Predicting leptomeningeal disease spread after resection of brain metastases using machine learning.

OBJECTIVE: The incidence of leptomeningeal disease (LMD) has increased as treatments for brain metastases (BMs) have improved and patients with metastatic disease are living longer. Sample sizes of individual studies investigating LMD after surgery for BMs and its risk factors have been limited, ranging from 200 to 400 patients at risk for LMD, which only allows the use of conventional biostatistics. Here, the authors used machine learning techniques to enhance LMD prediction in a cohort of surgically treated BMs. METHODS: A conditional survival forest, a Cox proportional hazards model, an extreme gradient boosting (XGBoost) classifier, an extra trees classifier, and logistic regression were trained. A synthetic minority oversampling technique (SMOTE) was used to train the models and handle the inherent class imbalance. Patients were divided into an 80:20 training and test set. Fivefold cross-validation was used on the training set for hyperparameter optimization. Patients eligible for study inclusion were adults who had consecutively undergone neurosurgical BM treatment, had been admitted to Brigham and Women's Hospital from January 2007 through December 2019, and had a minimum of 1 month of follow-up after neurosurgical treatment. RESULTS: A total of 1054 surgically treated BM patients were included in this analysis. LMD occurred in 168 patients (15.9%) at a median of 7.05 months after BM diagnosis. The discrimination of LMD occurrence was optimal using an XGboost algorithm (area under the curve = 0.83), and the time to LMD was prognosticated evenly by the random forest algorithm and the Cox proportional hazards model (C-index = 0.76). The most important feature for both LMD classification and regression was the BM proximity to the CSF space, followed by a cerebellar BM location. Lymph node metastasis of the primary tumor at BM diagnosis and a cerebellar BM location were the strongest risk factors for both LMD occurrence and time to LMD. CONCLUSIONS: The outcomes of LMD patients in the BM population are predictable using SMOTE and machine learning. Lymph node metastasis of the primary tumor at BM diagnosis and a cerebellar BM location were the strongest LMD risk factors.

Survival Prediction After Neurosurgical Resection of Brain Metastases: A Machine Learning Approach.

BACKGROUND: Current prognostic models for brain metastases (BMs) have been constructed and validated almost entirely with data from patients receiving up-front radiotherapy, leaving uncertainty about surgical patients. OBJECTIVE: To build and validate a model predicting 6-month survival after BM resection using different machine learning algorithms. METHODS: An institutional database of 1062 patients who underwent resection for BM was split into an 80:20 training and testing set. Seven different machine learning algorithms were trained and assessed for performance; an established prognostic model for patients with BM undergoing radiotherapy, the diagnosis-specific graded prognostic assessment, was also evaluated. Model performance was assessed using area under the curve (AUC) and calibration. RESULTS: The logistic regression showed the best performance with an AUC of 0.71 in the hold-out test set, a calibration slope of 0.76, and a calibration intercept of 0.03. The diagnosis-specific graded prognostic assessment had an AUC of 0.66. Patients were stratified into regular-risk, high-risk and very high-risk groups for death at 6 months; these strata strongly predicted both 6-month and longitudinal overall survival ( P < .0005). The model was implemented into a web application that can be accessed through http://brainmets.morethanml.com . CONCLUSION: We developed and internally validated a prediction model that accurately predicts 6-month survival after neurosurgical resection for BM and allows for meaningful risk stratification. Future efforts should focus on external validation of our model.

Sensory environment affects Icelandic threespine stickleback's anti-predator escape behaviour.

Human-induced changes in climate and habitats push populations to adapt to novel environments, including new sensory conditions, such as reduced visibility. We studied how colonizing newly formed glacial lakes with turbidity-induced low-visibility affects anti-predator behaviour in Icelandic threespine sticklebacks. We tested nearly 400 fish from 15 populations and four habitat types varying in visibility and colonization history in their reaction to two predator cues (mechano-visual versus olfactory) in high versus low-visibility light treatments. Fish reacted differently to the cues and were affected by lighting environment, confirming that cue modality and light levels are important for predator detection and evasion. Fish from spring-fed lakes, especially from the highlands (likely more diverged from marine fish than lowland fish), reacted fastest to mechano-visual cues and were generally most active. Highland glacial fish showed strong responses to olfactory cues and, counter to predictions from the flexible stem hypothesis, the greatest plasticity in response to light levels. This study, leveraging natural, repeated invasions of novel sensory habitats, (i) illustrates rapid changes in anti-predator behaviour that follow due to adaptation, early life experience, or both, and (ii) suggests an additional role for behavioural plasticity enabling population persistence in the face of frequent changes in environmental conditions.

