Improved Pathologic response to chemoradiation in MGMT methylated locally advanced rectal cancer.

Background and Purpose: With the growing interest in total neoadjuvant treatment for locally advanced rectal adenocarcinoma (LARC) there is an urgent unmet need to identify predictive markers of response to long-course neoadjuvant concurrent chemoradiotherapy (LCRT). O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated in some malignancies with response to concurrent chemoradiotherapy. We attempted to find if pathologic response to LCRT was associated with MGMT promoter hypermethylation (MGMTh). Materials and Methods: Patients were identified with LARC, available pre-treatment biopsy specimens, and at least 1 year of follow-up who received LCRT followed by surgical resection within 6 months. Biopsies were tested for MGMTh using a Qiagen pyrosequencing kit (Catalog number 970061). The primary outcome of LCRT responsiveness was based on tumor regression grade (TRG), with grades of 0-1 considered to have excellent response and grades of 2-3 considered to be non-responders. Secondary outcomes included overall survival (OS) and recurrence free survival (RFS). Results: Of 96 patients who met inclusion criteria, 76 had samples which produced reliable assay results. MGMTh corresponded with higher grade and age of the biopsy specimen. The percentage of responders to LCRT was higher amongst the MGMTh patients than the MGMTn patients (60.0% vs 27.5%, p value = 0.0061). MGMTh was not significantly associated with improved OS (2-year OS of 96.0% vs 98.0%, p = 0.8102) but there was a trend for improved RFS (2-year RFS of 87.6% vs 74.2%, p = 0.0903). Conclusion: Significantly greater tumor regression following LCRT was seen in MGMTh LARC. Methylation status may help identify good candidates for close observation without surgery following LCRT.

The cost of elective nodal coverage in prostate cancer: Late quality of life outcomes and dosimetric analysis with 0, 45 or 54 Gy to the pelvis.

Purpose: Elective pelvic lymph node radiotherapy (PLNRT) in prostate cancer is often omitted from definitive (n = 267) and post prostatectomy (n = 160) radiotherapy (RT) due to concerns regarding toxicity and efficacy. Data comparing patient-reported outcome measures (PROMs) with or without PLNRT is limited. Our long-term supposition is that PLNRT, particularly to higher doses afforded by IMRT, will decrease pelvic failure rate in select patients. We aim to establish the impact of two different PLNRT doses on long term quality of life (QOL). Methods and materials: Prostate cancer patients (n = 428) recorded baseline scores using the Expanded Prostate Cancer Index Composite (EPIC), prior to definitive or post-prostatectomy RT. PLNRT, if given, was prescribed to 45 or 54 Gy at 1.8 Gy per fraction. New EPIC scores were recorded 20-36 months after radiotherapy. Absolute change in each domain subscale and summary score was recorded, along with if these changes met minimally important difference (MID) criteria. A separate multivariate analysis (MVA) was performed for each measure. Subsequent dosimetric analysis was performed. Results: Frequency of a MID decline was significantly greater with PLNRT to 54 Gy for urinary function, incontinence, and overall. No urinary decline was correlated with PLNRT to 45 Gy. PLNRT to 54 Gy was significant for decline in urinary function, bother, irritative, incontinence, and overall score in one or both MVA models while 45 Gy was not. Postoperative status was significant for decline in urinary function, incontinence, and overall. Amongst postoperative patients, there was significantly greater decline in urinary function score in the salvage setting. Neither 54 nor 45 Gy significantly affected bowel subscale or overall score decline. Conclusions: Using conventional fractionation, adding PLNRT to 54 Gy, but not 45 Gy, correlates with worse urinary QOL, with postoperative patients experiencing a steeper decline. PLNRT had no significant impact on bowel QOL with either dose.

Ad Astra - telomeres in space!

PURPOSE: My journey to the stars began as I - along with the whole world - stood still and watched Neil Armstrong take those first small steps on the Moon. Fast forward 50 years and NASA astronauts Scott Kelly and Christina Koch each spend nearly a year in space aboard the International Space Station (ISS), a remarkable multinational collaborative project and floating U.S. National Laboratory that has supported continuous human presence in low Earth orbit for the past 20 years. Marking a new era of human space exploration, the first commercial rocket, SpaceX Falcon 9, recently launched NASA astronauts Doug Hurley and Bob Behnken in the Crew Dragon spacecraft Endeavor to the ISS and returned safely to Earth. NASA and its commercial partners are rapidly advancing innovative space technologies, and with the recently announced Artemis team of astronauts, plans to send the first woman and next man back to the moon and establish sustainable exploration by the end of the decade. Humankind will then be poised to take the next giant leap - pioneering human exploration of Mars. CONCLUSIONS: Historically, fewer than 600 individuals have participated in spaceflight, the vast majority of whom have been middle aged males (35-55 years) on short duration missions (less than 20 days). Thus, as the number and diversity of space travelers increase, a better understanding of how long-duration spaceflight affects human health is essential to maintaining individual astronaut performance during, and improving disease and aging trajectories following, future exploration missions. Here, I review findings from our NASA Twins Study and Telomeres investigations, highlighting potential mechanistic roles of chronic space radiation exposure in changes in telomere length and persistent DNA damage responses associated with long-duration spaceflight. Importantly, similar trends were observed in prostate cancer patients undergoing intensity-modulated radiation therapy (IMRT), additional support specifically for the role of radiation exposure. Individual differences in response were also observed in both cohorts, underscoring the importance of developing personalized approaches for evaluating human health effects and long-term outcomes associated with radiation exposures, whether on Earth or living in the extreme environment of space.

