Surviving Over a Decade With Glioblastoma: A Clinical Course Characterized by Multiple Recurrences, Numerous Salvage Treatments, and Novel Use of Cesium-131 Tiles.

The prognosis for patients diagnosed with recurrent glioblastoma (GBM) remains poor, with no clear standard of care regarding salvage therapy. Common approaches include chemotherapy, re-resection, tumor treating fields, and reirradiation. However, most studies have shown these to have limited benefits. Reirradiation is particularly difficult due to concern for increased risk of toxicity to surrounding normal brain tissue. A novel intracranial brachytherapy system called GammaTile® (GT Medical Technologies, Tempe, Arizona) involves the placement of Cesium-131 radioactive tiles in the tumor cavity following maximal safe resection. This allows for a highly conformal dose distribution with rapid fall-off to minimize overlap with prior radiation fields and for the application of radiation directly to the high-risk tumor bed. This case report highlights a patient with GBM who survived 11.5 years through multiple recurrences and discusses the many salvage treatments he received, including bevacizumab, irinotecan, and stereotactic radiosurgery (SRS). This case exemplifies that aggressive systemic and local therapies can work well in select patients allowing for long-term survival with a good quality of life. Further efforts should be made to identify which patients may benefit from these therapies. The case study additionally reports on the use of GammaTile therapy. Due to prior external beam radiation therapy and SRS to the treatment site, further external beam radiation options were limited, and the patient was offered GammaTile as local therapy. Although it did not provide a survival benefit in this case due to progressive disease outside of the field of treatment, GammaTile serves as a valuable option in providing local therapy to patients who can no longer receive further radiation. It should be used with careful consideration in lesions characterized by aggressive local invasion.

Racial disparities in the use of palliative radiotherapy for black patients with multiple myeloma in the United States.

Multiple myeloma (MM) is characterized by painful lesions that are amenable to palliative radiotherapy (PRT) but racial disparities may exist. In the current study, the National Cancer Database was queried for patients diagnosed with MM from 2004 to 2016 who received PRT. The percentages of patients receiving PRT within 12 months of diagnosis by race/ethnicity were: 15.5% non-Hispanic white (NHW), 14.3% African American (AA), 15.8% Hispanic, and 14.4% other. On multivariable logistic regression, the odds of receiving RT were 13% less for AAs compared to NHWs (OR = 0.87, 95% CI = 0.83-0.90, p < .0001) and the odds of dying within 30 days of PRT were 18% less for AAs compared to NHWs (OR = 0.82, 95% CI = 0.67-1.00, p = .046). This study highlights a health disparity affecting AA patients who despite having a higher incidence and mortality from MM are also less likely to receive PRT within 1 year of diagnosis and near the end of life.

Role of Ki-67, MRE11, and PD-L1 as Predictive Biomarkers for Recurrence Pattern in Muscle-invasive Bladder Cancer.

BACKGROUND/AIM: Muscle invasive bladder cancer (MIBC) is an aggressive disease with high rates of local recurrence following radical cystectomy (RC). Currently, there are no clinically validated biomarkers to predict local only recurrence (LOR) and guide adjuvant treatment decisions. This pilot study evaluated the role of Ki-67, MRE11 and PD-L1 as predictive biomarkers for recurrence patterns in patients undergoing RC for MIBC. PATIENTS AND METHODS: Our institutional cystectomy database containing cases from 1992-2014 was queried for patients with local only recurrence (LOR), and case-matched to patients with distant recurrence (DR) and no recurrence (NR). Clinicopathological data were collected and a tissue microarray was analyzed for presence of Ki-67, MRE11, and PD-L1 using immunofluorescence and immunohistochemistry. RESULTS: Pathologic specimens from 42 patients (18 NR, 16 LOR, and 8 DR) were reviewed. Compared to normal bladder tissue, tumors had increased expression of Ki-67 (p<0.01) and PD-L1 (p<0.05). High Ki-67 was associated with recurrence pattern (local vs. distant) on univariate analysis (p<0.05). Ki-67 cell density varied by recurrence type: LOR (1354 cells/mm2), DR (557 cells/mm2) and NR (1111 cells/mm2) (p=0.034). CONCLUSION: Our selected biomarkers could distinguish MIBC from normal bladder tissue but could not classify samples by recurrence pattern.

Disparities in male versus female oncologic outcomes following bladder preservation: A population-based cohort study.

INTRODUCTION: In surgical series of muscle-invasive bladder cancer (MIBC), women have higher recurrence rates, disease progression, and mortality following radical cystectomy than men. Similar reports of oncologic differences between men and women following trimodality therapy (TMT) are rare. Our hypothesis was that there would be no difference in overall survival (OS) between sexes receiving TMT. METHODS: We queried the National Cancer Database (NCDB) for patients diagnosed with clinical stage T2-T4aN0 M0 MIBC between 2004-2016. We considered patients to have received TMT if they received 55 Gy in 20 fractions or 59.4-70.2 Gy of radiotherapy with concurrent chemotherapy following a transurethral resection of bladder tumor (TURBT). We used multivariable Cox proportional hazard models to determine whether sex was associated with risk of mortality. In addition to OS, we calculated relative survival (RS) to adjust for the fact that females generally survive longer than males. RESULTS: Of the patients, 1960 underwent TMT and had survival data. Less than one quarter were female. In the first year following treatment, women had worse OS and RS than men (p = 0.093 and p = 0.030, respectively). However, overall and relative survival differences between sexes were not statistically significantly different in Years 2 and later. Unlike with OS, the RS between sexes remained significant at 9 years; in multivariable analysis based on RS, women were 43% more likely to die than men (p < 0.001). CONCLUSIONS: Women had a higher initial risk of death than men in the first year following TMT. However, long-term survival between sexes was similar. TMT is an important treatment option in both men and women seeking bladder preservation.