Neurosurgical resection for locally recurrent brain metastasis.

BACKGROUND: In patients with locally recurrent brain metastases (LRBMs), the role of (repeat) craniotomy is controversial. This study aimed to analyze long-term oncological outcomes in this heterogeneous population. METHODS: Craniotomies for LRBM were identified from a tertiary neuro-oncological institution. First, we assessed overall survival (OS) and intracranial control (ICC) stratified by molecular profile, prognostic indices, and multimodality treatment. Second, we compared LRBMs to propensity score-matched patients who underwent craniotomy for newly diagnosed brain metastases (NDBM). RESULTS: Across 180 patients, median survival after LRBM resection was 13.8 months and varied by molecular profile, with >24 months survival in ALK/EGFR+ lung adenocarcinoma and HER2+ breast cancer. Furthermore, 102 patients (56.7%) experienced intracranial recurrence; median time to recurrence was 5.6 months. Compared to NDBMs (n = 898), LRBM patients were younger, more likely to harbor a targetable mutation and less likely to receive adjuvant radiation (P < 0.05). After 1:3 propensity matching stratified by molecular profile, LRBM patients generally experienced shorter OS (hazard ratio 1.67 and 1.36 for patients with or without a mutation, P < 0.05) but similar ICC (hazard ratio 1.11 in both groups, P > 0.20) compared to NDBM patients with similar baseline. Results across specific molecular subgroups suggested comparable effect directions of varying sizes. CONCLUSIONS: In our data, patients with LRBMs undergoing craniotomy comprised a subgroup of brain metastasis patients with relatively favorable clinical characteristics and good survival outcomes. Recurrent status predicted shorter OS but did not impact ICC. Craniotomy could be considered in selected, prognostically favorable patients.

The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI. METHODS: A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies. RESULTS: After screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS (HR = 1.84, 95% CI 1.22-2.77) and systemic progression-free survival (PFS; HR = 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR = 1.31, 95% CI 0.42-4.07). CONCLUSIONS: Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.

Programmed Death Receptor Ligand One Expression May Independently Predict Survival in Patients With Non-Small Cell Lung Carcinoma Brain Metastases Receiving Immunotherapy.

PURPOSE: Programmed death receptor ligand 1 (PD-L1) expression is known to predict response to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). However, the predictive role of this biomarker in brain metastases (BMs) is unknown. The aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with PD-1/PD-L1 inhibitors, after adjusting for established prognostic models. METHODS AND MATERIALS: In this multi-institutional retrospective cohort study, we identified patients with NSCLC-BM treated with PD-1/PD-L1 inhibitors after local BM treatment (radiation therapy or neurosurgery) but before intracranial progression. Cox proportional hazards models were used to assess the predictive value of PD-L1 expression for overall survival (OS) and intracranial progression-free survival (IC-PFS). RESULTS: Forty-eight patients with BM with available PD-L1 expression were identified. PD-L1 expression was positive in 33 patients (69%). Median survival was 26 months. In univariable analysis, PD-L1 predicted favorable OS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.19-1.02; P = .055). This effect persisted after correcting for lung-graded prognostic assessment and other identified potential confounders (HR, 0.24; 95% CI, 0.10-0.61; P = .002). Moreover, when modeled as a continuous variable, there appeared to be a proportional relationship between percentage of PD-L1 expression and survival (HR, 0.86 per 10% expression; 95% CI, 0.77-0.98; P = .02). In contrast, PD-L1 expression did not predict IC-PFS in uni- or multivariable analysis (adjusted HR, 0.54; 95% CI, 0.26-1.14; P = .11). CONCLUSIONS: In patients with NSCLC-BMs treated with PD-1/PD-L1 checkpoint inhibitors and local treatment, PD-L1 expression may predict OS independent of lung-graded prognostic assessment. IC-PFS did not show association with PD-L1 expression, although the present analysis may lack power to assess this. Larger studies are required to validate these findings.

