A randomized phase II trial of MR-guided prostate stereotactic body radiotherapy administered in 5 or 2 fractions for localized prostate cancer (FORT).

BACKGROUND: Ultra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT-utilizing potentially fewer treatments-is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment. METHODS/DESIGN: A total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10-14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7-10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score. DISCUSSION: FORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04984343 . Date of registration: July 30, 2021. PROTOCOL VERSION: 4.0, Nov 8, 2022.

Absolute Percentage of Pattern 4 Disease as a Prognostic Measure for Intermediate-risk Prostate Cancer Treated with Stereotactic Body Radiotherapy.

AIMS: Intermediate-risk prostate cancer is heterogenous. The absolute percentage of biopsied tissue positive for Gleason pattern 4 disease (APP4) is a possible prognostic measure. Here we sought to determine the impact of APP4 in a prospective multi-institutional pooled analysis of men with intermediate-risk prostate cancer treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Patients with intermediate-risk prostate cancer treated with SBRT (40 Gy in five fractions or 26 Gy in two fractions) with or without androgen deprivation therapy treated on prospective clinical trials were included. Pathology reports were queried to obtain APP4, calculated as the percentage of Gleason pattern 4 disease within the tumour(s) multiplied by the percentage of total biopsied tissue positive for disease divided by 100. The optimal APP4 cut-off points for biochemical failure and distant metastasis were calculated and used as a stratification in the cumulative incidence of biochemical failure and distant metastasis. Multivariable competing risk models were developed. RESULTS: In tota, 227 patients were included. The median follow-up was 56.5 months. The optimal APP4 cut-off points were 5% for biochemical failure and 20% for distant metastasis. At 4 years, the cumulative incidence of biochemical failure was 23.6% and 2.3% for APP4 >5% and ≤ 5%, respectively (P < 0.0001). The cumulative incidence of distant metastasis was 12.5% for APP4 >20% and 1% for APP4 ≤ 20% (P = 0.02). APP4 sub-stratified favourable intermediate-risk prostate cancer and unfavourable intermediate-risk prostate cancer into groups at similarly low and similarly high risk of biochemical failure and distant metastasis. On multivariable competing risk analysis, APP4 >5% (P = 0.0004) was significantly associated with biochemical failure, but APP4 (log) was not for distant metastasis (P = 0.08). CONCLUSION: APP4 may be an easily accessible promising prognostic measure for patients with intermediate-risk prostate cancer treated with SBRT. Incorporation of APP4 into prospective trials will help to determine its value.

Four-year Prostate-specific Antigen Response Rate as a Predictive Measure in Intermediate-risk Prostate Cancer Treated With Ablative Therapies: The SPRAT Analysis.

AIMS: There is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). The aim of the present study was to explore 4-year prostate-specific antigen response rate (4yPSARR) as an early predictive measure. MATERIALS AND METHODS: Individual patient data from six institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42-54 months) PSA available were analysed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan-Meier method. Biochemical failure-free survival was analysed according to 4yPSARR, with groups dichotomised based on PSA <0.4 ng/ml or ≥0.4 ng/ml and compared using the Log-rank test. A multivariable competing risk analysis was carried out to predict for biochemical failure and the development of metastases. RESULTS: Six hundred and thirty-seven patients were included, including 424 (67%) with favourable and 213 (33%) with unfavourable intermediate-risk disease. The median follow-up was 6.2 years (interquartile range 4.9-7.9). The cumulative incidence of biochemical failure and metastasis was 7 and 0.6%, respectively; overall survival at 6 years was 97%. The cumulative incidence of biochemical failure at 6 years if 4yPSARR <0.4 ng/ml was 1.7% compared with 27% if 4yPSARR ≥0.4 ng/ml (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (subdistribution hazard ratio 15.3, 95% confidence interval 7.5-31.3, P < 0.001) and metastasis-free survival (subdistribution hazard ratio 31.2, 95% confidence interval 3.1-311.6, P = 0.003). CONCLUSION: 4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted.

MRI-guided radiotherapy for head and neck cancer: initial clinical experience.

