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Supplementary Data from Identification of Markers of Taxane Sensitivity Using Proteomic and Genomic Analyses of Breast Tumors from Patients Receiving Neoadjuvant Paclitaxel and Radiation

Purpose: To identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies.Experimental Design: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR).Results: Proteomic and validation immunohistochemical analyses revealed that α-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery.Conclusion: We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxane–based therapy. Clin Cancer Res; 16(2); 681–90

ImportanceProton radiation therapy (PRT) has reduced radiation-induced toxic effects, such as mucositis and xerostomia, over conventional photon radiation therapy, leading to significantly improved quality of life in patients with head and neck cancers. However, the prevalence of osteoradionecrosis (ORN) of the jaw following PRT in these patients is less clear.ObjectiveTo report the prevalence and clinical characteristics of ORN in patients with oral and oropharyngeal cancer (OOPC) treated with PRT.Design, Setting, and ParticipantsThis case series reports a single-institution experience (Memorial Sloan Kettering Cancer Center, New York, New York) between November 2013 and September 2019 and included 122 radiation therapy–naive patients with OOPC treated with PRT. Data were analyzed from 2013 to 2019.Main Outcomes and MeasuresClinical parameters, including sex, age, comorbidities, tumor histology, concurrent chemotherapy, smoking, comorbidities, and preradiation dental evaluation, were obtained from the medical record. Patients with clinical or radiographic signs of ORN were identified and graded using the adopted modified Glanzmann and Grätz grading system. Characteristics of ORN, such as location, clinical presentation, initial stage at diagnosis, etiology, time to diagnosis, management, and clinical outcome at the last follow-up, were also collected.ResultsOf the 122 patients (mean [SD] age, 63 [13] years; 45 [36.9%] women and 77 [63.1%] men) included in this study, 13 (10.6%) developed ORN following PRT during a median (range) follow-up time of 40.6 (Conclusions and RelevanceIn this case series, the prevalence of ORN following PRT was found to be 10.6%, indicating that ORN remains a clinical challenge even in the era of highly conformal PRT. Clinicians treating patients with OOPC with PRT should be mindful of this complication.

Patients with previously treated, recurrent or metastatic sarcomas who have progressed on multiples lines of systemic therapy may have limited options for local control. We evaluated outcomes of palliative proton therapy with the quad shot regimen to unresectable disease for patients with recurrent and/or metastatic sarcoma. From 2014 to 2018, 28 patients with recurrent or metastatic sarcomas were treated to 40 total sites with palliative proton RT with quad shot (14.8 Gy/4 twice daily). Outcomes included toxicity, ability to receive further systemic therapy, and subjective palliative response. Univariate analysis was performed for local progression‐free survival (LPFS) and overall survival (OS). Of the 40 total sites, 25 (62.5%) received ≥3 cycles with median follow up of 12 months (IQR 4–19). The most common histologies were GIST (9; 22.5%) and leiomyosarcoma (7; 17.5%). A total of 27 (67.5%) sites were located in the abdomen or pelvis. Seventeen (42.5%) treatments involved concurrent systemic therapy and 13 (32.5%) patients received further systemic therapy following proton therapy. Overall subjective palliative response was 70%. Median LPFS was 11 months and 6‐month LPFS was 66.1%. On univariate analysis, receipt of four cycles of quad shot (HR 0.06, p = 0.02) and receipt of systemic therapy after completion of radiation therapy (HR 0.17, p = 0.02) were associated with improved LPFS. Three grade 3 acute toxicities were observed. The proton quad shot regimen serves as a feasible alternative for patients with previously treated, recurrent or metastatic sarcomas where overall treatment options may be limited., Patients with previously treated, recurrent or metastatic sarcomas who have progressed on multiple lines of systemic therapy have limited options for local control. We report on 28 patients treated to 40 sites with proton therapy using the quad shot regimen and found subjective palliative response rate of 70% and median LPFS of 11 months with little toxicity.

Publisher Copyright: © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged

BACKGROUND Proton therapy (PT) improves outcomes in patients with nasal cavity (NC) and paranasal sinus (PNS) cancers. Herein, the authors have reported to their knowledge the largest series to date using intensity-modulated proton therapy (IMPT) in the treatment of these patients. METHODS Between 2013 and 2018, a total of 86 consecutive patients (68 of whom were radiation-naive and 18 of whom were reirradiated) received PT to median doses of 70 grays and 67 grays relative biological effectiveness, respectively. Approximately 53% received IMPT. RESULTS The median follow-up was 23.4 months (range, 1.7-69.3 months) for all patients and 28.1 months (range, 2.3-69.3 months) for surviving patients. The 2-year local control (LC), distant control, disease-free survival, and overall survival rates were 83%, 84%, 74%, and 81%, respectively, for radiation-naive patients and 77%, 80%, 54%, and 66%, respectively for reirradiated patients. Among radiation-naive patients, when compared with 3-dimensional conformal proton technique, IMPT significantly improved LC (91% vs 72%; P

