A population-based analysis of the impact of 1 vs. 2 doses of mitomycin on patterns of failure of anal cancer patients treated with concurrent chemoradiotherapy.

PURPOSE: We report the impact of 1 vs. 2 doses of mitomycin-C (MMC) based chemoradiation (CRT) on patterns of treatment failure and long-term patient outcomes in anal squamous cell carcinoma (ASCC) and the predictors for locoregional failure (LRF) and distant metastasis (DM). METHODS: In this population-based study, we identified all patients with anal cancer in our province treated radically with radiation and concurrent 5-Fluorouracil (5FU) and 1 vs. 2 doses of MMC between the years 2000-2019. The primary outcomes analyzed were locoregional recurrence (LRR), disease free survival (DFS), ASCC cancer-specific survival (ASCC-CSS) and overall survival (OS). RESULTS: 451 patients were identified. 272 (60%) patients received 1 cycle of MMC (MMC1) and 179 (40%) received 2 cycles (MMC2) as part of the CRT regimen. The median follow-up was 57 (36-252) and 97 (38-239) months for MMC1 and MMC2, respectively. Cox Regression analysis showed stage IIIb and IIIc were associated with worse locoregional recurrence free survival (RFS) (HR=2.851, p=<0.001) and distant RFS (HR=3.391, p=<0.001). Similarly, stage IIIb and IIIc patients had poorer DFS (HR 3.439, p=<0.001), ASCC-SS (HR 3.729, p=<0.001) and OS (2.230, p=<0.001). The use of MMC2 showed a positive impact on improved ASCC-SS (HR 0.569, p=0.029) and distant RFS (HR 0.555, p=0.040) in patients with stage IIIb and IIIc. CONCLUSIONS: Our analysis showed that 1 vs. 2 cycles of MMC along with 5FU and radiation is associated with comparable treatment outcomes in general. However, in patients with stage IIIb and IIIc cancer, 2 doses of MMC were associated with improved ASCC-SS and distant DFS.

Long-Term Patient-Reported Quality of Life of Anal Cancer Survivors Treated With Intensity Modulated Radiation Therapy and Concurrent Chemotherapy: Results From a Prospective Phase II Trial.

PURPOSE: Intensity modulated radiation therapy (IMRT) has confirmed its superiority in improving acute treatment-related toxicities in anal cancer, without compromising tumor control. However, the effect of IMRT on long-term quality of life (QOL) is poorly documented. The study prospectively evaluated the long-term patient-reported QOL after IMRT-based chemoradiation in anal cancer. METHODS AND MATERIALS: Fifty-eight patients treated with IMRT and concurrent 5 fluorouracil/mitomycin-C were enrolled in the study. A prespecified secondary endpoint was prospective evaluation of long-term QOL. Fifty-four patients underwent QOL evaluation at baseline, after treatment, and during follow-up until 60 months, with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) scales and the Colorectal Cancer-Specific Quality Of Life Questionnaire (QLQ-CR29) scales. The QOL scores at baseline and posttreatment periods were compared. RESULTS: For QLQ-C30, at 60 months, the mean scores of global health status, all functional scales, and all symptoms except diarrhea had improved, indicating normalization of QOL. Clinically and statistically significant improvements in the global health status (15.4; P = .003), role functioning (19.3; P = .0017), emotional functioning (18.9; P = .008), and social functioning (29.8; P ≤ .001) were observed. Diarrhea persisted as a concern over the years (P = .172). For European Organization for Research and Treatment of Cancer QLQ-CR29, rectal pain (-38.6; P = .001), mucous or blood discharge per rectum (-22.8; P = .005), and perianal soreness (-37.3; P ≤ .001) were improved both clinically and statistically. Clinically significant fecal leakage was reported by 16% of patients (5.6; P = .421). Volumes receiving 45 and 54 Gy were independent predictors for fecal incontinence. Clinically and statistically significant urinary incontinence occurred in 21% of patients (17.5; P = .014). Deterioration of dyspareunia was clinically significant (26.7; P = .099) at 60 months. CONCLUSIONS: Compared with historical data, IMRT is associated with reduced long-term effects on QOL. The majority of patients treated with IMRT experienced clinically significant recovery of function and improvement in QOL over 5 years after completion of treatment. Specific toxicities such as chronic diarrhea, fecal incontinence, and urinary and sexual dysfunction were primarily responsible for deterioration of the long-term QOL. Future research aimed at reducing such toxicities is needed to further improve long-term QOL in anal cancer.