Academic ecosystems must evolve to support a sustainable postdoc workforce.

The postdoctoral workforce comprises a growing proportion of the science, technology, engineering and mathematics (STEM) community, and plays a vital role in advancing science. Postdoc professional development, however, remains rooted in outdated realities. We propose enhancements to postdoc-centred policies and practices to better align this career stage with contemporary job markets and work life. By facilitating productivity, wellness and career advancement, the proposed changes will benefit all stakeholders in postdoc success-including research teams, institutions, professional societies and the scientific community as a whole. To catalyse reform, we outline recommendations for (1) skills-based training tailored to the current career landscape, and (2) supportive policies and tools outlined in postdoc handbooks. We also invite the ecology and evolution community to lead further progressive reform.

Archipelago-Wide Patterns of Colonization and Speciation Among an Endemic Radiation of Galápagos Land Snails.

Newly arrived species on young or remote islands are likely to encounter less predation and competition than source populations on continental landmasses. The associated ecological release might facilitate divergence and speciation as colonizing lineages fill previously unoccupied niche space. Characterizing the sequence and timing of colonization on islands represents the first step in determining the relative contributions of geographical isolation and ecological factors in lineage diversification. Herein, we use genome-scale data to estimate timing of colonization in Naesiotus snails to the Galápagos islands from mainland South America. We test inter-island patterns of colonization and within-island radiations to understand their contribution to community assembly. Partly contradicting previously published topologies, phylogenetic reconstructions suggest that most Naesiotus species form island-specific clades, with within-island speciation dominating cladogenesis. Galápagos Naesiotus also adhere to the island progression rule, with colonization proceeding from old to young islands and within-island diversification occurring earlier on older islands. Our work provides a framework for evaluating the contribution of colonization and in situ speciation to the diversity of other Galápagos lineages.

Local control after brain-directed radiation in patients with cystic versus solid brain metastases.

PURPOSE: Brain metastases can be radiographically cystic or solid. Cystic metastases are associated with a greater intracranial disease burden and poorer oncologic outcomes, but the impact of cystic versus solid appearance on local control after radiation remains unknown. We investigated whether cystic versus solid nature is predictive of local control after management with stereotactic or whole brain radiation (WBRT) and whether the radiation modality utilized is an effect modifier. METHODS: We identified 859 patients with 2211 newly-diagnosed brain metastases managed with upfront stereotactic radiation or WBRT without preceding resection/aspiration at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2000 and 2015. Multivariable Cox regression with an interaction term and sandwich covariance matrix was used to quantify local failure. RESULTS: Cystic lesions were more likely to recur than solid ones when managed with stereotactic radiation (HR 2.33, 95% CI 1.32-4.10, p = 0.004) but not WBRT (HR 0.92, 95% CI 0.62-1.36, p = 0.67), p-interaction = 0.007. 1 year local control rates for cystic versus solid metastases treated with stereotactic radiation were 75% versus 88%, respectively; estimates with WBRT were 76% versus 76%, respectively. However, no significant differences were noted between the two cohorts in post-radiation outcomes including all-cause mortality and neurologic death (p > 0.05). CONCLUSIONS: Among patients with brain metastases, stereotactic radiation yields improved local control and less morbidity than WBRT, and consequently for many patients the cystic versus solid designation does not impact treatment selection. However, our results suggest that in patients with a large number of cystic brain metastases, a lower threshold to consider WBRT, as opposed to stereotactic radiation, should be employed. If our results can be confirmed, further investigation into the underlying mechanism(s) would be warranted.

Neurosurgical Resection and Stereotactic Radiation Versus Stereotactic Radiation Alone in Patients with a Single or Solitary Brain Metastasis.