C-Reactive Protein Is a Poor Marker of Baseline Inflammation in Prostate Cancer and Response to Radiotherapy or Androgen Ablation.

Introduction C-reactive protein (CRP) is an acute-phase reactant used as a general marker for inflammation. Isolated levels have been associated with prostate cancer development, prostate-specific antigen (PSA), Gleason score, and treatment response. We seek to establish whether CRP levels reflect inflammation caused by prostate cancer by comparing levels at various points of time before, during, and after therapy. Materials and methods A total of 209 patients had a complete blood count (CBC), PSA, and CRP taken at up to four different time points. Labs were performed up to one week prior to androgen ablation via leuprolide injection (pre-AA), up to one week prior to radiotherapy (RT) (pre-RT), within one week of RT completion (post-RT), and three months following RT completion (FU [follow-up]). Results Significant relationships were found between CRP and WBC pre-AA (p-value=0.0050), pre-RT (p-value=0.0170), and post-RT (p-value=0.0113), but not at FU (p=.096). CRP had no significant relationship with PSA or lymphocytes at any time points. PSA was significantly affected by androgen ablation but lymphocytes, WBCs, and CRP were not. No CRP levels were associated with risk groups or FU-PSA. Lymphatic radiation fields significantly decreased WBCs and lymphocytes but not CRP. PSA, WBC, and lymphocytes all significantly decreased from pre-RT to post-RT, followed by a significant recovery. CRP did not significantly change during any of these periods and was not significantly related to changes in PSA, WBCs, or lymphocytes. Conclusion CRP is not a sensitive marker of the acute inflammatory effects of non-metastatic prostate cancer and treatment response with androgen ablation or radiation therapy.

Telomere Length Dynamics and Chromosomal Instability for Predicting Individual Radiosensitivity and Risk via Machine Learning.

The ability to predict a cancer patient's response to radiotherapy and risk of developing adverse late health effects would greatly improve personalized treatment regimens and individual outcomes. Telomeres represent a compelling biomarker of individual radiosensitivity and risk, as exposure can result in dysfunctional telomere pathologies that coincidentally overlap with many radiation-induced late effects, ranging from degenerative conditions like fibrosis and cardiovascular disease to proliferative pathologies like cancer. Here, telomere length was longitudinally assessed in a cohort of fifteen prostate cancer patients undergoing Intensity Modulated Radiation Therapy (IMRT) utilizing Telomere Fluorescence in situ Hybridization (Telo-FISH). To evaluate genome instability and enhance predictions for individual patient risk of secondary malignancy, chromosome aberrations were assessed utilizing directional Genomic Hybridization (dGH) for high-resolution inversion detection. We present the first implementation of individual telomere length data in a machine learning model, XGBoost, trained on pre-radiotherapy (baseline) and in vitro exposed (4 Gy γ-rays) telomere length measurements, to predict post radiotherapy telomeric outcomes, which together with chromosomal instability provide insight into individual radiosensitivity and risk for radiation-induced late effects.

Improved local control in p16 negative oropharyngeal cancers with hypermethylated MGMT.

INTRODUCTION: Patients with oropharyngeal cancers that are p16 negative (p16-) have worse outcomes than those who are p16 positive (p16+) and there is an unmet need for prognostic markers in this population. O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated with response to chemoradiotherapy (CRT) in glioblastoma. We sought to find if MGMT promoter methylation was associated with outcomes of locally advanced oropharyngeal and oral cavity squamous cell carcinoma (OOSCC) in patients treated with definitive concurrent CRT. METHODS: Patients were identified with primary OOSCC, known p16 status, retrievable pre-treatment biopsies, and at least 6 months of follow-up who received definitive concurrent CRT from 2004 to 2015. Biopsies were tested for MGMT hypermethylation (MGMT+) using a Qiagen pyrosequencing kit (Catalog number 970061). Outcomes were subsequently recorded and analyzed. RESULTS: Fifty-eight patients were included with a median follow up of 78 (range 6-196) months. Fourteen patients (24.1%) had oral cavity cancer and 44 (75.9%) had oropharyngeal cancer. A significant difference was found for local recurrence free survival (LRFS) by combined MGMT and p16 status (p = 0.0004). Frequency of LR in MGMT+/p16+, MGMT+/p16-, MGMT-/p16+, and MGMT-p16- patients was 14.3%, 14.3%, 13.0%, and 69.2%, respectively (p = 0.0019). A significant difference was not found for distant recurrence free survival (p = 0.6165) or overall survival (p = 0.1615). LRFS remained significant on analysis restricted to oropharyngeal cancer patients (p-value = 0.0038). CONCLUSION: Patients who are p16- and MGMT+ with oropharyngeal and oral cavity squamous cell carcinoma have significantly better LC with definitive CRT than those who are p16- and MGMT-. Prospective studies are needed to verify these findings.