PURPOSE A circulating tumor DNA (ctDNA) test to detect plasma Epstein-Barr viral DNA can be used to screen for early nasopharyngeal cancers; however, the reported sensitivity of viral ctDNA tests to detect human papillomavirus (HPV)–associated cancers is modest. We assessed the utility of droplet digital polymerase chain reaction (ddPCR) to detect early-stage HPV-associated cancers using sequential HPV16 and HPV33 assays that account for HPV subtype distribution and subtype sequence variants. PATIENTS AND METHODS We collected plasma specimens from 97 HPV-positive patients with oropharyngeal squamous cell carcinoma and eight patients with HPV-positive anal squamous cell carcinoma, each with locoregionally confined disease. Negative controls included samples from seven patients with HPV-negative head and neck cancers and 20 individuals without cancer. RESULTS Of 97 patients with nonmetastatic, locoregionally confined oropharyngeal squamous cell carcinoma, 90 patients had detectable HPV16 ctDNA and three patients had HPV33 ctDNA, indicating an overall sensitivity of 95.6%. Seven of eight patients with early anal cancer were HPV16 ctDNA positive. No HPV ctDNA was detected in 27 negative controls, indicating 100% specificity. HPV16 ctDNA was detected in 19 of 19 patients with low-volume disease, defined as patients with a single, asymptomatic positive lymph node (N1) or an isolated T1-2 asymptomatic primary tumor. HPV16 ctDNA levels directly corresponded to tumor responses to chemoradiation and surgery. CONCLUSION With an updated understanding of HPV subtypes and sequence variation, HPV ctDNA by ddPCR is highly sensitive and specific, identifying HPV16 and HPV33 subtypes in a similar distribution as reported in major genomic profiling studies. The detection of small tumors indicates that HPV16 and HPV33 ctDNA ddPCR could be readily used in early detection screening trials and in disease response monitoring, analogous to Epstein-Barr virus DNA.

In oncology, the term "big data" broadly describes the rapid acquisition and generation of massive amounts of information, typically from population cancer registries, electronic health records, or large-scale genetic sequencing studies. The challenge of using big data in cancer research lies in interdisciplinary collaboration and information processing to unify diverse data sources and provide valid analytics to harness meaningful information. This article provides an overview of how big data approaches can be applied in cancer research, and how they can be used to translate information into new ways to ultimately make informed decisions that improve cancer care and delivery.

ImportancePatients with oropharyngeal carcinoma (OPC) treated with radiotherapy often experience substantial toxic effects, even with modern techniques such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) has a potential advantage over IMRT due to reduced dose to the surrounding organs at risk; however, data are scarce given the limited availability and use of IMPT.ObjectiveTo compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic OPC treated with IMPT vs IMRT with or without chemotherapy.Design, Setting, and ParticipantsThis retrospective cohort study included patients aged 18 years or older with newly diagnosed nonmetastatic OPC who received curative-intent radiotherapy with IMPT or IMRT at a single-institution tertiary academic cancer center from January 1, 2018, to December 31, 2021, with follow-up through December 31, 2021.ExposuresIMPT or IMRT with or without chemotherapy.Main Outcomes and MeasuresThe main outcomes were the incidence of acute and chronic (present after ≥6 months) treatment-related adverse events (AEs) and oncologic outcomes, including locoregional recurrence (LRR), progression-free survival (PFS), and overall survival (OS). Fisher exact tests and χ2 tests were used to evaluate associations between toxic effects and treatment modality (IMPT vs IMRT), and the Kaplan-Meier method was used to compare LRR, PFS, and OS between the 2 groups.ResultsThe study included 292 patients with OPC (272 [93%] with human papillomavirus [HPV]-p16–positive tumors); 254 (87%) were men, 38 (13%) were women, and the median age was 64 years (IQR, 58-71 years). Fifty-eight patients (20%) were treated with IMPT, and 234 (80%) were treated with IMRT. Median follow-up was 26 months (IQR, 17-36 months). Most patients (283 [97%]) received a dose to the primary tumor of 70 Gy. Fifty-seven of the patients treated with IMPT (98%) and 215 of those treated with IMRT (92%) had HPV-p16–positive disease. There were no significant differences in 3-year OS (97% IMPT vs 91% IMRT; P = .18), PFS (82% IMPT vs 85% IMRT; P = .62), or LRR (5% IMPT vs 4% IMRT; P = .59). The incidence of acute toxic effects was significantly higher for IMRT compared with IMPT for oral pain of grade 2 or greater (42 [72%] IMPT vs 217 [93%] IMRT; P P P P P = .003), nausea of grade 2 or greater (0 [0%] IMPT vs 18 [8%] IMRT; P = .04), and weight loss of grade 2 or greater (22 [37%] IMPT vs 138 [59%] IMRT; P Conclusions and RelevanceIn this study, curative-intent radiotherapy with IMPT for nonmetastatic OPC was associated with a significantly reduced acute toxicity burden compared with IMRT, with few chronic toxic effects and favorable oncologic outcomes, including locoregional recurrence of only 5% at 2 years. Prospective randomized clinical trials comparing these 2 technologies and of patient-reported outcomes are warranted.