BACKGROUND: Brain metastases commonly manifest in patients with cancer, with ∼20%-50% presenting with 1 intracranial lesion. Among patients with 1, small brain metastasis and controlled or absent extracranial disease, it remains unclear whether aggressive intracranial management using neurosurgical resection plus cavity stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) rather than SRS/SRT alone is beneficial. In patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size, we evaluated the effect of surgery plus SRS/SRT compared with SRS/SRT on oncologic outcomes, including overall survival. METHODS: We retrospectively identified 86 patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size who had been treated from 2000 to 2015 at our institution. We examined differences in the rates of local and distant failure, use of salvage treatment, and other oncologic outcomes, including all-cause mortality. RESULTS: The baseline characteristics were similar between the 2 cohorts. The median follow-up period for the surviving patients was 38 months. On multivariable analysis, surgical resection plus cavity SRS/SRT was associated with a lower risk of all-cause mortality (hazard ratio, 0.44; 95% confidence interval, 0.19-1.00; P = 0.05) compared with SRS/SRT alone. The 1- and 2-year rates of overall survival were 100% and 88% versus 74% and 52% for surgery plus cavity SRS/SRT versus SRS/SRT alone, respectively. CONCLUSIONS: Aggressive, local therapy, including neurosurgical resection, might benefit patients with 1 brain metastasis in the context of controlled or absent systemic disease, even if the lesion in question is small. Further studies are needed to evaluate these associations.

Rapid phenotypic evolution following shifts in life cycle complexity.

Life cycle strategies have evolved extensively throughout the history of metazoans. The expression of disparate life stages within a single ontogeny can present conflicts to trait evolution, and therefore may have played a major role in shaping metazoan forms. However, few studies have examined the consequences of adding or subtracting life stages on patterns of trait evolution. By analysing trait evolution in a clade of closely related salamander lineages we show that shifts in the number of life cycle stages are associated with rapid phenotypic evolution. Specifically, salamanders with an aquatic-only (paedomorphic) life cycle have frequently added vertebrae to their trunk skeleton compared with closely related lineages with a complex aquatic-to-terrestrial (biphasic) life cycle. The rate of vertebral column evolution is also substantially lower in biphasic lineages, which may reflect the functional compromise of a complex cycle. This study demonstrates that the consequences of life cycle evolution can be detected at very fine scales of divergence. Rapid evolutionary responses can result from shifts in selective regimes following changes in life cycle complexity.

The Effects of 405-nm Visible Light on the Survival of Campylobacter on Chicken Skin and Stainless Steel.

Campylobacter spp. are foodborne pathogens responsible for a significant portion of human cases of bacterial-mediated gastrointestinal disease. A primary method for the introduction of Campylobacter into the food supply is through poultry products. Reducing the number of Campylobacter on poultry products may reduce the incidence of human disease. Research has been conducted on the use of light to inactivate Campylobacter on poultry products and processing environments. More recently, the use of high intensity visible 405-nm light has been proposed for the elimination of pathogenic bacteria. This study investigated the ability of 405-nm light to reduce Campylobacter jejuni and Campylobacter coli in poultry products. Campylobacter in chicken exudate were placed onto chicken skin or food-grade stainless steel before treatment with 405-nm light. A range of 405-nm light doses were applied to cocktails of six C. jejuni or six C. coli strains in exudate at 10°C to minimize thermal effects. Little difference was observed between inactivation of C. jejuni and C. coli on poultry skin with only minor average reductions of 1.7 logs and 2.1 logs, respectively, at the maximal dose of 184-186 J/cm(2). More noticeable differences were observed when the samples were placed on stainless steel and treated with a dose of 89 J/cm(2), producing an average reduction of 3.0 logs for C. coli but only 1.1 logs for C. jejuni. The maximal dose (181-183 J/cm(2)) applied to Campylobacter on stainless steel produced significant (p ≤ 0.05) reductions for C. jejuni and C. coli of 4.9 logs and 5.1 logs, respectively. However, significant 405-nm-mediated reductions in Campylobacter numbers required exposure times to achieve necessary dose levels that might be impractical under processing conditions. In addition, the most potent exposure times likely produced secondary thermal effects by raising sample surface temperatures above 48°C.

Acute gastrointestinal toxicity and bowel bag dose-volume parameters for preoperative radiation therapy for retroperitoneal sarcoma.