The effect of pelvic radiation alone on lymphocyte subgroups.

There is a lack of information on the radiosensitivity of lymphocyte subgroups to radiation alone. CD4+ and CD8+ lymphocytes respond similarly. CD 19+ dropped most precipitously, but recovered to levels similar to the other subgroups by 3 months. NK cells decline more modestly and recover more fully by 3 months.

The effect of radiation therapy on post-prostatectomy urinary function.

AIM: We sought to evaluate the effect of radiation therapy on post-prostatectomy urinary quality of life in prostate cancer patients. BACKGROUND: In some men with non-metastatic prostate cancer, radiation therapy is indicated following prostatectomy. The radiation toxicity and quality of life considerations are unique in the post-prostatectomy setting. MATERIALS AND METHODS: A total of 106 patients receiving post-prostatectomy radiation therapy completed the Expanded Prostate Cancer Index Composite questionnaire before radiation and at 2-year follow-up. The primary outcomes of this study were the urinary domain summary score and subscale scores. Planned analysis was performed based on time interval from prostatectomy to radiation therapy. RESULTS: Among the 106 patients analyzed, the mean urinary domain summary score worsened at 2-year follow-up after radiation therapy, lowering from 77.23-72.51 (p = 0.0085). Similar worsening was observed in the subscales of function (p = 0.003), bother (p = 0.0397), and incontinence (p = 0.0003). Urinary incontinence showed the greatest observable change among subscales. While the summary score worsened (p = 0.0031) among patients receiving radiation therapy more than 1 year after prostatectomy, it did not show statistically significant change in those treated 1 year or less after prostatectomy. CONCLUSION: Our results demonstrate that post-prostatectomy radiation therapy is associated with modest declines in reportable urinary quality of life. Patients receiving radiation therapy more than 1 year after prostatectomy showed greater worsening of urinary quality of life, which indicates that there may be no functional advantage to delaying radiation therapy beyond the initial postoperative period.

To B(iopsy) or not to B(iopsy).

Often in metastatic disease, biopsy confirmation of suspicious central nervous system (CNS) lesions is not mandated according to the American College of Radiology, International Radiosurgery Association, and the National Comprehensive Cancer Network. We present a case of an individual who was thought to have metastatic nonsmall cell lung cancer (NSCLC) T2aN0M1b with motor deficits and CNS metastasis to the left postcentral gyrus. The patient underwent biopsy of the primary lung mass confirming NSCLC. He subsequently underwent treatment with stereotactic radiosurgery (SRS) for presumed CNS oligometastatic disease and palliative chemotherapy. Two months after SRS, the patient had progression of CNS disease with new motor deficits. A magnetic resonance imaging revealed and enlarging mass in the previously radiated area. The patient underwent craniotomy with tumor resection and a second primary CNS tumor was discovered. That patient was downstaged from a Stage IV to a Stage IIB lung cancer with concomitant CNS primary.

Identification of new genetic risk factors for prostate cancer.

There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Multiple newly identified loci associated with prostate cancer susceptibility.

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at

Females with paired occurrence of cancers in the UADT and genital region have a higher frequency of either Glutathione S-transferase M1/T1 null genotype.

Upper Aero digestive Tract (UADT) is the commonest site for the development of second cancer in females after primary cervical cancer. Glutathione S-transferase (GSTM1 and / or T1) null genotype modulates the risk of developing UADT cancer (primary as well as second cancer). The aim of this study was to evaluate the difference in GST null genotype frequencies in females with paired cancers in the UADT and genital region as compared to females with paired cancers in the UADT and non-genital region. Forty-nine females with a cancer in the UADT and another cancer (at all sites-genital and non-genital) were identified from a database of patients with multiple primary neoplasms and were analyzed for the GSTM1 and T1 genotype in addition to known factors such as age, tobacco habits, alcohol habits and family history of cancer. Frequencies of GSTM1 null, GSTT1 null, and either GSTM1/T1 null were higher in females with paired occurrence of cancer in the UADT and genital site (54%, 33% and 75% respectively) in comparison to females with paired occurrence of cancer in the UADT and non-genital sites (22%, 6% and 24% respectively). The significantly higher inherited frequency of either GSTM1/T1 null genotype in females with a paired occurrence of cancers in UADT and genital region (p = 0.01), suggests that these females are more susceptible to damage by carcinogens as compared to females who have UADT cancers in association with cancers at non-genital sites.