Assessment of Familiarity With Work-up Guidelines for Bone and Soft Tissue Sarcoma Among Primary Care Practitioners in Minnesota.

OBJECTIVE: To assess familiarity with sarcoma guidelines among primary care practitioners (PCPs) in Minnesota. PARTICIPANTS AND METHODS: Surveys were distributed at 2 educational conferences held in Minnesota on April 16-17, 2015, and October 24, 2015. The PCPs were asked a series of questions about their current practice, past experience with sarcoma, and familiarity with sarcoma guidelines. They were then given a series of case presentations and asked to indicate if they would pursue a sarcoma work-up given the information provided. RESULTS: The study group included 80 physicians and 32 nurse practitioners (NPs). Over their careers (median, 14 years), physicians reported seeing a mean of 2.2 cases of soft tissue sarcoma and 0.7 cases of bone sarcoma. The NPs reported seeing a mean of 0.7 and 0.2 cases, respectfully, over their careers (median, 8 years). Both physicians and NPs reported low familiarity with sarcoma guidelines. When challenged with case presentations for which urgent referral to a sarcoma specialist is recommended, more than 50% of PCPs did not indicate that they would refer patients. The PCPs who had previous experience with soft tissue sarcoma and bone sarcoma estimated that only 17% and 23% of their patients, respectively, were diagnosed within 1 month of presentation. The most reported reason for a delayed diagnosis was the PCP advising the patient to "watch and wait." CONCLUSION: Minnesota PCPs have seen very few cases of sarcoma and report low familiarity with sarcoma guidelines. When challenged with case presentations, PCPs made decisions inconsistent with established guidelines. This study supports ongoing efforts to increase sarcoma awareness.

The role of neoadjuvant radiotherapy for locally-advanced rectal cancer with resectable synchronous metastasis.

BACKGROUND: Although neoadjuvant radiotherapy is typically administered for locally-advanced rectal cancer to reduce local recurrence (LR), its role for patients who present with synchronous resectable liver and/or lung metastasis is not well defined. The aim of this study was to evaluate the role of neoadjuvant radiotherapy for patients with stage IV rectal cancer undergoing curative-intent surgery. METHODS: This study is a retrospective review of a prospectively maintained surgical registry of all consecutive adult patients who underwent curative-intent resection at Mayo Clinic in Rochester, MN, from January 1990 until December 2014 with a median follow-up time of 43 (IQR 16-67) months. Eligible patients had locally-advanced rectal cancer (T3, T4 and/or nodal involvement) with synchronous resectable liver and/or lung metastasis. Exclusion criteria were as follows: patients with primary tumor stage of T1N0 or T2N0, patients with metastasis to organs other than the liver or lung, patients who had palliative resection, patients who had non-surgical treatment of synchronous metastasis (e.g., radiofrequency ablation), patients who received postoperative radiotherapy, or absence of research authorization. Ninety three patients were included of which 47 received neoadjuvant radiotherapy and 46 did not. All patients received neoadjuvant chemotherapy +/- radiotherapy followed by curative-intent surgery with metastasectomy performed either simultaneously with resection of the primary tumor or as a planned staged resection. The primary outcomes of this study are LR, distant metastasis, overall and disease-specific survival (DSS). RESULTS: LR was observed in 12 patients (26%) who did not receive radiotherapy, while no LR developed in those who received neoadjuvant radiotherapy, P<0.001. Univariate analysis showed that neither age, sex, ASA class, BMI, tumor location, procedure performed, or neoadjuvant chemotherapy were associated with subsequent LR. The 5-year overall survival (OS) rates were: 43.3% (95% CI: 30.1, 62.3) for no radiotherapy vs. 58.3% (95% CI: 43.4, 78.2) with radiotherapy. CONCLUSIONS: Neoadjuvant radiotherapy should be considered in patients with locally-advanced stage IV rectal cancer. These data add to the evidence supporting neoadjuvant radiotherapy in the setting of resectable metastatic disease.

Biological Model for Predicting Toxicity in Head and Neck Cancer Patients Receiving Proton Therapy.