Background Radiotherapy (RT), the main treatment for patients with head and neck cancer, can lead to dental complications. Methods We identified 244 patients with squamous cell carcinoma of the tonsil treated with RT from 2004 to 2013. For each patient, we contoured the 10 tooth-bearing regions and calculated the radiation dose (gray, Gy) to each region. From this data set, we built two predictive models to determine the expected maximum radiation dose, one for the non-molar regions and another for the molar regions. Results For the non-molars, the final model included location, T-classification, and overall stage, with a median absolute prediction error of 7.0 Gy. For the molars, the final model included location, T-classification, overall stage, and treatment year, with a median absolute error of 6.0 Gy. Conclusions Our current model offers a good estimation of the maximum radiation dose delivered to different regions of the jaw; future work will independently validate these models.

Randomized control trials and population-based studies do not demonstrate a definitive benefit for adjuvant chemotherapy (ACT) in stage II colon cancer (CC). Tumor sidedness and microsatellite instability (MSI) status may predict response to ACT, but previous studies have limited microsatellite data. We assessed the efficacy of ACT and possible interaction with MSI status and tumor sidedness in patients with resected stage II CC diagnosed between 2010 and 2013 using the National Cancer Database.Overall survival was evaluated with the Kaplan-Meier method and multivariate and propensity score matched Cox proportional hazards models. The interaction between receipt of ACT, MSI status, and tumor sidedness was evaluated. The efficacy of ACT was assessed in patient subgroups by MSI status and tumor sidedness.Among 6964 stage II CC patients with known MSI status, 1497 (21.5%) received ACT, 843 had MSI tumors, and 6121 had microsatellite stable (MSS) tumors. In multivariate and propensity score matched analyses, ACT was associated with improved survival after adjusting for factors including high-risk features, MSI status, and tumor sidedness (multivariate hazard ratio, 0.52; P0.001). There was no interaction between receipt of ACT and MSI status (P=0.25). Patients with MSS tumors benefitted from ACT (multivariate hazard ratio, 0.47; P0.001), even without other high-risk features. Patients with MSI tumors did not (P=0.671). ACT was associated with improved survival regardless of tumor sidedness.MSS alone may warrant ACT in stage II CC while patients with MSI tumors may not derive significant benefit from ACT.

Background Fanconi anemia (FA) is associated with an increased risk of developing head and neck squamous cell cancer (HNSCC) and presents a treatment dilemma due to concerns of increased toxicities from chemotherapy and radiation therapy (RT). Methods We reviewed the literature on HNSCC in FA patients and report on our experience treating 9 FA patients with HNSCC. Results Surgery was generally well-tolerated and surgery alone resulted in durable local control for 2 patients. Four patients received adjuvant RT that was tolerable in most cases, although 1 patient required a treatment break and early cessation of RT. Three of the irradiated patients received concurrent cetuximab. Conclusions In patients with adverse features, adjuvant radiation with concurrent cetuximab may be feasible with careful monitoring, although local disease control is infrequent. Early detection via screening permitting a surgery-alone approach represents the best opportunity for cure in FA patients with HSNCC.

To explore the influence of treatment package time(TPT) in high-risk oral cavity squamous cell carcinoma(OCSCC) receiving adjuvant radiotherapy with concurrent chemotherapy(CRT).We queried our multi-institutional OCSCC collaborative database for cases diagnosed between 2005 and 2015 who underwent surgery followed by adjuvant CRT. All patients had high-risk features: extranodal extension(ENE) and/or positive surgical margin(PM). TPT was days between surgery to last radiotherapy fraction. Kaplan-Meier curves, log-rank p-values and multivariate analysis(MVA) were used to investigate the impact of TPT on overall(OS), disease-free(DFS), locoregional failure-free(LRFS) and distant metastases-free(DMFS) survival.We identified 187 cases: median age 58 (range, 24-87 years), males 66%, and ever smokers 69%. ENE and PM were detected in 85% and 32%, and oral tongue and floor of the mouth constituted 49% and 18%, respectively. Median radiotherapy and cisplatin doses received were 66 Gy and 200 mg/m2. Overall, median TPT was 98 (range, 63-162 days). OS was worse for TPT 90-days (n = 134) than TPT ≤ 90 (n = 53) at two-(65% vs. 71%) and five-years (45% vs. 62%); p = 0.05, with similar results for DFS. No influence on LRFS or DMFS was noted. More lymph nodes(LN) dissected(P = 0.039), T3-4 disease(P = 0.017), and unplanned reoperations(P = 0.037) occurred with TPT 90-days. On MVA, TPT in 10-day increments was independently detrimental for OS (Hazard Ratio: 1.14; 95 %Confidence Interval [1-1.28]; P = 0.043), perineural invasion, age and positive LN (p 0.05 for all).In one of the largest multi-institutional cohorts, TPT 90-days predicted worse OS for high-risk OCSCC receiving adjuvant CRT. All efforts are needed to optimize perioperative care and baseline conditions for favorable outcomes.

