Gaps in Confirmatory Fibrosis Risk Assessment in Primary Care Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: As recommendations for non-invasive fibrosis risk assessment in nonalcoholic fatty liver disease (NAFLD) emerge, it is not known how often they are performed in primary care. AIMS: We investigated the completion of confirmatory fibrosis risk assessment in primary care patients with NAFLD and indeterminate-risk or greater Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Scores (NFS). METHODS: This retrospective cohort study of electronic health record data from a primary care clinic identified patients with diagnoses of NAFLD from 2012 through 2021. Patients with a diagnosis of a severe liver disease outcome during the study period were excluded. The most recent FIB-4 and NFS scores were calculated and categorized by advanced fibrosis risk. Charts were reviewed to identify the outcome of a confirmatory fibrosis risk assessment by liver elastography or liver biopsy for all patients with indeterminate-risk or higher FIB-4 (≥ 1.3) and NFS (≥ - 1.455) scores. RESULTS: The cohort included 604 patients diagnosed with NAFLD. Two-thirds of included patients (399) had a FIB-4 or NFS score greater than low-risk, 19% (113) had a high-risk FIB-4 (≥ 2.67) or NFS (≥ 0.676) score, and 7% (44) had high-risk FIB-4 and NFS values. Of these 399 patients with an indication for a confirmatory fibrosis test, 10% (41) underwent liver elastography (24) or liver biopsy (18) or both (1). CONCLUSIONS: Advanced fibrosis is a key indicator of future poor health outcomes in patients with NAFLD and a critical signal for referral to hepatology. Significant opportunities exist to improve confirmatory fibrosis risk assessment in patients with NAFLD.

Overcoming sociodemographic factors in the care of patients with testicular cancer at a safety net hospital.

BACKGROUND: The objective of this study was to determine whether standardized treatment of germ cell tumors (GCTs) could overcome sociodemographic factors limiting patient care. METHODS: The records of all patients undergoing primary treatment for GCTs at both a public safety net hospital and an academic tertiary care center in the same metropolitan area were analyzed. Both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center; clinicopathologic features and outcomes were analyzed. RESULTS: Between 2006 and 2018, 106 and 95 patients underwent initial treatment for GCTs at the safety net hospital and the tertiary care center, respectively. Safety net patients were younger (29 vs 33 years; P = .005) and were more likely to be Hispanic (79% vs 11%), to be uninsured (80% vs 12%; P < .001), to present via the emergency department (76% vs 8%; P < .001), and to have metastatic (stage II/III) disease (42% vs 26%; P = .025). In a multivariable analysis, an absence of lymphovascular invasion (odds ratio [OR], 0.30; P = .008) and an embryonal carcinoma component (OR, 0.36; P = .02) were associated with decreased use of adjuvant treatment for stage I patients; hospital setting was not (OR, 0.67; P = .55). For patients with stage II/III nonseminomatous GCTs, there was no difference in the performance of postchemotherapy retroperitoneal lymph node dissection between the safety net hospital and the tertiary care center (52% vs 64%; P = .53). No difference in recurrence rates was observed between the cohorts (5% vs 6%; P = .76). CONCLUSIONS: Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCTs; they may be overcome with integrated, standardized management of testicular cancer.

Comparison of treatment planning approaches for spatially fractionated irradiation of deep tumors.

PURPOSE: The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets. METHODS: Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined. RESULTS: The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min). CONCLUSION: Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.

Thyroid storm and warm autoimmune hemolytic anemia.

Graves' disease is often associated with other autoimmune disorders, including rare associations with autoimmune hemolytic anemia (AIHA). We describe a unique presentation of thyroid storm and warm AIHA diagnosed concurrently in a young female with hyperthyroidism. The patient presented with nausea, vomiting, diarrhea and altered mental status. Laboratory studies revealed hemoglobin 3.9g/dL, platelets 171×109L-1, haptoglobin <5mg/dL, reticulocytosis, and positive direct antiglobulin test (IgG, C3d, warm). Additional workup revealed serum thyroid stimulating hormone (TSH) <0.01µIU/mL and serum free-T4 (FT4) level 7.8ng/dL. Our patient was diagnosed with concurrent thyroid storm and warm AIHA. She was started on glucocorticoids to treat both warm AIHA and thyroid storm, as well as antithyroid medications, propranolol and folic acid. Due to profound anemia and hemodynamic instability, the patient was transfused two units of uncrossmatched packed red blood cells slowly and tolerated this well. She was discharged on methimazole as well as a prolonged prednisone taper, and achieved complete resolution of the thyrotoxicosis and anemia at one month. Hyperthyroidism can affect all three blood cell lineages of the hematopoietic system. Anemia can be seen in 10-20% of patients with thyrotoxicosis. Several autoimmune processes can lead to anemia in Graves' disease, including pernicious anemia, celiac disease, and warm AIHA. This case illustrates a rarely described presentation of a patient with Graves' disease presenting with concurrent thyroid storm and warm AIHA.