PURPOSE: To report a single-institutional experience with the use of magnetic resonance imaging (MRI)-guided radiotherapy for cancers of the head and neck. MATERIALS AND METHODS: Between October 2014 and October 2016, 18 patients with newly diagnosed cancers of the head and neck were prospectively enrolled on an institutional registry trial investigating the feasibility and efficacy of external-beam radiotherapy delivered using on-board MRI. All patients had biopsy-proven evidence of malignancy, measurable disease, and the ability to provide consent. None had previously received any treatment. Median dose was 70 Gy (range 54-70 Gy). MRI scans were obtained as part of an image-guided registration protocol for alignment prior to and during each treatment. Concurrent chemotherapy was administered to 14 patients (78%). Patient-reported outcomes were assessed using the University of Washington quality of life instrument. RESULTS: Seventeen of 18 patients completed the planned intensity-modulated radiotherapy (IMRT) treatment of which 15 (83%) had a complete response and 2 (11%) had a partial response based on initial post-therapy positron emission tomography (PET) at 3 months. The 1-year estimates of progression-free survival, overall survival, and local-regional control were 95, 96, and 95%, respectively. There were no treatment-related fatalities. The incidence of grade 3+ acute toxicity was 44%. The proportion of patients rating their health-related quality of life as "very good" or "outstanding" at 6 months and 1 year after completion of radiation therapy was 60 and 70%, respectively. CONCLUSIONS: MRI-guided radiotherapy achieves clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Establishing the distribution of satellite lesions in intermediate- and high-risk prostate cancer: implications for focused radiotherapy.

BACKGROUND: In focused radiotherapy for prostate cancer (PC), a full dose of radiation is delivered to the index lesion while reduced dose is delivered to the remaining prostate to reduce morbidity. As PC is commonly multifocal, we investigated whether baseline clinical characteristics or multiparametric magnetic resonance imaging (mpMRI) may be useful to predict the actual pathologic distribution of PC in men with intermediate- or high-risk PC, which may better inform how to deliver focused radiotherapy. METHODS: A retrospective single-institutional study was performed on 71 consecutive men with clinically localized, intermediate- or high-risk PC who underwent mpMRI followed by radical prostatectomy (RP) from January 2012 to December 2012. Logistic regression analysis was performed to evaluate preoperative predictors for satellite lesions. Performance characteristics of mpMRI to detect satellite lesions and the extent of prostate disease (one hemi-gland vs both) were also evaluated. RESULTS: In all, 50.7% had satellite lesions on mpMRI. On RP specimen analysis, 66.2% had satellite lesions and 55.3% of these satellite lesions had pathologic Gleason score (pGS)⩾3+4. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for mpMRI detecting a satellite lesion being present in the RP specimen were 59.6%, 66.7%, 77.8%, 45.7% and 62.0%, respectively. The presence of MRI satellite lesions was the only preoperative predictor significantly associated with finding satellite lesions on final pathology (hazard ratio (HR), 2.95, P=0.040). There was agreement in 76.1% of the entire cohort for unilateral vs bilateral disease when incorporating both biopsy and mpMRI information and comparing with the RP specimen. CONCLUSIONS: In intermediate risk or greater PC, only the presence of mpMRI satellite lesions could predict for pathologic satellite lesions. While combining biopsy and mpMRI information may improve preoperative disease localization, the relatively high incidence of bilateral hemi-gland involvement with pGS ⩾7 satellite lesions makes it challenging to appropriately select men eligible for hemi-gland therapy.

Comparing and predicting the costs and outcomes of patients with major and minor stroke using the Boston Acute Stroke Imaging Scale neuroimaging classification system.

BACKGROUND AND PURPOSE: A neuroimaging-based ischemic stroke classification system that predicts costs and outcomes would be useful for clinical prognostication and hospital resource planning. The Boston Acute Stroke Imaging Scale (BASIS), a neuroimaging-based ischemic stroke classification system, was tested to determine whether it was able to predict the costs and clinical outcomes of patients with stroke at an urban academic medical center. MATERIALS AND METHODS: Patients with ischemic stroke who presented in the emergency department in 2000 (230 patients) and 2005 (250 patients) were classified by using BASIS as having either a major or minor stroke. Compared outcomes included death, length of hospitalization, discharge disposition, use of imaging and intensive care unit (ICU) resources, and total in-hospital cost. Continuous variables were compared by univariate analysis by using the Student t test or the Satterthwaite test adjusted for unequal variances. Categoric variables were tested with the chi(2) test. Multiple regression analyses related total hospital cost (dependent variable) to stroke severity (major versus minor), sex, age, presence of comorbidities, and death during hospitalization. Logistic regression analysis was applied to identify the significant predictive variables indicating a greater likelihood of discharge home. RESULTS: In both years, individuals with strokes classified as major had a significantly longer length of stay, spent more days in the ICU, and had a higher cost of hospitalization than patients with minor strokes (all outcomes, P < .0001). All deaths (8 in 2000, 26 in 2005) occurred in patients with major stroke. Whereas 73% of patients with minor stroke were discharged home, only 12.2% of patients with major stroke were discharged home (P < .0001); 61% of patients with major stroke were discharged to a rehabilitation or skilled nursing facility. Patients with major stroke cost 4.4 times and 3.0 times that of patients with minor stroke in 2000 and 2005, respectively. Making up less than one third of all patients, patients with major stroke accounted for 60% of the total in-hospital cost of acute stroke care. CONCLUSIONS: BASIS, a neuroimaging-based stroke classification system, is highly effective at predicting in-hospital resource use, acute-hospitalization cost, and outcome. Predictive ability was maintained across the years studied.