Highlights • Median local recurrence free survival after repeat reirradiation was 9.1 months. • Grade 4 toxicities were reported in 21% of patients. • 61% of patients underwent subsequent therapies following repeat reirradiation. • Subsequent therapies following repeat reirradiation included surgery, chemotherapy and immunotherapy. • Repeat reirradiation is feasible and should be balanced against risk for toxicities., Purpose Recurrent head and neck cancers are associated with significant morbidity and mortality. Outcomes of multiple courses of radiation have not yet been described. Methods and Materials A single institution database was queried to retrospectively review treatment plans and select patients who underwent ≥ 3 courses of radiation to the head and neck region. Results Thirty-three patients were found to have ≥ 3 courses of radiation with overlapping fields. Median local recurrence free survival after last course of reirradiation was 9.1 months and median overall survival was 10 months. Grade 3 and above toxicities were reported in 15 patients (45%). Grade 4 and above toxicities were reported in seven patients (21%). There was no grade 5 toxicity. 20 patients (61%) underwent subsequent therapies following completion of repeat reirradiation. Conclusions Repeat reirradiation to the head and neck region is feasible and carries significant risks that are most appropriately managed with a multi-disciplinary team and must be balanced against the potential for local control and opportunities for emerging systemic therapies.

Exposure at the World Trade Center (WTC) terrorist collapse site on September 11, 2001 has been associated with increased cancer risk, though observational studies have identified very few cases of head and neck cancer (HNC) in exposed individuals. Eighty seven patients were identified who presented to our institution with HNC diagnosed from 2002 to 2017 who reported WTC exposure. The annual number and proportion of WTC-exposed HNC patients has been steadily increasing since 2002, with most cancers developing >10 years following the event. Furthermore, WTC-exposed patients with human papillomavirus (HPV)-positive OPC experienced significantly inferior outcomes compared with non-WTC exposed patients with HPV+ OPC (disease free survival 80.1% vs. 65.6% at 4 years, p = 0.04). This single institution study cannot establish evidence of exposure-mediated causation but higher recurrence rates in the WTC-exposed HPV+ OPC population suggest a treatment refractory tumor biology and possible exposure synergism with HPV-mediated oncogenesis.

Purpose To develop personalized multivariate dose-response models for late dysphagia in patients with head and neck cancer treated in the modern era of combined chemotherapy with intensity-modulated radiation therapy. Patients and Methods The analysis included 424 patients (oropharyngeal cancer [n = 295] and nasopharyngeal, hypopharyngeal, or laryngeal cancer [n = 129]) who received definitive chemoradiation between January 2004 and April 2009. The superior, middle, and inferior pharyngeal constrictor muscles were contoured. We calculated generalized equivalent uniform dose (gEUD) for each and the total constrictor muscle volume, with the volume effect parameter a varying from log10 a = −1 to +1 in steps of 0.1. We used the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3.0) to grade late dysphagia and logistic regression to evaluate the correlation of gEUD( a) with grade 2 or higher (≥ G2) and grade 3 or higher (≥ G3) late dysphagia at each value of a. Results Median follow-up was 33.3 months (range, 6 to 69 months). There were 41 cases (10%) of ≥ G2 dysphagia and 22 cases (5%) of ≥ G3 dysphagia. Mean doses to the total constrictor ranged from 30.1 to 85.7 Gy (median, 61.2 Gy). The predicted rate of ≥ G2 dysphagia increased by approximately 3.4% per Gy at the mean dose, for which the probability of ≥ G2 dysphagia is 50%. The threshold mean total constrictor doses that limited rates of ≥ G2 and ≥ G3 dysphagia to < 5% were < 58 Gy and < 61 Gy, respectively. Other significant factors in the multivariate predictive model included disease site, mean dose to total constrictor muscle, and patient age. Conclusion Incidences of both ≥ G2 and ≥ G3 dysphagia were dependent on the mean radiation dose to the total constrictor muscle volume, disease site, and patient age. Limiting the total volume of constrictor muscle to < 58 Gy could keep the predicted rate of ≥ G2 dysphagia to < 5%.

Large nodal masses shrink during head-and-neck radiation treatment. If the shrinkage is dramatic, nearby organs at risk (OARs) may receive potentially harmful radiation dose. In an institutional IRB-approved protocol, patients were monitored with weekly T2-weighted MRIs. Gross tumor volumes (GTV) from pre-treatment MRI were propagated to weekly MRIs via deformable image registrations (DIR) for tracking the change of GTV nodal volume and detection of significant shrinkage. This detection method, however, becomes problematic when a significant amount of the nodal mass dissolves during treatment, invalidating the assumption of correspondence between images for accurate deformable registration. We presented a novel method using image saliency to detect whether a involved nodal volume becomes significantly small during the treatment. We adapted a multi-resolution pyramid method and introduced symmetry in calculating image saliency of MRI images. The ratio of mean saliency value (RSal) from the propagated nodal volume on a weekly image to the mean saliency value of the pre-treatment nodal volume was calculated to assess whether the nodal volume shrank significantly. We evaluated our method using 94 MRI scans from 19 patients enrolled in the protocol. We achieved AUC of 0.97 in detection of significant shrinkage (smaller than 30% of the original volume) and the optimal RSal is 0.698.

Purpose: Some patients with previously treated, unresectable, recurrent or metastatic head and neck malignancies are not amenable to curative-intent treatment. Here, we investigated the quad-shot (RTOG 8502) regimen of hypofractionated proton radiotherapy (RT) in that patient population. Materials and Methods: From 2013 to 2015, 26 patients with recurrent or metastatic cancers were treated with palliative proton RT to the head and neck with quad shot (3.7 Gy twice daily for 2 days). Patient characteristics and survival data were reviewed. Results: Seventeen (65%) patients received ≥ 3 quad-shot cycles and 23 (88%) had prior head and neck RT. Overall palliative response was 73% (n = 19). The most common presenting symptom was pain (50%; n = 13), which improved in 85% (n = 22) of all patients. The overall grade-1 acute-toxicity rate was 58% (n = 15), and no acute grade 3 to 5 toxicities were observed. Conclusions: The proton quad-shot regimen demonstrates favorable palliative response and toxicity ...