Predictive Factors for Prophylactic Percutaneous Endoscopic Gastrostomy (PEG) Tube Placement and Use in Head and Neck Patients Following Intensity-Modulated Radiation Therapy (IMRT) Treatment: Concordance, Discrepancies, and the Role of Gabapentin.

The prophylactic placement of a percutaneous endoscopic gastrostomy (PEG) tube in the head and neck cancer (HNC) patient is controversial. We sought to identify factors associated with prophylactic PEG placement and actual PEG use. Since 2010, data regarding PEG placement and use were prospectively recorded in a departmental database from January 2010 to December 2012. HNC patients treated with intensity-modulated radiation therapy (IMRT) were retrospectively evaluated from 2010 to 2012. Variables potentially associated with patient post-radiation dysphagia from previous literature, and our experience was evaluated. We performed multivariate logistic regression on these variables with PEG placement and PEG use, respectively, to compare the difference of association between the two arms. We identified 192 HNC patients treated with IMRT. Prophylactic PEG placement occurred in 121 (63.0 %) patients, with PEG use in 97 (80.2 %) patients. PEG placement was associated with male gender (p < .01), N stage ≥ N2 (p < .05), pretreatment swallowing difficulties (p < .01), concurrent chemotherapy (p < .01), pretreatment KPS ≥80 (p = .01), and previous surgery (p = .02). Concurrent chemotherapy (p = .03) was positively associated with the use of PEG feeding by the patient, whereas pretreatment KPS ≥80 (p = .03) and prophylactic gabapentin use (p < .01) were negatively associated with PEG use. The analysis suggests there were discrepancies between prophylactic PEG tube placement and actual use. Favorable pretreatment KPS, no pretreatment dysphagia, no concurrent chemotherapy, and the use of gabapentin were significantly associated with reduced PEG use. This analysis may help refine the indications for prophylactic PEG placement.

Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice.

Recently, we demonstrated in female mice that protection against ANG II-induced hypertension and associated cardiovascular changes depend on cytochrome P-450 (CYP)1B1. The present study was conducted to determine if Cyp1b1 gene disruption ameliorates renal dysfunction and organ damage associated with ANG II-induced hypertension in female mice. ANG II (700 ng·kg(-1)·min(-1)) infused by miniosmotic pumps for 2 wk in female Cyp1b1(+/+) mice did not alter water consumption, urine output, Na(+) excretion, osmolality, or protein excretion. However, in Cyp1b1(-/-) mice, ANG II infusion significantly increased (P < 0.05) water intake (5.50 ± 0.42 ml/24 h with vehicle vs. 8.80 ± 0.60 ml/24 h with ANG II), urine output (1.44 ± 0.37 ml/24 h with vehicle vs. 4.30 ± 0.37 ml/24 h with ANG II), and urinary Na(+) excretion (0.031 ± 0.016 mmol/24 h with vehicle vs. 0.099 ± 0.010 mmol/24 h with ANG II), decreased osmolality (2,630 ± 79 mosM/kg with vehicle vs. 1,280 ± 205 mosM/kg with ANG II), and caused proteinuria (2.60 ± 0.30 mg/24 h with vehicle vs. 6.96 ± 0.55 mg/24 h with ANG II). Infusion of ANG II caused renal fibrosis, as indicated by an accumulation of renal interstitial α-smooth muscle actin, collagen, and transforming growth factor-ß in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. ANG II also increased renal production of ROS and urinary excretion of thiobarburic acid-reactive substances and reduced the activity of antioxidants and urinary excretion of nitrite/nitrate and the 17ß-estradiol metabolite 2-methoxyestradiol in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. These data suggest that Cyp1b1 plays a critical role in female mice in protecting against renal dysfunction and end-organ damage associated with ANG II-induced hypertension, in preventing oxidative stress, and in increasing activity of antioxidant systems, most likely via generation of 2-methoxyestradiol from 17ß-estradiol.