Association between sweet preference and paternal history of alcoholism in psychiatric and substance abuse patients.

BACKGROUND: The relationship between preference for stronger sweet solutions and propensity to excessive alcohol drinking is supported by both animal and human studies. This study was designed to test the hypothesis that sweet preference is associated with the genetic risk of alcoholism as measured by a paternal history of alcoholism. METHODS: Participants were 180 patients admitted to a residential treatment program for the treatment of alcoholism, drug dependence, or psychiatric conditions. In addition to a routine medical examination, patients completed the standard sweet preference test twice (on the 9th and 24th days after admission), and the family history of alcoholism was evaluated. RESULTS: Sweet preference was shown to be stable over time. It was strongly associated with a paternal history of alcoholism, with family history-positive patients approximately 5 times more likely to prefer stronger sweet solutions than family history-negative subjects. Such factors as dependence on alcohol, cocaine, opiates, cannabis, other drugs (including prescription drugs), and tobacco smoking, as well as demographics (gender and age), did not significantly interfere with association between sweet preference and paternal history of alcoholism. CONCLUSIONS: These findings provide some support for the hypothesis that preference for stronger sweet solutions is associated with a genetic predisposition to alcoholism as measured by a paternal history of alcoholism.

Effectiveness of screening instruments in detecting substance use disorders among prisoners.

This study examined the effectiveness of several screening instruments in detecting substance use disorders among prison inmates. A sample of 400 male inmates were administered eight different substance abuse screening instruments and the Structured Clinical Interview for DSM-IV (SCID-IV), Version 2.0, Substance Abuse Disorders module. The latter was used as a diagnostic criterion measure to determine the presence of substance use disorders. Based on positive predictive value, sensitivity, and overall accuracy, the Texas Christian University Drug Screen, the Simple Screening Instrument, and a combined instrument-Alcohol Dependence Scale/Addiction Severity Index-Drug Use section were found to be the most effective in identifying substance abuse and dependence disorders.

Enhancement of PCRs by partial restriction digestion of genomic templates.

Genomic DNA preparations derived from mammalian cells can often exhibit poor template activity in PCR, particularly when carried out on target sequences present at low copy number. Using genomic DNA bearing SV40 sequences integrated into host chromosomal DNA at low copy number as a target, we show that template efficiency can be dramatically enhanced after treatment of the genomic template with restriction enzymes for varying periods of time. Also, our results indicate that, while template activity was enhanced by all of the restriction enzymes tested, optimal digestion time varied for each enzyme.

Fluorescence spectroscopy of normal, SV40-transformed human keratinocytes, and carcinoma cells.

Native fluorescence emission and excitation spectra of SV40 infected human keratinocytes, A431 and SCC324 carcinoma cells, and normal human keratinocytes were measured and compared. A difference in the intracellular metabolic state of NADH was found between the normal cells and the cancer or virus-transformed cells. The observed difference, namely an increased proportion of bound, mitochondrial NADH in the cancer and virus-infected cells, manifests as a blue spectral shift in the emission spectra.

Sources of motivation in a couples outpatient alcoholism treatment program.

This study examines sources of motivation to seek treatment. Participants were 105 male alcoholics and their non-alcoholic female partners who participated in a study of three different approaches to the conjoint treatment of alcoholism. Participants' sources of motivation were coded from responses to questions at the initial clinical screening interview. Sources of motivation were classified as "internal" or "external." More participants had internal sources of motivation (74%) than external sources. Participants with internal sources of motivation scored higher on the Michigan Alcoholism Screening Test than participants with external sources of motivation, but did not differ on other measures of pretreatment severity of alcohol problems. About half of the participants (53%) cited their partner as a primary source of motivation to seek treatment. Other sources of motivation cited were: increasing problems with alcohol, mental health problems, and physical health problems. There was greater variability among internal sources of motivation than among external sources of motivation. Participants' partners but not the male participants themselves, experienced an increase in marital satisfaction from pre- to within-treatment when the participant was motivated to come to treatment by his partner.

Post-cesarean section pain secondary to intussuscepting colonic adenocarcinoma.

The differential diagnosis for lower abdominal and pelvic pain following Cesarean section includes many causes, such as endometritis, abscess, pelvic hematoma, wound complications, pelvic vein thrombophlebitis, gastrointestinal dysfunction and obstruction. Colonic obstruction secondary to intussusception is a rare cause. We present a case of post-Cesarean section pain in a 26-year-old patient due to obstructing colonic intussusception secondary to colonic adenocarcinoma. Review of the literature failed to identify a previous case report of colonic adenocarcinoma with intussusception presenting early in the postpartum period. The diagnosis was initially made by ultrasound, and later corroborated by computed tomography, barium enema and laparotomy.