The application of proton beam radiation therapy in the treatment of head and neck cancer has grown tremendously in the past few years. Globally, widespread interest in proton beam therapy has led to multiple research efforts regarding its therapeutic value and cost-effectiveness. The current standard of care using modern photon radiation technology has demonstrated excellent treatment outcomes, yet there are some situations where disease control remains suboptimal with the potential for detrimental acute and chronic toxicities. Due to the advantageous physical properties of the proton beam, proton beam therapy may be superior to photon therapy in some patient subsets for both disease control and patient quality of life. As enthusiasm and excitement for proton beam therapy continue to increase, clinical research and widespread adoption will elucidate the true value of proton beam therapy and give a greater understanding of the full risks and benefits of proton therapy in head and neck cancer.

Exposure at the World Trade Center (WTC) terrorist collapse site on September 11, 2001 has been associated with increased cancer risk, though observational studies have identified very few cases of head and neck cancer (HNC) in exposed individuals. Eighty seven patients were identified who presented to our institution with HNC diagnosed from 2002 to 2017 who reported WTC exposure. The annual number and proportion of WTC-exposed HNC patients has been steadily increasing since 2002, with most cancers developing10 years following the event. Furthermore, WTC-exposed patients with human papillomavirus (HPV)-positive OPC experienced significantly inferior outcomes compared with non-WTC exposed patients with HPV+ OPC (disease free survival 80.1% vs. 65.6% at 4 years, p = 0.04). This single institution study cannot establish evidence of exposure-mediated causation but higher recurrence rates in the WTC-exposed HPV+ OPC population suggest a treatment refractory tumor biology and possible exposure synergism with HPV-mediated oncogenesis.

High-level evidence is lacking to guide treatment decisions about postmastectomy radiation therapy (PMRT) in patients who have breast cancer with 1 to 3 positive lymph nodes who receive contemporary systemic therapies, leading to potential variations in PMRT delivery. The objective of this study was to examine nationwide trends in PMRT use in this group.The National Cancer Data Base (NCDB) was used to identify 93,372 women who had T1-T2N1 breast cancer diagnosed between 2003 and 2012. Patients who received neoadjuvant chemotherapy or radiation therapy (RT) and those who had bilateral breast cancers were excluded. Time trends were evaluated using the Cochrane-Armitage test and correlated the receipt of PMRT with various patient demographic, facility, clinicopathologic, and treatment variables using multivariable logistic regression. A second analysis was performed for patients who were diagnosed during 2010 and included radiation oncologist density as an additional covariate. P values .0001 were considered statistically significant.Overall, 22.5% of the study population received PMRT, representing an increase from 19.1% in 2003 to 30.3% in 2012. Factors associated with greater PMRT use included younger age, lower Charlson-Deyo comorbidity scores, shorter distance to the treating facility, treatment at a comprehensive cancer program, facility location in the New England Census division, and higher density of radiation oncologists. Increased PMRT use was associated with later year of diagnosis, receipt of chemotherapy, receipt of hormone therapy, higher grade disease, larger tumor size, greater numbers of positive lymph nodes, positive margins, and absence of immediate breast reconstruction (all P .0001).The receipt of PMRT by patients with breast cancer who have 1 to 3 positive lymph nodes has increased over time, with wide variability in practice patterns in the United States. Cancer 2018;124:482-90. © 2017 American Cancer Society.

To evaluate outcomes and toxicity in patients treated with hyperfractionated pelvic reirradiation for recurrent rectal cancer.102 patients with recurrent rectal adenocarcinoma were treated with pelvic reirradiation with a hyperfractionated accelerated approach, consisting of 1.5Gy twice daily fractions to a total dose of 30-45Gy (median 39Gy), with the most common total dose 39Gy (n=90, 88%). The median dose of prior pelvic radiation therapy (RT) was 50.4Gy (range: 25-63Gy).The median follow-up was 40months for living patients (range, 3-150months). The 3-year freedom from local progression (FFLP) rate was 40% and the 3-year overall survival (OS) rate was 39%. Treatment with surgery was significantly associated with improved FFLP and OS, with 3-year FFLP rate of 49% vs. 30% (P=0.013), and 3-year OS rate of 62% vs. 20% (P0.0001), compared to those without surgery. The actuarial 3-year rate of grade 3-4 late toxicity was 34%; patients who underwent surgery had a significantly higher rate of grade 3-4 late toxicity compared to those without surgery (54% vs. 16%, P=0.001).This large, retrospective, single-institution study shows that hyperfractionated accelerated reirradiation was well tolerated. The rate of FFLP was promising, given that the study comprised heavily pre-treated patients with recurrences. Rates of FFLP and OS were particularly impressive in patients who underwent both reirradiation and surgery.