Tumor Volume Predicts for Pathologic Complete Response in Rectal Cancer Patients Treated With Neoadjuvant Chemoradiation.

OBJECTIVES: Nonoperative management (NOM) of locally advanced rectal cancer is an emerging approach allowing patients to preserve their anal sphincter. Identifying clinical factors associated with pathologic complete response (pCR) is essential for physicians and patients considering NOM. MATERIALS AND METHODS: In total, 412 locally advanced rectal cancer patients were included in this retrospective analysis. Tumor volumes were derived from pretreatment MRI. Clinical parameters such as tumor volume, stage, and location were analyzed by univariate and multivariate analysis, against pCR. A receiver operator characteristic curve was generated to identify a tumor volume cut-off with the highest clinically relevant Youden index for predicting pCR. RESULTS: Seventy-five of 412 patients (18%) achieved pCR. A tumor volume threshold of 37.3 cm 3 was identified as predictive for pCR. On regression analysis, a tumor volume >37.3 cm 3 was associated with a greater than 78% probability of not achieving pCR. On multivariate analysis, a GTV <37.3 cm 3 [odds ratio (OR)=3.7, P <0.0001] was significantly associated with an increased pCR rate, whereas tumor length > 4.85 cm was associated with pCR on univariate (OR=3.03, P <0.01) but not on multivariate analysis (OR=1.45, P =0.261). Other clinical parameters did not impact pCR rates. CONCLUSIONS: A tumor volume threshold of 37.3 cm 3 was identified as predictive for pCR in locally advanced rectal cancer patients receiving neoadjuvant chemoradiation. Tumors above this volume threshold corresponded to a greater than 78% probability of not achieving pCR. This information will be helpful at diagnosis for clinicians who are considering potential candidates for NOM.

Report from the Western Canadian Gastrointestinal Consensus Cancer Conference-Management of Total Neoadjuvant Therapy in Rectal Cancer.

An educational session related to the Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held virtually on 14 October 2020. The WCGCCC is an interactive multidisciplinary conference attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba), who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists, radiologists, and allied health care professionals participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of total neoadjuvant therapy in rectal cancer.

Is Radiation-Induced Cardiac Toxicity Reversible? Prospective Evaluation of Patients With Breast Cancer Enrolled in a Phase 3 Randomized Controlled Trial.

PURPOSE: Myocardial perfusion defects after breast radiation therapy (RT) correlate with volume of irradiated left ventricle (LV). We aimed to determine the relationship between myocardial perfusion, LV dosimetry, and grade ≥2 late cardiac events in patients with breast cancer undergoing adjuvant RT. METHODS AND MATERIALS: A randomized study evaluated the benefit of inverse-planned intensity modulated radiation therapy over forward-planned intensity modulated radiation therapy for radiation toxicity in breast cancer. A secondary endpoint was evaluating cardiac perfusion by single-photon emission computed tomography done at baseline, 6 months, 1 year, 2 years, and 5 years post-RT. We used receiver operating curve and regression analysis to identify association between perfusion, radiation dose-volumes, and the risk of late cardiac events. RESULTS: Of 181 patients who received adjuvant RT, 102 were patients with cancer in the left breast (called in this study the left-sided group) and 79 were patients with cancer in the right breast (called in this study the right-sided group). Median follow-up was 127 months (range, 19-160 months). A significant worsening of perfusion defects occurred after RT in the left-sided group, which improved by 1 year. Late cardiac events were found among 16 patients (17.2%) in the left-sided group and 4 patients (5.5%) in the right-sided group. Perfusion changes did not correlate with late cardiac events, but LV dose-volumes correlated with late cardiac events. Maintaining the LV volume receiving 5 Gy and 10 Gy to <42 cc and <38cc, respectively, can reduce the risk of radiation-related late cardiac events at 10 years to <5% over baseline. CONCLUSIONS: RT was associated with short-term perfusion defects that improved within 1 year and was not correlated with late cardiac events. The ventricular volumes receiving 5 Gy and 10 Gy were correlated with late cardiac events.