PURPOSE: Acute gastrointestinal (GI) toxicity has been studied in GI and gynecological (GYN) cancers, with volume receiving 15 Gy (V15) <830 mL, V25 <650 mL, and V45 <195 mL identified as dose constraints for the peritoneal space (bowel bag [BB]). There are no reported constraints derived from retroperitoneal sarcoma (RPS), and prospective trials for RPS have adopted some of the GI and GYN constraints. This study quantified GI toxicity during preoperative radiation therapy (RT) for RPS, assessed toxicity using published constraints, and evaluated predictors for toxicity. METHODS AND MATERIALS: From 2003 to 2013, 56 patients with RPS underwent preoperative RT at 2 institutions. Toxicity was scored using Radiation Therapy Oncology Group criteria for upper and lower acute GI toxicity. BB was contoured on planning computed tomography scans per Radiation Therapy Oncology Group atlas guidelines with review by a radiologist. Relationships among toxicity, clinical factors, and BB dose were analyzed. RESULTS: Three patients (5%) developed grade ≥3 acute GI toxicity: 2 grade 3 toxicities (anorexia and nausea) and 1 grade 5 toxicity (tumor-bowel fistula). Thirty-six patients (64%) had grade 2 toxicity (nausea, 55%; diarrhea, 23%; pain, 20%). Tumor size was the only significant clinical predictor of grade ≥2 acute GI toxicity. Larger mean BB volumes predicted for grade ≥2 toxicity (P = .001). On receiver operating characteristics analysis, V30 was the best discriminator for toxicity (P = .0001). Median BB V15 was 1375 mL; 75% of patients had V15 ≥830 mL. Median V25 was 1083 mL; 68% had V25 ≥650 mL. Median V45 was 575 mL; 82% had V45 ≥195 mL. V25 ≥650 mL was significantly associated with grade ≥2 toxicity (P = .01). CONCLUSIONS: Among patients treated with preoperative RT for RPS, significant acute GI toxicity was very low despite BB dose exceeding established constraints for most cases. Acceptable dose constraints for RPS may be higher than those for GI or GYN cancers. Further assessment of dose-volume constraints for RPS is needed.

Short communication: Measuring the angiotensin-converting enzyme inhibitory activity of an 8-amino acid (8mer) fragment of the C12 antihypertensive peptide.

An 8-AA (8mer) fragment (PFPEVFGK) of a known antihypertensive peptide derived from bovine αS1-casein (C12 antihypertensive peptide) was synthesized by microwave-assisted solid-phase peptide synthesis and purified by reverse phase HPLC. Its ability to inhibit angiotensin-converting enzyme (ACE) was assessed and compared with that of the parent 12mer peptide (FFVAPFPEVFGK) to determine the effect of truncating the sequence on overall hypotensive activity. The activity of the truncated 8mer peptide was found to be almost 1.5 times less active than that of the 12mer, with ACE-inhibiting IC50 (half-maximal inhibitory concentration) values of 108 and 69µM, for the 8mer and 12mer, respectively. Although the 8mer peptide is less active than the original 12mer peptide, its overall activity is comparable to activities reported for other small proteins that elicit physiological responses within humans. These results suggest that microbial degradation of the 12mer peptide would not result in a complete loss of antihypertensive activity if used to supplement fermented foods and that the stable 8mer peptide could have potential as a blood pressure-lowering agent for use in functional foods.

Biogeography and evolution of a widespread Central American lizard species complex: Norops humilis, (Squamata: Dactyloidae).

BACKGROUND: Caribbean anole lizards (Dactyloidae) have frequently been used as models to study questions regarding biogeography and adaptive radiations, but the evolutionary history of Central American anoles (particularly those of the genus Norops) has not been well studied. Previous work has hypothesized a north-to-south dispersal pattern of Central American Norops, but no studies have examined dispersal within any Norops lineages. Here we test two major hypotheses for the dispersal of the N. humilis/quaggulus complex (defined herein, forming a subset within Savage and Guyer's N. humilis group). RESULTS: Specimens of the N. humilis group were collected in Central America, from eastern Mexico to the Canal Zone of Panama. Major nodes were dated for comparison to the geologic history of Central America, and ancestral ranges were estimated for the N. humilis/quaggulus complex to test hypothesized dispersal patterns. These lineages displayed a northward dispersal pattern. We also demonstrate that the N. humilis/quaggulus complex consists of a series of highly differentiated mitochondrial lineages, with more conserved nuclear evolution. The paraphyly of the N. humilis species group is confirmed. A spatial analysis of molecular variance suggests that current populations are genetically distinct from one another, with limited mitochondrial gene flow occurring among sites. CONCLUSIONS: The observed south-to-north colonization route within the Norops humilis/quaggulus complex represents the first evidence of a Norops lineage colonizing in a south-to-north pattern, (opposite to the previously held hypothesis for mainland Norops). One previously described taxon (N. quaggulus) was nested within N. humilis, demonstrating the paraphyly of this species; while our analyses also reject the monophyly of the Norops humilis species group (sensu Savage and Guyer), with N. tropidonotus, N. uniformis, and N. marsupialis being distantly related to/highly divergent from the N. humilis/quaggulus complex. Our work sheds light on mainland anole biogeography and past dispersal events, providing a pattern to test against other groups of mainland anoles.