Interventions to address overuse of health care services may help reduce costs and improve care. Understanding physician-level variation and behavior patterns can inform such interventions.To assess patterns of physician ordering of services that tend to be overused in the treatment of patients with cancer. We hypothesized that physicians exhibit consistent behavior.Retrospective study of patients 66 years and older diagnosed with cancer between 2004 and 2011, using population-based Surveillance, Epidemiology, and End Results (SEER)-Medicare data to assess physician-level variation in 5 nonrecommended services. Services included imaging for staging and surveillance in low-risk disease, intensity-modulated radiation therapy (IMRT) after breast-conserving surgery, and extended fractionation schemes for palliation of bone metastases.To assess variation in service use between physicians, we used a random effects model and a logistic regression model with a lag variable to assess whether a physician's use of a service for a prior patient predicts subsequent service use.Cohorts ranged from 3464 to 89 006 patients. The total proportion of patients receiving each service varied from 14% for imaging in staging early breast cancer to 41% in early prostate cancer. From the random effects analysis, we found significant unexplained variation in service use between physicians (P .001 for each service; ICC, 0.04-0.59). Controlling for case mix, whether a physician ordered a service for the prior patient was highly predictive of service use, with adjusted odds ratios (aORs) ranging from 1.12 (95% CI, 1.07-1.18) for surveillance imaging for patients with breast cancer (28% service use if prior patient had imaging vs 25% if not), to 24.91 (95% CI, 22.86-27.15) for IMRT for whole breast radiotherapy (69% vs 7%, respectively).Physicians' utilization of nonrecommended services that tend to be overused exhibit patterns that suggest consistent behavior more than personalized patient care decisions. Reducing overuse may require understanding cognitive drivers of repetitive inappropriate decisions.

Many studies have explored the use of (18)F-flurodeoxyglucose (FDG-PET) with CT for radiation therapy planning. The addition of PET/CT could improve tumor volume delineation, reduce geographic misses, and decrease treatment-related toxicity. For cancers of the gastrointestinal tract, the potential benefit of FDG-PET in radiation therapy management is less frequently studied. This article reviews the literature concerning PET/CT in radiation treatment planning. PET/CT appears to have an impact on tumor volume definition. More studies are needed to determine the impact of PET/CT-based radiation therapy on local control, patterns of failure, and treatment-related toxicity.

BACKGROUND: Preoperative chemoradiation for rectal cancer can decrease the number of evaluable lymph nodes. Hence, the prognostic role of lymph node evaluation in patients with rectal cancer who receive preoperative chemoradiation is unclear. The authors of this report evaluated the prognostic impact of the number of lymph nodes examined in patients with rectal cancer who had negative lymph nodes based on the pathologic extent of disease (ypN0) after they received preoperative chemoradiation. METHODS: Between 1990 and 2004, 372 patients with nonmetastatic rectal adenocarcinoma received preoperative chemoradiation followed by mesorectal excision and had ypN0 disease. The median radiation dose was 45 gray, and 68% of patients received adjuvant chemotherapy. RESULTS: Patients had a median of 7 lymph nodes examined after preoperative chemoradiation. Compared with patients who had ≤7 lymph nodes examined, patients who had >7 lymph nodes had higher 5-year rates of freedom from relapse (86% vs 72%; log-rank P = .005) and cancer-specific survival (95% vs 86%; log-rank P = .0004), but no significant difference was observed in the overall survival rate (87% vs 81%; log-rank P = .07). Multivariate Cox proportional models demonstrated that patients who had >7 lymph nodes examined had a significantly lower risk of relapse (hazard ratio [HR], 0.39; P = .003) and death from rectal cancer (HR, 0.45; P = .04) but a similar risk of all-cause mortality (HR, 0.75; 95% CI, 0.46-1.20; P = .23) compared with patients who had ≤7 lymph nodes examined. CONCLUSIONS: The number of lymph nodes examined was associated independently with disease relapse and cancer-specific survival in patients with rectal cancer who had ypN0 disease after receiving preoperative chemoradiation. Hence, the authors concluded that the number of negative lymph nodes examined may be a prognostic factor in patients with rectal cancer who receive preoperative chemoradiation. Cancer 2011;. © 2011 American Cancer Society.

Exposure at the World Trade Center (WTC) terrorist collapse site on September 11, 2001 has been associated with increased cancer risk, though observational studies have identified very few cases of head and neck cancer (HNC) in exposed individuals. Eighty seven patients were identified who presented to our institution with HNC diagnosed from 2002 to 2017 who reported WTC exposure. The annual number and proportion of WTC-exposed HNC patients has been steadily increasing since 2002, with most cancers developing >10 years following the event. Furthermore, WTC-exposed patients with human papillomavirus (HPV)-positive OPC experienced significantly inferior outcomes compared with non-WTC exposed patients with HPV+ OPC (disease free survival 80.1% vs. 65.6% at 4 years, p = 0.04). This single institution study cannot establish evidence of exposure-mediated causation but higher recurrence rates in the WTC-exposed HPV+ OPC population suggest a treatment refractory tumor biology and possible exposure synergism with HPV-mediated oncogenesis.