More Is Not Better When It Comes to Treating Rectal Cancer With Multimodal Chemoradiation Beyond the Standard Radiation Dose of 5040 cGy.

BACKGROUND: Radiation dose schedules for neoadjuvant chemoradiation for rectal cancers differ, with the most common dose schedule using 5040 cGy in 28 fractions. OBJECTIVES: The aim of this retrospective study was to assess the benefit of higher radiation doses beyond 5040 cGy in the context of pathological response and follow-up events. SETTING: The database from a provincial tertiary cancer center in Canada was the source of information for this study. PATIENTS: Included in this study were 508 consecutive patients with rectal cancer with locally advanced disease (clinical T3/T4 or N1/N2) who received neoadjuvant chemoradiation followed by surgery. Of the 508 patients, 281 received the standard radiation dose of 4500 to 5040 cGy and 227 received a dose >5040 cGy. MAIN OUTCOME MEASURE: The postsurgical pathology, late toxicities, and follow-up outcomes were analyzed. The outcomes were evaluated in relation to the dose of radiation received. RESULTS: Data regarding the clinical outcomes were comparable between the 4500 to 5040 cGy and >5040 cGy radiation groups with pathological complete response rates of 20.9% and 15.4% (p = 0.104); distant recurrence rates of 17.4% and 19.4% (p = 0.36); local recurrence rates of 3.2% and 3.5% (p = 0.36); and the median overall survival rates of 61 and 60.5 months (p = 0.8). No statistically significant correlation of improvement in outcomes was noted with radiation doses beyond 5040 cGy. LIMITATIONS: This is a retrospective study. CONCLUSION: Our study showed that dose escalation beyond the standard dose of 4500 to 5040cGy failed to achieve meaningful clinical outcomes. See Video Abstract at http://links.lww.com/DCR/B633. MS NO ES MEJOR CUANDO SE TRATA DE TRATAR EL CNCER DE RECTO CON QUIMIORRADIACIN MULTIMODAL MS ALL DE LA DOSIS DE RADIACIN ESTNDAR DE CGY: ANTECEDENTES:En neoadyuvancia de cáncer rectal es posible encontrar muchas variaciones, en radioterapia la dosis más común que usa 5040 cGy en 28 fracciones.OBJETIVOS:El objetivo de este estudio retrospectivo fue evaluar el beneficio de dosis de radiación más altas más allá de 5040cGy en el contexto de la respuesta patológica y en su seguimiento.AJUSTE:Base de datos de un centro de cáncer terciario provincial en Canadá.PACIENTES:Se incluyeron en este estudio quinientos ocho pacientes consecutivos con cáncer de recto y enfermedad localmente avanzada (clínica T3 / T4 o N1 / N2) que recibieron quimiorradiación neoadyuvante seguida de cirugía. De los 508 pacientes, 281 recibieron la dosis de radiación estándar de 4500-5040 cGy y 227 recibieron una dosis > 5040 cGy.PRINCIPAL MEDIDA DE RESULTADO:Se analizo evolucion posquirúrgica, toxicidad tardía y seguimiento. Los resultados se evaluaron en relación con la dosis de radiación recibida.RESULTADOS:Los datos con respecto a los resultados clínicos fueron comparables entre los grupos de radiación de 4500-5040 cGy y> 5040 cGy con tasas de respuesta patológica completa de 20,9% y 15,4% respectivamente (p = 0,104); tasas de recurrencia a distancia de 17,4% y 19,4%, respectivamente (p = 0,36); tasas de recurrencia local de 3,2% y 3,5%, respectivamente (p = 0,36); y la mediana de las tasas de supervivencia global de 61 y 60,5 meses, respectivamente (p = 0,8). No se observó una correlación estadísticamente significativa de mejoría en los resultados con dosis de radiación superiores a 5040 cGy.LIMITACIONES:Este es un estudio retrospectivo.CONCLUSIONES:Nuestro estudio mostró que el aumento de la dosis más allá de la dosis estándar de 4500-5040cGy no logró resultados clínicos significativos. Consulte Video Resumen en http://links.lww.com/DCR/B633. (Traducción-Dr. Gunther Bocic).

