, various irrelevant control shRNAs similarly induced a rapid onset of tumorigenesis, comparable to carbon tetrachloride (CCl4), a potent carcinogen. We found that even marginal shRNA doses can already trigger histologically detectable hepatoxicity and increased hepatocyte apoptosis. Moreover, we noted that shRNA expression globally dysregulated hepatic microRNA (miRNA) expression, and that shRNA levels and activity further increased in the presence of MYC. In MYC-expressing transgenic mice, the marginal shRNA-induced liver injury sufficed to further stimulate hepatocellular division that was in turn associated with markedly increased expression of the mitotic cyclin B1. Hence, even at low doses, shRNAs can cause low-level hepatoxicity that can facilitate the ability of the MYC oncogene to induce liver tumorigenesis. Our data warrant caution regarding the possible carcinogenic potential of shRNAs when used as clinical agent, particularly in circumstances where tissues are genetically predisposed to cellular transformation and proliferation.

Radiomics Predicts for Distant Metastasis in Locally Advanced Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma.

(1) Background and purpose: clinical trials have unsuccessfully tried to de-escalate treatment in locally advanced human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) with the goal of reducing treatment toxicity. The aim of this study was to explore the role of radiomics for risk stratification in this patient population to guide treatment. (2) Methods: the study population consisted of 225 patients with locally advanced HPV+ OPSCC treated with curative-intent radiation or chemoradiation therapy. Appearance of distant metastasis was used as the endpoint event. Radiomics data were extracted from the gross tumor volumes (GTVs) identified on the planning CT, with gray level being discretized using three different bin widths (8, 16, and 32). The data extracted for the groups with and without distant metastasis were subsequently balanced using three different algorithms including synthetic minority over-sampling technique (SMOTE), adaptive synthetic sampling (ADASYN), and borderline SMOTE. From these different combinations, a total of nine radiomics datasets were derived. Top features that minimized redundancy while maximizing relevance to the endpoint were selected individually and collectively for the nine radiomics datasets to build support vector machine (SVM) based predictive classifiers. Performance of the developed classifiers was evaluated by receiver operating characteristic (ROC) curve analysis. (3) Results: of the 225 locally advanced HPV+ OPSCC patients being studied, 9.3% had developed distant metastases at last follow-up. SVM classifiers built for the nine radiomics dataset using either their own respective top features or the top consensus ones were all able to differentiate the two cohorts at a level of excellence or beyond, with ROC area under curve (AUC) ranging from 0.84 to 0.95 (median = 0.90). ROC comparisons further revealed that the majority of the built classifiers did not distinguish the two cohorts significantly better than each other. (4) Conclusions: radiomics demonstrated discriminative ability in distinguishing patients with locally advanced HPV+ OPSCC who went on to develop distant metastasis after completion of definitive chemoradiation or radiation alone and may serve to risk stratify this patient population with the purpose of guiding the appropriate therapy.

In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses.

Adeno-associated virus (AAV) serotypes differ broadly in transduction efficacies and tissue tropisms and thus hold enormous potential as vectors for human gene therapy. In reality, however, their use in patients is restricted by prevalent anti-AAV immunity or by their inadequate performance in specific targets, exemplified by the AAV type 2 (AAV-2) prototype in the liver. Here, we attempted to merge desirable qualities of multiple natural AAV isolates by an adapted DNA family shuffling technology to create a complex library of hybrid capsids from eight different wild-type viruses. Selection on primary or transformed human hepatocytes yielded pools of hybrids from five of the starting serotypes: 2, 4, 5, 8, and 9. More stringent selection with pooled human antisera (intravenous immunoglobulin [IVIG]) then led to the selection of a single type 2/type 8/type 9 chimera, AAV-DJ, distinguished from its closest natural relative (AAV-2) by 60 capsid amino acids. Recombinant AAV-DJ vectors outperformed eight standard AAV serotypes in culture and greatly surpassed AAV-2 in livers of naïve and IVIG-immunized mice. A heparin binding domain in AAV-DJ was found to limit biodistribution to the liver (and a few other tissues) and to affect vector dose response and antibody neutralization. Moreover, we report the first successful in vivo biopanning of AAV capsids by using a new AAV-DJ-derived viral peptide display library. Two peptides enriched after serial passaging in mouse lungs mediated the retargeting of AAV-DJ vectors to distinct alveolar cells. Our study validates DNA family shuffling and viral peptide display as two powerful and compatible approaches to the molecular evolution of novel AAV vectors for human gene therapy applications.

The hedgehog-patched signaling pathway and function in the mammalian ovary: a novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells.