PURPOSE We previously developed a model to more accurately predict life expectancy for stage IV cancer patients referred to radiation oncology. The goals of this study are to validate this model and to compare competing published models. Materials and Methods From May 2012 to March 2015, 280 consecutive patientswith stage IV cancerwere prospectively evaluated by a single radiation oncologist. Patients were separated into training, validation and combined sets. TheNEAT model evaluated number of active tumors ("N"), Eastern Cooperative Oncology Group performance status ("E"), albumin ("A") and primary tumor site ("T"). The Odette Cancer Center model validated performance status, bone only metastases and primary tumor site. The Harvard TEACHH model investigated primary tumor type, performance status, age, prior chemotherapy courses, liver metastases, and hospitalization within 3 months. Cox multivariable analyses and logisticalregressionwere utilized to compare model performance. RESULTS Number of active tumors, performance status, albumin, primary tumor site, prior hospitalizationwithin the last 3 months, and liver metastases predicted overall survival on uinvariate and multivariable analysis (p < 0.05 for all). The NEAT model separated patients into four prognostic groups with median survivals of 24.9, 14.8, 4.0, and 1.2 months, respectively (p < 0.001). The NEAT model had a C-index of 0.76 with a Nagelkerke's R2 of 0.54 suggesting good discrimination, calibration and total performance compared to competing prognostic models. CONCLUSION The NEAT model warrants further investigation as a clinically useful approach to predict survival in patients with stage IV cancer.

This population-based study examines the association of of lymph node dissection count with survival in patients with oral cavity squamous cell carcinoma using the National Cancer Database.

Helicobacter pylori causes gastric preneoplasia and neoplasia. Eradicating H. pylori can result in partial regression of preneoplastic lesions; however, the molecular underpinning of this change is unknown. To identify molecular changes in the gastric mucosa following H. pylori eradication, we used cDNA microarrays (with each array containing ∼30,300 genes) to analyze 54 gastric biopsies from a randomized, placebo-controlled trial of H. pylori therapy. The 54 biopsies were obtained from 27 subjects (13 from the treatment and 14 from the placebo group) with chronic gastritis, atrophy, and/or intestinal metaplasia. Each subject contributed one biopsy before and another biopsy 1 year after the intervention. Significant analysis of microarrays (SAM) was used to compare the gene expression profiles of pre-intervention and post-intervention biopsies. In the treatment group, SAM identified 30 genes whose expression changed significantly from baseline to 1 year after treatment (0 up-regulated and 30 down-regulated). In the placebo group, the expression of 55 genes differed significantly over the 1-year period (32 up-regulated and 23 down-regulated). Five genes involved in cell-cell adhesion and lining (TACSTD1 and MUC13), cell cycle differentiation (S100A10), and lipid metabolism and transport (FABP1 and MTP) were down-regulated over time in the treatment group but up-regulated in the placebo group. Immunohistochemistry for one of these differentially expressed genes (FABP1) confirmed the changes in gene expression observed by microarray. In conclusion, H. pylori eradication may stop or reverse ongoing molecular processes in the stomach. Further studies are needed to evaluate the use of these genes as markers for gastric cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(2):272–80)

Background The role of radiotherapy after surgery for myxopapillary ependymoma (MPE) is unclear. Objective To review long-term outcomes after surgery, with or without radiation, for spinal MPE. Methods Fifty-one patients with spinal MPE treated from 1968 to 2007 were included. Associations between clinical variables and overall survival (OS), progression-free survival (PFS), and local control (LC) were tested with Cox regression analysis. Results The median age at diagnosis was 35 years (range, 8-63 years). Twenty patients (39%) had surgery alone, 30 (59%) had surgery plus radiotherapy (RT), and 1 (2%) had RT only. At a median follow-up of 11 years (range, 0.2-37 years), 10-year OS, PFS, and LC for the entire group were 93%, 63%, and 67%, respectively. Nineteen patients (37%) had disease recurrence, and the recurrence was mostly local (79%). Twenty-eight of 50 patients who had surgery (56%) had gross total resection; 10-year LC was 56% after surgery vs 92% after surgery and RT (log-rank P = .14); the median time of LC was 10.5 years for patients receiving gross total resection plus RT, and 4.75 years for gross total resection only (P = .03). Among 16 patients with subtotal resection and follow-up data, 10-year LC was 0% after surgery vs 65% for surgery plus RT (log-rank P = .008). On multivariate analyses adjusting for resection type, age older that 35 years at diagnosis and receipt of adjuvant radiation were associated with improved PFS (hazard ratio [HR]: 0.14, P = .003 and HR: 0.45, P = .009) and LC (HR: 0.22, P = .02 and HR: 0.45, P = .009). Conclusion Postoperative radiotherapy after resection of MPE was associated with improved PFS and LC.