Integration of the SV40 promoter/enhancer sequences in an anchorage-independent clonal subline of SV40-infected human keratinocytes.

Long-term cultures of SV40-infected human keratinocytes contain integrated, but structurally altered copies of the viral sequences. The presence of these sequences is required for expression of properties associated with the transformed phenotype including immortalization. The integrated viral sequences in an anchorage-independent line of viral-transformed human keratinocytes have been found to be contained on two BamHI fragments of about 6.9 and 5.2 kb. In the larger fragment the viral sequences were present as two tandemly repeated subgenomic fragments containing the viral origin/promoter region with nucleotide alterations that affect enhancer function, the origin of replication and T antigen binding site 1. The viral early gene promoter in one integrant gave rise to an unspliced fusion transcript comprised of a short portion of the viral early gene leader sequence and the flanking human sequences. The smaller fragment consisted of full-length SV40 containing a nine-nucleotide insertion in the C-terminal portion of the SV40 T antigen, a region involved in the regulation of viral host range.

Posttreatment follow-up of radiation oncology patients in a managed care environment.

PURPOSE: Health care delivery in the United States is in the midst of a structural revolution called managed care. Demands for cost control within the managed care environment force radiation oncologists to defend the need and obligation to follow their patients. METHODS AND MATERIALS: We have analyzed this follow-up requirement from six potential justifications: patient care, medical-legal, quality assurance, outcome measurement, cost, and improvement of care. RESULTS: Practical recommendations for discussing the need for follow-up with the medical directors and primary care physicians of managed care entities are given. Follow-up without valid documentation of benefit is hard to justify in this era of managed care. CONCLUSIONS: Collaborative follow-up between the referring physician, the treating radiation oncologist, and the other oncologic specialists will allow for outcome measurement and improvement in practice without driving up cost or exposing the patient to undue risk.

Characterization of a 1.8-kb DNA segment located upstream from the human Ha-ras protooncogene and possibly regulating its function.

We have cloned a 1.8-kb segment of DNA just adjacent to the 5' end of the 6.4-kb BamHI fragment which contains the Ha-ras oncogene (ras1; GenBank notation HUMRASH). Electrophoretic mobility shift assays (EMSA) indicate the presence of multiple nuclear protein-binding sites within the 1.8-kb segment. At least three putative regulatory protein-binding sites have been identified in a 206-bp subfragment by DNase I footprint analysis. Within the subfragment containing the DNase-protected regions, there is also a segment containing a number of consensus sequences for DNA-binding proteins and two sub-sequences that exhibit strong sequence homology to at least two previously characterized enhancers. These data suggest that a novel set of regulatory elements may lie as far as 2 kb upstream from the normal Ha-ras transcription start points.

Case report: intraspinal synovial cyst containing gas.

With MRI, an intraspinal synovial cyst appears as a hypointense, rounded, intraspinal lesion bearing similar signal characteristics to cerebrospinal fluid containing a signal void within it; this can be confused with calcium or hemosiderin within the cyst. In such cases, CT imaging can lead to a diagnosis.

MRI and CT features of polycystic liver disease.

The authors report two cases of polycystic liver (PCL) disease with no other organ involvement. PCL, an uncommon disease that usually is asymptomatic, was diagnosed using computed tomography for one patient and magnetic resonance imaging for the other patient.

Proliferating cell nuclear antigen/cyclin in cultured human keratinocytes.

Expression of proliferating cell nuclear antigen (PCNA)/cyclin in cultured human keratinocytes was studied using an antibody from an SLE patient as the reagent. By indirect immunofluorescence staining, SV40-transformed human keratinocytes expressed PCNA/cyclin in 40-45% of the cells as a nulcear granular fluorescence. After synchronization of these cells, their nuclear distribution pattern during the S phase was sequential and showed a clear correlation with DNA synthesis. Primary cultured keratinocytes grown in high Ca+ medium expressed PCNA/cyclin in 10-15% of the cells with a similar staining pattern. These positively stained cells were confined to the basal and immediate suprabasal layers of the stratified culture sheet. The keratinocytes disaggregated by trypsin were separated according to cell size through a screen of Nitex monofilament cloth. The cells smaller than 15 microns in diameter synthesized abundant PCNA/cyclin, while the larger cells expressed very low levels. These results indicate that the expression of PCNA/cyclin correlates with DNA synthesis in cultured keratinocytes, but is not associated with their differentiation process.