PURPOSE: To use a linear energy transfer (LET) dependent formula for relative biological effectiveness (RBE) to generate a biological model that can be used to predict toxicity in patients treated with proton therapy for cancer of the head and neck. PATIENTS AND METHODS: Patients treated with protons to a dose of 60 to 70 Gy (RBE = 1.1) for head and neck cancer were eligible to participate in this study. Treatment plans were developed using graphics processing unit Monte Carlo calculations. The equation, RBE = (1.1)[0.08(LETd)+0.88], was the biological model. The physical model assumes RBE = 1.1. Tumor volumes and organs at risk (OARs) were contoured, and isodose lines were created for 105%-120% of the prescribed dose. Dose to volume of OARs was calculated for both models for comparative purposes. Physician-reported toxicity was graded from 0 to 5 using the Common Terminology Criteria for Adverse Events, version 4.03. Patient-reported outcomes were obtained using the Promis10 and European Organisation for Research and Treatment of Cancer's QLQ-H&N35 instruments. RESULTS: Eleven patients were included in this study. In each case the biological model revealed an increased dose to several OARs compared with the physical model. For selected OARs, the volume receiving >105% of the target dose was 2-fold to 15-fold greater in the biological model than the volume predicted by the physical model. Patients experienced toxicity that was consistent with the dose to OARs predicted by the biological model. Furthermore, 1 patient developed mucosal ulceration and another developed osteoradionecrosis at the location of a biological hot spot. In each case, the biological hot spot was located 2 mm inside the clinical target volume. CONCLUSION: The results suggest that increases in dose predicted by the biological model are clinically relevant and that LET and RBE corrections and optimization should be a component of the treatment-planning process in proton therapy.

Characterization of the oropharynx: anatomy, histology, immunology, squamous cell carcinoma and surgical resection.

Understanding the structure and function of the oropharynx is paramount for providing excellent patient care. In clinical oncology, the oropharynx is generally divided into four distinct components: (i) the base of the tongue; (ii) the soft palate; (iii) the palatine tonsillar fossa; and (iv) the pharyngeal wall. The oropharyngeal mucosa is distinct from other mucosal surfaces in the body, as it is composed of a reticulated epithelium with a discontinuous basement membrane, also known as lymphoepithelium. This review describes the anatomy, histology, immunology and surgical resection of the oropharynx as they relate to oncological care.

Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the uracil catabolic pathway, being critically important for inactivation of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). DPD impairment leads to increased exposure to 5-FU and, in turn, increased anabolism of 5-FU to cytotoxic nucleotides, resulting in more severe clinical adverse effects. Numerous variants within the gene coding for DPD, DPYD, have been described, although only a few have been demonstrated to reduce DPD enzyme activity. To identify DPYD variants that alter enzyme function, we expressed 80 protein-coding variants in an isogenic mammalian system and measured their capacities to convert 5-FU to dihydro-fluorouracil, the product of DPD catabolism. The M166V, E828K, K861R, and P1023T variants exhibited significantly higher enzyme activity than wild-type DPD (120%, P = 0.025; 116%, P = 0.049; 130%, P = 0.0077; 138%, P = 0.048, respectively). Consistent with clinical association studies of 5-FU toxicity, the D949V substitution reduced enzyme activity by 41% (P = 0.0031). Enzyme activity was also significantly reduced for 30 additional variants, 19 of which had <25% activity. None of those 30 variants have been previously reported to associate with 5-FU toxicity in clinical association studies, which have been conducted primarily in populations of European ancestry. Using publicly available genotype databases, we confirmed the rarity of these variants in European populations but showed that they are detected at appreciable frequencies in other populations. These data strongly suggest that testing for the reported deficient DPYD variations could dramatically improve predictive genetic tests for 5-FU sensitivity, especially in individuals of non-European descent.

microRNAs miR-27a and miR-27b directly regulate liver dihydropyrimidine dehydrogenase expression through two conserved binding sites.

Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) is the rate-limiting enzyme in the uracil catabolic pathway and has a pivotal role in the pharmacokinetics of the commonly prescribed anticancer drug 5-fluorouracil (5-FU). Deficiency of DPD, whether due to inadequate expression or deleterious variants in DPYD, has been linked to severe toxic responses to 5-FU. Little is known about the mechanisms governing DPD expression in the liver. In this report, we show increased accumulation of RNA-induced silencing complex (RISC) proteins on DPYD mRNA in cells overexpressing the highly homologous microRNAs (miRNA) miR-27a and miR-27b. These miRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells overexpressing miR-27a or miR-27b was 4.4 µmol/L (both), significantly lower than that for cells expressing a nontargeting (scramble) control miRNA (14.3 µmol/L; P = 3.3 × 10(-5) and P = 1.5 × 10(-7), respectively). Mouse liver DPD enzyme activity was inversely correlated with expression levels of miR-27a (R(2) = 0.49; P = 0.0012) and miR-27b (R(2) = 0.29; P = 0.022). A common variant in the hairpin loop region of hsa-mir-27a (rs895819) was also shown to be associated with elevated expression of the miR-27a in a panel of cell lines (P = 0.029) and in a transgenic overexpression model (P = 0.0011). Furthermore, rs895819 was associated with reduced DPD enzyme activity (P = 0.028) in a cohort of 40 healthy volunteers. Taken together, these results suggest that miR-27a and miR-27b expression may be pharmacologically relevant modulators of DPD enzyme function in the liver. Furthermore, our data suggest that rs895819 may be a potential risk allele for 5-FU sensitivity.