Patterns and predictors of relapse in Merkel cell carcinoma: Results from a population-based study.

BACKGROUND AND PURPOSE: Prospective data evaluating the role of adjuvant radiotherapy (RT) for Merkel Cell Carcinoma(MCC) is lacking. To better understand the efficacy of adjuvant RT, a population-based patterns of failure study was conducted. METHODS: We identified MCC patients treated from 1988 to 2018.Primary outcome measures were recurrence-free survival (RFS), overall survival (OS) and MCC-specific survival (MCC-SS). Charlson Co-morbidity Index (CCI) was also calculated. RESULTS: 217 patients with mean age 79 (range: 33-96) were analyzed. The median follow-up was 40 months. Treatments were: surgery(S) alone (n = 101, 45%) or S + RT(n = 116, 55%).Local recurrence (LR) was low in stage I (n = 6, 6.5%) with clear margin of ≥1 cm, negative sentinel lymph node biopsy (SLNB) without high-risk factors, irrespective of adjuvant RT. Tumor size ≥ 2 cm (HR:2.95; p = 0.024) and immunosuppression(HR:3.98; p = 0.001) were associated with high risk of nodal failure. Adjuvant RT was associated with significant reduction in regional failure (HR:0.36; p = 0.002). Distant metastases (DM) were infrequent in stage I (4/90) and stage II (4/34), compared to stage III (32/93). Adjuvant RT improvedRFS but did not influence MCC-SS and OS. CCI was a significant predictor of OS. CONCLUSIONS: Adjuvant RT improvedRFS, withoutimpact on MCC-SS and OS. Co-morbidity rather than RT influenced OS. Adjuvant RT may be avoided instage I patients with negative SLNB and no associated high-risk factors. Prophylactic RNI could be considered in stage II with high risk features, inspite of negative SLNB. Stage III patients benefited from adjuvant RNI, but no impact on prevention of DM.

Concomitant Use of Proton Pump Inhibitors With Capecitabine Based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: Is it Safe?

AIM: Capecitabine (Cape) is routinely used for the neoadjuvant chemoradiation treatment (NACRT) of locally advanced rectal cancers (LARCs). Previous reports have suggested that the concomitant use of proton pump inhibitors (PPIs) may affect the efficacy of Cape, although the true effect of PPIs when used with Cape as a radiosensitizer for neoadjuvant radiation is unclear. The aim of our study was to evaluate the impact of concurrent PPI use along with fluorouracil (FU) and Cape based NACRT in terms of pathologic and oncological outcomes, in patients with LARC. METHODS: LARC patients treated at our center with NACRT from 2010 to 2016 were identified. Postoperative pathology and follow-up outcomes were examined for any differences with relation to the use of PPIs concurrently with FU and Cape based NACRT and adjuvant chemotherapy regimens. RESULTS: Three hundred four and 204 patients received treatment with FU and Cape based NACRT. No difference in pathologic complete response rate was noted between the 2 arms with the concurrent use of PPIs (25.8% and 25%, respectively, P=0.633); or with and without the use of PPIs in the Cape-NACRT arm specifically (20% and 20.7%, P=0.945). At a median follow-up of 5 years, no statistical difference in local or distant control was noted in the Cape-NACRT patients, with and without concomitant PPI use (P=0.411 and 0.264, respectively).Multivariate analysis showed no association of PPI use and NACRT with Cape, in terms of local control (hazard ratio=0.001, P=0.988) or overall survival (hazard ratio=1.179, confidence interval=0.249-5.579, P=0.835). CONCLUSIONS: Our study revealed that there was no adverse pathologic or oncological outcome with the concurrent use of PPIs along with Cape-NACRT in the treatment of LARC. We report that it may be safe to use PPIs if essential, in this clinical setting, although it would be wise to exercise caution.