Conversations in cardiology: bridging antiplatelet therapy before surgery.

Bridging for antiplatelet therapy remains a subject of debate with data favoring GP blockers but at a risk of bleeding. This Conversation in Cardiology addresses a key and often asked question about use of alternatives to P2Y12 agents in patients requiring surgery within 6 months after drug eluting stent implantation.

Chronic liver disease is not associated with statin prescription in a primary care cohort.

Statins have historically been underutilized in patients with chronic liver disease (CLD). We sought to investigate the association between CLD and statin prescription in a primary care setting. Our retrospective cohort study identified primary care patients with a low-density lipoprotein value and more than one office visit from 2012 through 2018. Indication for statin therapy was determined using the Third Adult Treatment Panel criteria prior to November 2016 and the American College of Cardiology and American Heart Association guidelines thereafter. Indication for statin prescription and statin therapy by year was determined. Patients with CLD were identified using ICD-9/10 diagnosis codes. In total, 2119 individuals with an indication for statin therapy were identified. Of these individuals, 354 (16.7%) had CLD. Alcoholic and nonalcoholic fatty liver disease comprised 44.9% and 28.5% of the CLD population, respectively; 27.7% had cirrhosis. There was no difference in the prevalence of statin prescriptions when comparing patients with a CLD diagnosis to those without one (57.9 vs 59.9%, p = 0.48). A diagnosis of CLD was also not significantly associated with statin prescription when adjusting for other covariates (odds ratio (OR) 1.02; 95% confidence interval (CI) 0.78-1.33). An alanine aminotransferase level greater than 45 U/L significantly reduced the odds of a statin prescription (OR 0.62; 95% CI 0.44-0.87). Overall, the presence of a CLD diagnosis was not associated with attenuated statin utilization compared to those without a CLD diagnosis. Nevertheless, adherence to guideline indicated statin therapy remains suboptimal and efforts to increase statin utilization in this high-risk population remain prudent.

Predictive capacity of a miRNA panel in identifying teratoma in post-chemotherapy consolidation surgeries.

Objectives: To investigate the utility of a novel serum miRNA biomarker panel to distinguish teratoma from nonmalignant necrotic/fibrotic tissues or nonviable tumours in patients with NSGCT undergoing post-chemotherapy consolidation surgery. Patients and methods: We prospectively collected pre-surgical serum samples from 22 consecutive testicular NSGCT patients with residual NSGCT after chemotherapy undergoing post-chemotherapy consolidation surgery. We measured serum miRNA expression of four microRNAs (miRNA-375, miRNA-200a-3p, miRNA-200a-5p and miRNA-200b-3p) and compared with pathologic findings at time of surgery. Receiver operating characteristic (ROC) curves were performed to assess the ability of these miRNA to differentiate between teratoma and necrosis or viable malignancy. Results: Twenty-two patients with NSGCT were split into two groups based on pathology at time of post-chemotherapy consolidation surgery (teratoma group vs. necrosis/fibrosis/viable tumour group, i.e., NFVT). Patients with teratoma were older at diagnosis compared with those patients with NFVT (median age 28.7 vs. 23.9). Patients with NFVT were more likely to have embryonal carcinoma in their primary tumour (81.8% vs. 27.3%; p = 0.01). The majority of patients in both groups were stage III (63.6% vs. 72.7%). In this analysis, none of the miRNAs had good sensitivity or specificity to predict teratoma. There was no significant association between the expression levels of the miRNAs and the presence of teratoma. There was no statistically significant correlation between any of the miRNAs and teratoma size. Conclusion: This novel miRNA panel (miRNA-375, miRNA-200a-3p, miRNA-200a-5p and miRNA-200b-3p) did not distinguish teratoma from nonmalignant necrotic/fibrotic tissues or nonviable tumours in patients with NSGCT undergoing post-chemotherapy consolidation surgery.

Clinical Utility of Genomic Recurrence Risk Stratification in Early, Hormone-Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Real-World Experience.