The expression of hedgehog (Hh) genes, their receptor, and the co-receptor in mice, rat, and bovine ovaries were investigated. RT-PCR of ovarian transcripts in mice showed amplification of transcripts for Indian (Ihh) and desert (Dhh) Hh, patched 1 (Ptch1), and smoothened (Smo) genes. Semi-quantitative RT-PCR and northern blot analyses showed that whole ovarian Ihh and Dhh transcripts decreased 4-24 h after hCG versus 0-48 h after pregnant mares serum gonadotrophin treatment in mice, whereas mouse Ptch1 and Smo transcripts were expressed throughout the gonadotropin treatments. Quantitative real-time RT-PCR (qRT-PCR) revealed that the expression of the Hh-patched signaling system with Ihh mRNA abundance in granulosa cells was greater, whereas Smo and Ptch1 mRNA abundance was less in theca cells of small versus large follicles of cattle. In cultured rat and bovine theca-interstitial cells, qRT-PCR analyses revealed that the abundance of Gli1 and Ptch1 mRNAs were increased (P<0.05) with sonic hedgehog (SHH) treatment. Additional studies using cultured bovine theca cells indicated that SHH induces proliferation and androstenedione production. IGF1 decreased Ihh mRNA abundance in bovine granulosa cells. The expression and regulation of Ihh transcripts in granulosa cells and Ptch1 mRNA in theca cells suggest a potential paracrine role of this system in bovine follicular development. This study illustrates for the first time Hh activation of Gli1 transcriptional factor in theca cells and its stimulation of theca cell proliferation and androgen biosynthesis.

Predictors of Hematologic Toxicity and Chemotherapy Dose Intensity in Patients Undergoing Chemoradiation for Pancreatic Cancer.

OBJECTIVES: Intensity-modulated radiation therapy (IMRT) has been shown to decrease abdominal toxicity in patients undergoing chemoradiation (CRT) for pancreatic cancer. We evaluated whether IMRT impacts the rates of hematologic toxicity and chemotherapy dose intensity in patients undergoing CRT. METHODS: We retrospectively reviewed patients with borderline resectable or locally advanced pancreatic cancer undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of non-gemcitabine therapy, chemotherapy before CRT, or abnormal baseline hematologic indices. Endpoints included total gemcitabine dose received, dose intensity, unplanned dose reductions, and hematologic toxicity (WBC, ANC, platelet, and hemoglobin). Patient/treatment factors were evaluated for their relationship to the above endpoints during CRT and within the first 3 months post-CRT. Statistical analysis was performed using the Fisher exact test and regression models. Because of the multiple comparisons in the presented analysis, a false discovery rate adjustment was performed at the 5% false discovery rate level. RESULTS: Eighty-five patients met the inclusion criteria. Fifty-eight (68.2%) patients received treatment with IMRT, and 27 (31.8%) patients were treated with 3D-conformal radiation. During CRT, there was no relationship between radiation technique and gemcitabine dose received, dose intensity, or hematologic grade 3+ toxicity. Post-CRT, there was no relationship between radiation technique and total gemcitabine dose received, dose intensity, or dose reduction. Patients receiving IMRT were more likely to have ANC grade 3+ toxicity (P=0.007) post-CRT, although this was no longer statistically significant after correction. There were no other relationships between treatment technique and hematologic toxicity. CONCLUSIONS: IMRT technique may be associated with higher hematologic toxicity in patients undergoing CRT for pancreatic cancer. Given the expanding use of CRT, additional study is needed to identify the impact of IMRT on myelosuppression in these patients.

Surgery and Adjuvant Radiation for High-risk Skin Adnexal Carcinoma of the Head and Neck.

OBJECTIVES: Skin adnexal carcinoma (SAC) is a rare cutaneous malignancy that arises from sebaceous and sweat glands. These carcinomas are believed to behave more aggressively than cutaneous squamous cell carcinomas (SCC) with a propensity for local recurrence. The role of adjuvant radiotherapy in SAC is undefined. METHODS: We retrospectively reviewed all cases of head and neck SAC treated with surgery and adjuvant radiation from 2000 to 2012 at a single institution. RESULTS: Nine cases were identified. Median age was 67 (range, 52 to 88) years. The histologies were: adnexal carcinoma (n=1), adnexal carcinoma with sebaceous differentiation (n=1), adnexal carcinoma with squamous differentiation (n=1), skin appendage carcinoma (n=1), sclerosing sweat duct carcinoma (n=1), mucinous carcinoma (n=1), ductal eccrine adenocarcinoma (n=1), porocarcinoma (n=1), and trichilemmal carcinoma (n=1). All tumors were reviewed by a dermatopathologist to confirm the SAC diagnosis.All patients had undergone surgery. Indications for adjuvant radiation included involved lymph nodes (n=4), perineural invasion (n=2), nodal extracapsular extension (n=2), positive margin (n=1), high-grade histology (n=6), multifocal disease (n=2), and/or recurrent disease (n=5). Radiation was delivered to the primary site alone (n=3), to the draining lymphatics alone (n=2), or to both (n=4). One patient received concurrent cisplatin. Median dose to the primary site was 60 Gy and to the neck was 50 Gy.Median follow-up was 4.0 years (range, 0.6 to 11.4 y). Locoregional control was 100%. Five-year progression-free survival was 89%. There was 1 acute grade 3 toxicity and no greater than or equal to grade 2 late toxicities were recorded. CONCLUSIONS: Surgery and adjuvant radiation for high-risk SAC offers excellent locoregional control with acceptable toxicity.