Hippocampal avoidance in prophylactic cranial irradiation for small cell lung cancer: benefits and pitfalls.

Small cell lung cancers (SCLC) are a group of cancers that are clinically and pathologically different from other lung cancers. They are associated with high recurrence rates and mortality, and many patients present with metastatic disease. Approximately ten percent of SCLC patients have brain metastases at time of diagnosis, and the cumulative incidence of brain metastases increases to more than fifty percent at two years, even with optimal treatment. Hence, in patients without brain metastases at presentation, prophylactic cranial irradiation (PCI) is an important component of treatment along with systemic chemotherapy and radiotherapy. The goal of PCI is to decrease the incidence of subsequent symptomatic brain metastases in patients who show an initial response to the systemic treatment. Various clinical trials have evaluated the utility of PCI and found substantial benefit. Unfortunately, the long-term toxicity associated with PCI, namely the neuro-cognitive impairment that may develop in patients as a result of the radiation toxicity to the hippocampal areas of the brain, has raised concern both for patients and their treating physicians. Various techniques have been tried to ameliorate the neuro-cognitive impairment associated with PCI, including pharmacological agents and highly conformal hippocampal avoidance radiation. All of these have shown promise, but there is a lack of clarity about the optimal way forward. Hippocampal avoidance PCI appears to be an excellent option and a number of groups are currently evaluating this technique. Although there is clear benefit with this specialized radiation treatment, there are also concerns about the risk of disease recurrence in the undertreated hippocampal areas. This review attempts to compile the available data regarding the benefits and pitfalls associated with hippocampal avoidance PCI in the setting of SCLC.

TET2 Drives 5hmc Marking of GATA6 and Epigenetically Defines Pancreatic Ductal Adenocarcinoma Transcriptional Subtypes.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by advanced disease stage at presentation, aggressive disease biology, and resistance to therapy, resulting in an extremely poor 5-year survival rate of <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression, but exactly why is unclear and is hindered by the technical limitations of analyzing clinical samples. METHODS: We performed genome-wide epigenetic mapping of DNA modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmc) using oxidative bisulfite sequencing from formalin-embedded sections. We identified overlap with transcriptional signatures in formalin-fixed, paraffin-embedded tissue from resected patients, via bioinformatics using iCluster and mutational profiling and confirmed them in vivo. RESULTS: We found that aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci, including GATA6, which promote differentiated classical pancreatic subtypes. We showed that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5-methylcytosine hydroxylase TET2. Furthermore, we found that SMAD4 directly supports TET2 levels in classical pancreatic tumors, and loss of SMAD4 expression was associated with reduced 5hmc, GATA6, and squamous-like tumors. Importantly, enhancing TET2 stability using metformin and vitamin C/ascorbic acid restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo. CONCLUSIONS: We identified epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data showed that restoring epigenetic control increases biomarkers of classical pancreatic tumors that are associated with improved therapeutic responses and survival.

Recurrent radiation recall dermatitis 40 years after radiation therapy for breast cancer.

Radiation recall dermatitis is an inflammatory reaction of the skin, which occurs at previously irradiated areas, usually following a subsequent exposure to an aggravating factor. Recall dermatitis can occur weeks to months after radiation, and the longest duration between radiation and dermatitis has been reported to be about 25 years. Here, we report a case of recurrent radiation recall dermatitis that developed spontaneously after 40 years following radiation for breast cancer. This case suggests that radiation recall dermatitis can occur much later than previously reported. In spite of this late presentation, topical anti-inflammatory agents managed the condition well.

A Novel Composite Biomarker Panel For Detection Of Early Stage Non-small Cell Lung Cancer.