BACKGROUND: RNA-based genomic risk assessment estimates chemotherapy benefit in patients with hormone-receptor positive (HR+)/Human Epidermal Growth Factor 2-negative (ERBB2-) breast cancer (BC). It is virtually used in all patients with early HR+/ERBB2- BC regardless of clinical recurrence risk. PATIENTS AND METHODS: We conducted a retrospective chart review of adult patients with early-stage (T1-3; N0; M0) HR+/ERBB2- BC who underwent genomic testing using the Oncotype DX (Exact Sciences) 21-genes assay. Clinicopathologic features were collected to assess the clinical recurrence risk, in terms of clinical risk score (CRS) and using a composite risk score of distant recurrence Regan Risk Score (RRS). CRS and RRS were compared to the genomic risk of recurrence (GRS). RESULTS: Between January 2015 and December 2020, 517 patients with early-stage disease underwent genomic testing, and clinical data was available for 501 of them. There was statistically significant concordance between the 3 prognostication methods (P < 0.01). Within patients with low CRS (n = 349), 9.17% had a high GRS, compared to 8.93% in patients with low RRS (n = 280). In patients with grade 1 histology (n = 130), 3.85% had a high GRS and 68.46% had tumors > 1 cm, of whom only 4.49% had a high GRS. Tumor size > 1cm did not associate with a high GRS. CONCLUSION: Genomic testing for patients with grade 1 tumors may be safely omitted, irrespective of size. Our finds call for a better understanding of the need for routine genomic testing in patients with low grade/low clinical risk of recurrence.

Comparisons of treatment optimization directly incorporating systematic patient setup uncertainty with a margin-based approach.

PURPOSE: To develop a probabilistic treatment planning (PTP) method which is robust to systematic patient setup errors and to compare PTP plans with plans generated using a planning target volume (PTV) margin optimized to give the same target coverage probability as the PTP plan. METHODS: Plans adhering to the RTOG-0126 protocol are developed for 28 prostate patients using PTP and margin-based planning. For PTP, an objective function that simultaneously considers multiple possible patient positions is developed. PTP plans are optimized using clinical target volume (CTV) structures and organ at risk (OAR) structures. The desired CTV coverage probability is 95%. Plans that cannot achieve a 95% CTV coverage probability are re-optimized with a desired CTV coverage probability reduced by 5% until the desired CTV coverage probability is achieved. Margin-based plans are created which achieve the same CTV coverage probability as the PTP plans by iterative adjustment of the CTV-to-PTV margin. Postoptimization, probabilistic dose-volume coverage metrics are used to compare the plans. RESULTS: For equivalent target coverage probability, PTP plans significantly reduce coverage probability for rectum objectives (-17% for D(35) < 65 Gy, p = 0.0010; -23% for D(25) < 70 Gy, p < 0.0001; and -27% for D(15) < 75 Gy, p < 0.0001). Physician assessment indicates PTP plans are entirely preferred 71% of the time while margin-based plans are entirely preferred 7% of the time. CONCLUSIONS: For plans having the same target coverage probability, PTP has potential to reduce rectal doses while maintaining CTV coverage probability. In blind comparisons, physicians prefer PTP plans over optimized margin plans.

Very Late Recurrence in Germ Cell Tumor of the Testis: Lessons and Implications.

Background. Very late recurrence (LR), i.e., >5 years after initial presentation, occurs in about 1% of patients with germ cell tumors of the testis (TGCT) and is associated with poor prognosis. Methods. We retrospectively reviewed the records of patients at the M. D. Anderson Cancer Center who developed LR > 5 years after their initial diagnosis of TGCT. Results. We identified 25 patients who developed LR between July 2007 and August 2020. The median age at the time of LR was 46 years (range, 29−61). Pathology of LR: somatic transformation to carcinoma or sarcoma­11, nonseminoma with yolk sac tumor or teratoma­11, nonseminoma without yolk sac tumor or teratoma­2, not available­1. With a median follow-up of 3.5 years, 68% of patients are alive 3 years after LR. Patients with prior post-chemotherapy consolidation surgery do not have statistically significant longer survival compared to patients who did not receive post-chemotherapy consolidation surgery, 83.3% vs. 60.8% at 3 years, respectively, p = 0.50. Conclusions. Patients with LR > 5 years tend to harbor nonseminoma (with yolk sac tumor and or teratoma). Among these patients, a majority who did not undergo surgery to remove residual disease after chemotherapy developed somatic transformation and succumbed to their LR.