Dosimetric consequences of interobserver variability in delineating the organs at risk in gynecologic interstitial brachytherapy.

PURPOSE: To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy. METHODS AND MATERIALS: The rectum, bladder, and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using κ statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D0.1cc and D2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SD(TOT)) was calculated. RESULTS: The population mean ± 1 standard deviation of κ, CIgen, and volume CV were, respectively: 0.77 ± 0.06, 0.70 ± 0.08, and 20% ± 6% for bladder; 0.74 ± 06, 0.67 ± 0.08, and 20% ± 5% for rectum; and 0.33 ± 0.20, 0.26 ± 0.17, and 82% ± 42% for sigmoid. Dosimetric variability was as follows: for bladder, CV = 31% ± 19% (SD(TOT) = 72 ± 64 Gy) for D0.1cc and CV = 16% ± 10% (SD(TOT) = 9 ± 6 Gy) for D2cc; for rectum, CV = 11% ± 5% (SD(TOT) = 16 ± 17 Gy) for D0.1cc and CV = 7% ± 2% (SD(TOT) = 4 ± 3 Gy) for D2cc; for sigmoid, CV = 39% ± 28% (SD(TOT) = 12 ± 18 Gy) for D0.1cc and CV = 34% ± 19% (SD(TOT) = 4 ± 4 Gy) for D2cc. CONCLUSIONS: Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose-volume histogram parameters except bladder D0.1cc. Small delineation differences in high-dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study.

The effect of differing Gleason scores at biopsy on the odds of upgrading and the risk of death from prostate cancer.

INTRODUCTION/BACKGROUND: The GS is an established prostate cancer prognostic factor. Whether the presence of differing GSs at biopsy (eg, 4+3 and 3+3), which we term ComboGS, improves the prognosis that would be predicted based on the highest GS (eg, 4+3) because of decreased upgrading is unknown. Therefore, we evaluated the odds of upgrading at time of radical prostatectomy (RP) and the risk of PCSM when ComboGS was present versus absent. PATIENTS AND METHODS: Logistic and competing risks regression were performed to assess the effect that ComboGS had on the odds of upgrading at time of RP in the index (n = 134) and validation cohorts (n = 356) and the risk of PCSM after definitive therapy in a long-term cohort (n = 666), adjusting for known predictors of these end points. We calculated and compared the area under the curve using a receiver operating characteristic analysis when ComboGS was included versus excluded from the upgrading models. RESULTS: ComboGS was associated with decreased odds of upgrading (index: adjusted odds ratio [AOR], 0.14; 95% confidence interval [CI], 0.04-0.50; P = .003; validation: AOR, 0.24; 95% CI, 0.11-0.51; P < .001) and added significantly to the predictive value of upgrading for the in-sample index (P = .02), validation (P = .003), and out-of-sample prediction models (P = .002). ComboGS was also associated with a decreased risk of PCSM (adjusted hazard ratio, 0.40; 95% CI, 0.19-0.85; P = .02). CONCLUSION: Differing biopsy GSs are associated with a lower odds of upgrading and risk of PCSM. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered.

Greatest percentage of involved core length and the risk of death from prostate cancer in men with highest Gleason score ≥ 7.