PURPOSE: To investigate a novel composite methodology of using targeted serum microRNAs (micro ribonucleic acid; miRNA) and urine metabolites for the accurate detection of early stage non-small cell lung cancer (NSCLC). METHODS: Consecutively consenting NSCLC patients and matched control subjects were recruited to provide samples of serum for miRNA and/or urine for metabolite analyses. Serum miRNA levels were measured using quantitative real-time reverse-transcription with exogenous control, and the comparative delta cycle threshold (CT) method was used to calculate relative miRNA expression of two targeted miRNAs (miR-21 and miR-223). The concentrations of six targeted urinary metabolites in patients and healthy controls were measured using proton nuclear magnetic resonance (1H NMR) spectroscopy. A composite methodology of using the 35 accruals with both serum and urine biomarkers was then established with binary logistic regression, receiver operating characteristic (ROC) models with or without artificial intelligence (AI). RESULTS: The ROC analysis of miRNA expression yielded a sensitivity of 96.4% and a specificity of 88.2% for the detection of early stage NSCLC, with area under the curve (AUC) = 0.91 (CI 95%: 0.80-1.0). Relative urinary concentrations of 4-methoxyphenylacetic acid (4MPLA) were significantly different between NSCLC and healthy control (p=0.008). The ROC analysis of 4MPLA yielded a sensitivity of 82.1% and a specificity of 88.2%, with AUC = 0.85. The composite process combining miRNA and metabolite expression demonstrated a sensitivity and specificity of nearly 100% and AUC=1. CONCLUSIONS: A highly specific, sensitive and non-invasive detection method for NSCLC was developed. Pending validation, this can potentially improve the early detection and, hence, the treatment and survival outcomes of patients.

Circulating biomarkers and outcomes from a randomised phase 2 trial of gemcitabine versus capecitabine-based chemoradiotherapy for pancreatic cancer.

BACKGROUND: The Phase 2 SCALOP trial compared gemcitabine with capecitabine-based consolidation chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). METHODS: Thirty-five systematically identified circulating biomarkers were analysed in plasma samples from 60 patients enroled in SCALOP. Each was measured in triplicate at baseline (prior to three cycles of gemcitabine-capecitabine induction chemotherapy) and, for a subset, prior to CRT. Association with overall survival (OS) was determined using univariable Cox regression and optimal thresholds delineating low to high values identified using time-dependent ROC curves. Independence from known prognostic factors was assessed using Spearman correlation and the Wilcoxon rank sum test prior to multivariable Cox regression modelling including independent biomarkers and known prognostic factors. RESULTS: Baseline circulating levels of C-C motif chemokine ligand 5 (CCL5) were significantly associated with OS, independent of other clinicopathological characteristics. Patients with low circulating CCL5 (CCL5low) had a median OS of 18.5 (95% CI 11.76-21.32) months compared to 11.3 (95% CI 9.86-15.51) months in CCL5high; hazard ratio 1.95 (95% CI 1.04-8.65; p = 0.037). CONCLUSIONS: CCL5 is an independent prognostic biomarker in LAPC. Given the known role of CCL5 in tumour invasion, metastasis and the induction of an immunosuppressive micro-environment, targeting of CCL5-mediated pathways may offer therapeutic potential in pancreatic cancer. CLINICAL TRIAL REGISTRATION: The SCALOP trial was registered with ISRCTN, number 96169987 (registered 29 May 2008).

Adjuvant breast radiotherapy, endocrine therapy, or both after breast conserving surgery in older women with low-risk breast cancer: Results from a population-based study.