SAR of 2-amino and 2,4-diamino pyrimidines with in vivo efficacy against Trypanosoma brucei.

A series of 2,4-diaminopyrimidines was investigated and compounds were found to have in vivo efficacy against Trypanosoma brucei in an acute mouse model. However, in vitro permeability data suggested the 2,4-diaminopyrimidenes would have poor permeability through the blood brain barrier. Consequently a series of 4-desamino analogs were synthesized and found to have improved in vitro permeability.

A Prospective Cohort Study of Neural Progenitor Cell-Sparing Radiation Therapy Plus Temozolomide for Newly Diagnosed Patients With Glioblastoma.

BACKGROUND: In treating glioblastoma, irradiation of the neural progenitor cell (NPC) niches is controversial. Lower hippocampal doses may limit neurocognitive toxicity, but higher doses to the subventricular zones (SVZ) may improve survival. OBJECTIVE: To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with glioblastoma. METHODS: Patients with glioblastoma received resection followed by standard chemoradiation. Radiation dose to the NPC niches, including the bilateral hippocampi and SVZ, was minimized without compromising tumor coverage. The primary outcome was tumor progression in the spared NPC niches. Follow-up magnetic resonance imaging was obtained bimonthly. Neurocognitive testing was performed before treatment and at 6- and 12-mo follow-up. Cox regression evaluated predictors of overall and progression-free survival. Linear regression evaluated predictors of neurocognitive decline. RESULTS: A total of 30 patients enrolled prospectively. The median age was 58 yr. Median mean doses to the hippocampi and SVZ were 49.1 and 41.8 gray (Gy) ipsilaterally, and 16.5 and 19.9 Gy contralaterally. Median times to death and tumor progression were 16.0 and 7.6 mo, and were not significantly different compared to a matched historical control. No patients experienced tumor progression in the spared NPC-containing regions. Overall survival was associated with neurocognitive function (P ≤ .03) but not dose to the NPC niches. Higher doses to the hippocampi and SVZ predicted greater decline in verbal memory (P ≤ .01). CONCLUSION: In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes. Further studies are needed to confirm these results.

Isolated Erythrocytosis Associated With 3 Novel Missense Mutations in the EGLN1 Gene.

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.

Origin of Subsequent Malignant Neoplasms in Patients with History of Testicular Germ Cell Tumor.

Although genetic changes may be pivotal in the origin of cancer, cellular context is paramount. This is particularly relevant in a progenitor germ cell tumor and its differentiated mature teratoma counterpart when it concerns tumor heterogeneity and cancer dormancy in subsequent second malignancies (subsequent malignant neoplasms (SMNs)). From our tumor registry database, we identified 655 testicular germ cell tumor (TGCT) patients who developed SMNs between January 1990 and September 2018. Of the 113 solid organ SMNs, 42 had sufficient tumor tissue available for fluorescence in situ hybridization (FISH) analysis of isochromosome 12p [i(12p)]. We identified seven additional patients for targeted DNA and RNA sequencing of teratomas and adjacent somatic transformation. Finally, we established cell lines from freshly resected post-chemotherapy teratomas and evaluated the cells for stemness expression by flow cytometry and by the formation of teratomas in a xenograft model. In our cohort, SMNs comprising non-germ cell tumors occurred about 18 years after a diagnosis of TGCT. Of the 42 SMNs examined, 5 (12%) contained i(12p) and 16 (38%) had 12p gain. When comparing a teratoma and adjacent somatic transformation, targeted DNA and RNA sequencing demonstrated high concordance. Studies of post-chemotherapy teratoma-derived cell lines revealed cancer-initiating cells expressing multipotency as well as early differentiation markers. For the first time, we demonstrated the prevalence of i(12p) in SMNs and the presence of progenitor cells embedded within mature teratomas after chemotherapy. Our findings suggest a progenitor stem-like cell of origin in SMN and TGCT and highlight the importance of cellular context in this disease.

Comparisons of treatment optimization directly incorporating random patient setup uncertainty with a margin-based approach.