Objectives We previously reported survival trends among patients with inflammatory breast cancer (IBC) over a 30-year period before 2005. Here we evaluated survival outcomes for women with IBC diagnosed before or after October 2006, in the era of HER2-directed therapy and after opening a dedicated multidisciplinary IBC clinic. Methods We retrospectively identified and reviewed 260 patients with newly diagnosed IBC without distant metastasis, 168 treated before October 2006 and 92 treated afterward. Most patients received anthracycline and taxane-based neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Survival outcomes were compared between the 2 groups. Results Median follow-up time was 29 months for the entire cohort (39 and 24 mo for patients treated before and after October 2006). Patients treated more recently were more likely to have received neoadjuvant HER2-directed therapy for HER2-positive tumors (100% vs. 54%, P=0.001). No differences were found in receipt of hormone therapy. Three-year overall survival rates were 63% for those treated before and 82% for those treated after October 2006 (log-rank P=0.02). Univariate Cox analysis demonstrated better overall survival among patients treated after October 2006 than among those treated beforehand (hazard ratio [HR] 0.5; 95% confidence interval [CI], 0.34-0.94); a trend toward improved survival was noted in the multivariate analysis (HR=0.47; 95% CI, 0.19-1.16; P=0.10). Significant factors in the multivariate model included HER2-directed therapy (HR=0.38; 95% CI, 0.17-0.84; P=0.02) and estrogen receptor positivity (HR=0.32; 95% CI, 0.14-0.74; P=0.01). Conclusions Survival improved in the context of the IBC clinic and prompt initiation of neoadjuvant HER2-directed therapeutics.

Objective We previously found that galectin-7 was upregulated in patients with cervical cancer who remained recurrence-free after chemoradiation. We hypothesized that pretreatment levels of galectin-7 predict radiation response in patients with squamous cell carcinoma (SCC) of the cervix. Methods Galectin-7 expression was assessed by immunohistochemical staining of a tissue microarray of paraffin-embedded specimens from 161 patients with cervical SCC treated with definitive radiation therapy in 1980–1999. Galectin-7 expression was scored as absent or present. Distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were computed using the Kaplan–Meier method and log-rank tests. Results The median age at diagnosis was 45years (range 21–85) and median follow-up interval was 71months (range 0–285). Of the 161 patients, 105 (65%) had FIGO stage IB disease, 18 (11%) stage IIA, and 38 (24%) stage IIB. Median tumor diameter was 5.5cm (range 3.5–8). Seven patients (4%) received concurrent chemotherapy; 139 patients (86%) had galectin-7-positive tumors and 22 (14%) galectin-7-negative tumors. Five-year DMFS rates for patients with galectin-7-positive versus -negative tumors were 73% and 55% (p=0.05); DSS, 65% and 36% (p=0.004); and OS, 64% and 36% (p=0.005). In multivariate analysis adjusting for age, stage, and tumor diameter, galectin-7 expression remained a significant predictor of DMFS (hazard ratio [HR]=0.43, p=0.03), DSS (HR=0.34, p=0.001), and OS (HR=0.34, p=0.001). Conclusions Elevated galectin-7 expression is associated with improved outcomes after radiation therapy for cervical cancer. Further studies are required to validate these findings and clarify the role of galectin-7 in disease progression and radiation response.

Purpose To determine the association between radiation doses delivered to the mandible and the occurrence of osteoradionecrosis (ORN). Methods and Materials We reviewed the records of 402 oropharyngeal cancer patients with stage T1 or T2 disease treated with definitive radiation between January 2000 and October 2008 for the occurrence of ORN. Demographic and treatment variables were compared between patients with ORN and those without. To examine the dosimetric relationship further, a nested case-control comparison was performed. One to 2 ORN-free patients were selected to match each ORN patient by age, sex, radiation type, treatment year, and cancer subsite. Detailed radiation treatment plans for the ORN cases and matched controls were reviewed. Mann-Whitney test and conditional logistic regression were used to compare relative volumes of the mandible exposed to doses ranging from 10 Gy-60 Gy in 10-Gy increments. Results In 30 patients (7.5%), ORN developed during a median follow-up time of 31 months, including 6 patients with grade 4 ORN that required major surgery. The median time to develop ORN was 8 months (range, 0-71 months). Detailed radiation treatment plans were available for 25 of the 30 ORN patients and 40 matched ORN-free patients. In the matched case-control analysis, there was a statistically significant difference between the volumes of mandible in the 2 groups receiving doses between 50 Gy (V50) and 60 Gy (V60). The most notable difference was seen at V50, with a P value of .02 in the multivariate model after adjustment for the matching variables and dental status (dentate or with extraction). Conclusions V50 and V60 saw the most significant differences between the ORN group and the comparison group. Minimizing the percent mandibular volume exposed to 50 Gy may reduce ORN risk.

Purpose: To identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies. Experimental Design: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR). Results: Proteomic and validation immunohistochemical analyses revealed that α-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery. Conclusion: We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxane–based therapy. Clin Cancer Res; 16(2); 681–90

Background. Although hospitalizations due to invasive pneumococcal disease decreased after routine vaccination of young children with a 7-valent pneumococcal conjugate vaccine (PCV7) began in 2000, information on the trends in pneumococcal meningitis is limited. Methods. We estimated national trends in rates of hospitalization for pneumococcal meningitis, using data from the Nationwide Inpatient Sample, 1994-2004. Pneumococcal meningitis cases and deaths were identified on the basis of the International Classification of Diseases, Ninth Edition, Clinical Modification coded primary discharge diagnosis, and rates were calculated using US Census data as denominators. The year 2000 was considered to be a transition year, and the average annualized rate after PCV7 introduction (2001-2004) was compared with that during the baseline years (1994-1999). Results. During 1994-2004, there were 21,396 hospitalizations and 2684 deaths (12.5%) due to pneumococcal meningitis in the United States. In children aged