BACKGROUND AND PURPOSE: The relative benefit of adjuvant radiotherapy (RT) alone in older women with low-risk early breast cancer (EBC) remains unclear. It is hypothesized that adjuvant RT-alone can improve outcomes of older patients with low-risk EBC, similar to endocrine therapy (ET) alone or combination of RT + ET. METHODS: In this population based study, we identified all women aged ≥70 with T1-2, N0, ER+ve, Her-2/neu-ve EBC treated with breast conserving surgery (BCS), followed by adjuvant treatments (RT-alone, ET-alone, or RT + ET combination) from 2005 to 2015. Primary outcome measures were recurrence-free survival (RFS), overall survival (OS), and breast cancer specific survival (BCSS). Treatment details were collected and Charlson Comorbidity Index (CCI) was calculated. RESULTS: A total of 1166 patients were identified. Median follow-up was 76.5 months. Adjuvant treatments: BCS only 130 (11%), RT 378 (32.5%), ET 161 (14%), and RT + ET 497 (42.5%). Less than 60% of women completed 5-years of ET. Compared to BCS alone, RT resulted in significant improvement in RFS (HR = 0.174; p < 0.001), similar to ET (HR = 0.414; p = 0.007) and RT + ET (HR = 0.236; p < 0.001). Determinants of OS were age, tumor grade, comorbidities, and adjuvant therapy. Increased comorbidity scores (0 vs. 1; 0 vs. ≥2) were associated with reduced OS (HR = 1.40; p = 0.013 and HR = 1.98; p < 0.001), without impact on RFS or BCSS. CONCLUSIONS: Adjuvant RT-alone is a reasonable alternative to ET or RT + ET for older women with biologically favorable EBC. No difference in RFS or BCSS was noted between RT, ET, and RT + ET. Comorbidity was independently associated with reduced overall survival.

Dosimetric Parameters Predicting Late Small Bowel Toxicity in Patients With Rectal Cancer Receiving Neoadjuvant Chemoradiation.

PURPOSE: The aim of this study was to identify dosimetric parameters that predict late small bowel (SB) toxicity after neoadjuvant long course chemoradiation (CRT) for rectal cancer. METHODS AND MATERIALS: Four hundred eighty-six consecutive patients with locally advanced rectal cancers (clinical T3/T4 or N1/N2) who received CRT followed by surgery and had dosimetric data available for analysis were included in this study. The dose-volume relationship between small bowel irradiation and late small bowel toxicity was evaluated and a mathematical model to predict for late SB toxicity was derived. RESULTS: Among the 486 patients with a median follow-up of 60 months from completion of radiation, 36 (7.4%) patients experienced ≥ grade 2 and 21 (4.3%) developed ≥ grade 3 late SB toxicity. A statistically significant association between the development of grade ≥3 late small bowel toxicity and the volume of small bowel irradiated was found at each dose level from 5 to 40 Gy (P < .001 for all dose volumes) in 5 Gy intervals. The average SB volume for patients who experienced grade ≥2 SB toxicity was 2149.9 cm3 and the average SB volume for patients who experienced grade ≥3 SB toxicity was 2179.9 cm3. The predicted V30 for a 5% risk for grade ≥2 SB toxicity was 101.5 cm3 and for grade ≥3 SB toxicity was 201.5 cm3. The volume of small bowel receiving at least 30 Gy (V30) was most strongly associated with grade ≥3 SB toxicity. CONCLUSIONS: This study demonstrates the significant dose-volume relationship between volume of small bowel receiving 30 Gy (V30 Gy) and late grade ≥3 SB toxicity. When planning CRT for patients with rectal cancer, restricting V30 to <200 cm3 will be a useful guideline to minimize the 5 year grade ≥3 late SB toxicity to <5%.

Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a serious and potentially fatal acute inflammatory lung condition which currently has no specific treatments targeting its pathophysiology. However, mesenchymal stem cells have been shown to have very promising therapeutic potential, and recently, it has been established that their effect is largely due to the transfer of extracellular vesicles (EVs). EVs have been shown to transfer a variety of substances such as mRNA, miRNA, and even organelles such as mitochondria in order to ameliorate ARDS in preclinical models. In addition, the fact that they have been proven to have the same effect as their parent cells combined with their numerous advantages over whole cell administration means that they are a promising candidate for clinical application that merits further research.

Breast Cancer Care in South India: Is Practice Concordant With National Guidelines?