The purpose of this study is to incorporate the dosimetric effect of random patient positioning uncertainties directly into a commercial treatment planning system's IMRT plan optimization algorithm through probabilistic treatment planning (PTP) and compare coverage of this method with margin-based planning. In this work, PTP eliminates explicit margins and optimizes directly on the estimated integral treatment dose to determine optimal patient dose in the presence of setup uncertainties. Twenty-eight prostate patient plans adhering to the RTOG-0126 criteria are optimized using both margin-based and PTP methods. Only random errors are considered. For margin-based plans, the planning target volume is created by expanding the clinical target volume (CTV) by 2.1 mm to accommodate the simulated 3 mm random setup uncertainty. Random setup uncertainties are incorporated into IMRT dose evaluation by convolving each beam's incident fluence with a sigma = 3 mm Gaussian prior to dose calculation. PTP optimization uses the convolved fluence to estimate dose to ensure CTV coverage during plan optimization. PTP-based plans are compared to margin-based plans with equal CTV coverage in the presence of setup errors based on dose-volume metrics. The sensitivity of the optimized plans to patient-specific setup uncertainty variations is assessed by evaluating dose metrics for dose distributions corresponding to halving and doubling of the random setup uncertainty used in the optimization. Margin-based and PTP-based plans show similar target coverage. A physician review shows that PTP is preferred for 21 patients, margin-based plans are preferred in 2 patients, no preference is expressed for 1 patient, and both autogenerated plans are rejected for 4 patients. For the PTP-based plans, the average CTV receiving the prescription dose decreases by 0.5%, while the mean dose to the CTV increases by 0.7%. The CTV tumor control probability (TCP) is the same for both methods with the exception of one case in which PTP gave a slightly higher TCP. For critical structures that do not meet the optimization criteria, PTP shows a decrease in the volume receiving the maximum specified dose. PTP reduces local normal tissue volumes receiving the maximum dose on average by 48%. PTP results in lower mean dose to all critical structures for all plans. PTP results in a 2.5% increase in the probability of uncomplicated control (P+), along with a 1.9% reduction in rectum normal tissue complication probability (NTCP), and a 0.7% reduction in bladder NTCP. PTP-based plans show improved conformality as compared with margin-based plans with an average PTP-based dosimetric margin at 7100 cGy of 0.65 cm compared with the margin-based 0.90 cm and a PTP-based dosimetric margin at 3960 cGy of 1.60 cm compared with the margin-based 1.90 cm. PTP-based plans show similar sensitivity to variations of the uncertainty during treatment from the uncertainty used in planning as compared to margin-based plans. For equal target coverage, when compared to margin-based plans, PTP results in equal or lower doses to normal structures. PTP results in more conformal plans than margin-based plans and shows similar sensitivity to variations in uncertainty.

Synthesis and biological activity of anticoccidial agents: 2,3-diarylindoles.

Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.

Glioblastoma and Increased Survival with Longer Chemotherapy Duration.

INTRODUCTION: The five-year survival rate for patients with glioblastoma (GBM) is low at approximately 4.7%. Radiotherapy plus concomitant and adjuvant temozolomide (TMZ) remains the standard of care. The optimal duration of therapy with TMZ is unknown. This study sought to evaluate the survival benefit of two years of treatment. METHODS: This was a retrospective chart review of all patients diagnosed with GBM and treated with TMZ for up to two years between January 1, 2002 and December 31, 2011. The Kaplan-Meier method with log-rank test was used to estimate the progression-free survival (PFS) and the overall survival (OS). The results were compared to historical controls and data from previous clinical trials of patients treated up to one year. RESULTS: Data from 56 patients with confirmed GBM were evaluated. The OS probability was 54% (SE = 0.068) at one year, 28.3% (SE = 0.064) at two years, 17.8% (SE = 0.059) at three years, and 4% (SE = 0.041) at five years. Seven patients (12.5%) were treated with TMZ for two years. Their median time-to-progression was 28 months (95% CI = 5.0 - 28.0), and they had an increased survival probability at three years compared to other patients (log-rank test χ2 (1, N = 56) = 19.2, p < 0.0001). CONCLUSIONS: There may be an advantage for a longer duration of TMZ therapy among patients with GBM, but the sample size was too small for generalization. A multicenter prospective study is needed to identify optimal duration of TMZ therapy.