Lymph-node-positive cutaneous nonmelanoma skin cancer: A poor-prognosis disease in need of treatment intensification.

Locoregionally advanced nonmelanoma skin cancer (NMSC) has an aggressive clinical course characterized by high rates of treatment failure and poor survival compared with localized skin cancers. Our goal was to investigate multimodal therapy for lymph-node-positive NMSC. Data from patients with lymph-node-positive NMSC who underwent surgery and adjuvant therapy at a single tertiary center from 2002 to 2012 were retrospectively reviewed. Median follow-up was 1.8 years (range: 0.5 to 8.5). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The chi-square test and logistic regression were used to determine the association between locoregional control (LRC) and the following variables: evidence of extracapsular extension, number of lymph nodes positive, largest involved lymph node, presence of a positive margin, and use of concurrent chemoradiation (CRT). Forty-six patients were evaluated, 13 (28%) of whom received adjuvant CRT. CRT patients were younger (p < 0.001) and had a significantly greater number of positive lymph nodes (p = 0.016) than patients who received adjuvant radiation alone. At 5 years, LRC was 76%, PFS was 65%, and OS was 49%. Univariate analysis demonstrated that CRT (p = 0.006), largest lymph node measurement (p = 0.039), and ≥3 involved lymph nodes (p = 0.001) predicted local recurrence. CRT (p = 0.035, odds ratio [OR] 0.20 [95% confidence interval 0.05 to 0.90]) and ≥3 involved lymph nodes (p = 0.017, OR 0.07 [95% confidence interval 0.01 to 0.62]) remained significant on multivariate analysis. CRT was well tolerated. No grade ≥3 toxicities were observed except for 1 asymptomatic grade-4 thrombocytopenia. Patients with lymph-node-positive NMSC do poorly. Patient selection for intensification of adjuvant therapy needs clarification.

Long-Term Patient-Reported Outcomes From a Phase 3 Randomized Prospective Trial of Conventional Versus Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: To assess the long-term quality of life (QoL) outcomes from a phase 3 trial comparing 2 modes of intensity modulated radiation therapy (IMRT): conventional IMRT (CIMRT) versus hypofractionated IMRT (HIMRT) in patients with localized prostate cancer. METHODS AND MATERIALS: Between 2002 and 2006, 303 men with low-risk to high-risk prostate cancer were randomized to 76 Gy in 38 fractions (CIMRT) versus 70.2 Gy in 26 fractions (HIMRT). QoL was compared by use of the Expanded Prostate Cancer Index Composite (EPIC), the International Prostate Symptom Score (IPSS), and EuroQoL (EQ5D) questionnaires. The primary outcome of the QoL analysis was a minimum clinically important difference defined as a 0.5 standard deviation change from baseline for each respective QoL parameter. Treatment effects were evaluated with the use of logistic mixed effects regression models. RESULTS: A total of 286, 299, and 218 patients had baseline EPIC, IPSS, or EQ5D data available and were included in the analysis. Overall, there was no statistically significant difference between the 2 treatment arms in terms of EPIC, IPSS, or EQ5D scores over time, although there was a trend toward lower EPIC urinary incontinence scores in the HIMRT arm. More patients in the HIMRT arm had a lower EPIC urinary incontinence score relative to baseline versus patients in the CIMRT arm with long-term follow-up. On multivariable analysis, there was no association between radiation fractionation scheme and any QoL parameter. When other clinical factors were examined, lymph node radiation was associated with worse EPIC hormonal scores versus patients receiving no lymph node radiation. In general, QoL outcomes were generally stable over time, with the exception of EPIC hormonal and EQ5D scores. CONCLUSIONS: In this randomized prospective study, there were stable QoL changes in patients receiving HIMRT or CIMRT. Our results add to the growing body of literature suggesting that HIMRT may be an acceptable treatment modality in clinically localized prostate cancer.