PURPOSE: The National Cancer Grid (NCG) of India has recently published clinical practice guidelines that are relevant in the Indian context. We evaluated the extent to which breast cancer care at a teaching hospital in South India was concordant with NCG guidelines. METHODS: All patients who had surgery for breast cancer at a single center from January 2014 to December 2015 were included. Demographic, pathologic, and treatment characteristics were extracted from the electronic medical record. Patients were classified as being concordant with six elements selected from the NCG guideline. The indicators related to appropriate use of sentinel lymph node (SLN) biopsy, lymph node harvest, adjuvant radiotherapy, adjuvant chemotherapy, human epidermal growth factor receptor 2 (HER2) testing, and delivery of adjuvant trastuzumab. RESULTS: A total of 401 women underwent surgery for breast cancer; mean age (standard deviation) was 57 (12) years. Lymph node involvement was present in 47% (188 of 401) of the cohort; 23% (94 of 401) had T1 disease. Ninety-two percent (368 of 401) underwent radical modified mastectomy. SLN biopsy was performed in 75% (167 of 222) of eligible patients. Eighty percent (208 of 261) of patients with a positive SLN biopsy or no SLN biopsy had a lymph node harvest of more than 10. Adjuvant chemotherapy with an anthracycline and a taxane was delivered to 67% of patients (118 of 177) with node-positive disease. Adjuvant radiotherapy was delivered to 84% (180 of 213) of patients with breast-conserving surgery, T4 tumors, or 3+ positive lymph nodes. Fluorescent in situ hybridization testing was performed in 59% of patients (43 of 73) with 2+ HER2-positive lymph nodes on immunohistochemistry. Among patients with HER2 overexpression, 40% (36 of 91) received adjuvant trastuzumab. CONCLUSION: Concordance with NCG guidelines for breast cancer care ranged from 40% to 84%. Guideline concordance was lowest for those elements of care associated with the highest direct costs to patients.

TGF-ß Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation.

Epigenetic inactivation of the Hippo pathway scaffold RASSF1A is associated with poor prognosis in a wide range of sporadic human cancers. Loss of expression reduces tumor suppressor activity and promotes genomic instability, but how this pleiotropic biomarker is regulated at the protein level is unknown. Here we show that TGF-ß is the physiological signal that stimulates RASSF1A degradation by the ubiquitin-proteasome pathway. In response to TGF-ß, RASSF1A is recruited to TGF-ß receptor I and targeted for degradation by the co-recruited E3 ubiquitin ligase ITCH. RASSF1A degradation is necessary to permit Hippo pathway effector YAP1 association with SMADs and subsequent nuclear translocation of receptor-activated SMAD2. We find that RASSF1A expression regulates TGF-ß-induced YAP1/SMAD2 interaction and leads to SMAD2 cytoplasmic retention and inefficient transcription of TGF-ß targets genes. Moreover, RASSF1A limits TGF-ß induced invasion, offering a new framework on how RASSF1A affects YAP1 transcriptional output and elicits its tumor-suppressive function.

ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer.

BACKGROUND AND PURPOSE: Nelfinavir can enhance intrinsic radiosensitivity, reduce hypoxia and improve vascularity. We conducted a phase II trial combining nelfinavir with chemoradiotherapy (CRT) for locally advanced inoperable pancreatic cancer (LAPC). MATERIALS AND METHODS: Radiotherapy (50.4Gy/28 fractions; boost to 59.4Gy/33 fractions) was administered with weekly gemcitabine and cisplatin. Nelfinavir started 3-10days before and was continued during CRT. The primary end-point was 1-year overall survival (OS). Secondary end-points included histological downstaging, radiological response, 1-year progression free survival (PFS), overall survival (OS) and treatment toxicity. An imaging sub-study (n=6) evaluated hypoxia ((18)F-Fluoromisonidazole-PET) and perfusion (perfusion CT) during induction nelfinavir. RESULTS: The study closed after recruiting 23 patients, due to non-availability of Nelfinavir in Europe. The 1-year OS was 73.4% (90% CI: 54.5-85.5%) and median OS was 17.4months (90% CI: 12.8-18.8). The 1-year PFS was 21.8% (90% CI: 8.9-38.3%) and median PFS was 5.5months (90% CI: 4.1-8.3). All patients experienced Grade 3/4 toxicity, but many were asymptomatic laboratory abnormalities. Four of 6 patients on the imaging sub-study demonstrated reduced hypoxia and increased perfusion post-nelfinavir. CONCLUSIONS: CRT combined with nelfinavir showed acceptable toxicity and promising survival in pancreatic cancer.