INTRODUCTION/BACKGROUND: Men with highest GS ≥ 7 and a differing, lower GS core (ComboGS) have decreased PC-specific mortality (PCSM) risk after RT or RT and androgen deprivation therapy (ADT). Whether the greatest percentage of involved core length (GPC) modulates this risk is unknown. PATIENTS AND METHODS: Men with GS ≥ 7 PC (n = 333) consecutively treated between December 1989 and July 2000 using RT (n = 268; 80%) or RT and 6 months of ADT (n = 65; 20%) comprised the study cohort. The GPC was calculated using biopsy core and tumor lengths. We used competing risks regression to assess whether increasing GPC was associated with increased PCSM risk in men with or without ComboGS adjusting for risk group, age, and treatment. RESULTS: After a median follow-up of 5.36 years (interquartile range, 3.22-7.61 years), 92 (28%) men died, 28 (30%) of PC. Increasing GPC was significantly associated with increased risk of PCSM (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P = .005). Men with GPC ≥ 50% versus < 50% had significantly greater PCSM estimates when ComboGS was present (P < .001) versus absent (P = .55). Of the 127 men with ComboGS and GPC < 50%, 83% were treated with RT alone and 2 PC deaths were observed; neither in men with GS 7 and favorable intermediate-risk PC. CONCLUSION: Men treated with RT for ComboGS, GPC < 50%, GS 7, and favorable intermediate-risk PC have a very low risk of early PCSM. The RTOG 0815 trial will establish whether ADT is necessary to optimize curability in these men.

Dose to the inferior pharyngeal constrictor predicts prolonged gastrostomy tube dependence with concurrent intensity-modulated radiation therapy and chemotherapy for locally-advanced head and neck cancer.

BACKGROUND AND PURPOSE: To determine if dose and/or dose-volume parameters to anatomic swallowing structures are predictive of gastrostomy tube (PEG) dependence from chemotherapy-intensity modulated radiotherapy (IMRT) in locally advanced head and neck cancer (LAHNC). METHODS AND MATERIALS: A retrospective study was performed on 141 consecutive patients with LAHNC (squamous cell) treated with definitive chemoIMRT with weekly concurrent carboplatin and paclitaxel. Late dysphagia was assessed by length of PEG requirement. Analysis of IMRT dose was retrospectively performed for critical swallowing structures. RESULTS: Approximately 62% of patients required PEG, the majority placed during treatment. Mean and median time for PEG was 7.7 and 4.4 months respectively (range 1.4-43.8). Only IMRT dose to the inferior constrictor was significantly associated with length of PEG. Mean dose (of individual mean doses) was 47 Gy for prolonged PEG use versus 41 Gy for PEG ⩽ 12 months. V40 to the inferior constrictor also correlated with PEG >12 months (p = 0.02) with a mean V40 of 48% versus 41% for PEG ⩽ 12 months. CONCLUSIONS: IMRT dose to the inferior constrictor correlated with persistent dysphagia requiring prolonged PEG use. Maintaining mean inferior constrictor dose to ⩽ 41 Gy and V40 to ⩽ 41% may help minimize gastrostomy tube dependence.

Growth of a pYV-bearing Yersinia pestis KIM5 in retail raw ground pork.

Yersinia pestis can cause oropharyngeal plague as a result of consumption or handling of meat from infected animals. Thus, food naturally or intentionally contaminated can have a role in the dissemination of oropharyngeal plague. The growth of a conditionally virulent pYV-bearing rifampicin-resistant Y. pestis KIM5 (rif-Y. pestis KIM5) in retail raw ground pork (RGP) was studied at temperatures ranging from 4 to 30°C. At 4°C, rif-Y. pestis KIM5 did not grow but survived. In RGP, rif-Y. pestis KIM5 grew at refrigerated temperatures of 10 and 15°C with growth rates of 0.05 and 0.16 log(10) colony-forming units (CFU)/h. The growth rates at abusive temperatures of 20, 25, and 30°C were 0.26, 0.30, and 0.77 log(10) CFU/h. The growth rate was increased 15.4-fold with the increase of storage temperatures from 10°C to 30°C. The maximum population density ranged from 6.76 to 8.66 log(10) CFU/g. Furthermore, there was no detectable loss of pYV in surviving rif-Y. pestis KIM5 at any of the temperatures tested in retail RGP. This suggests that under these conditions, Y. pestis could cause oropharyngeal plague if the meat was not properly cooked. The individual infected by Y. pestis in food is a potential reservoir who can infect others, leading to outbreaks of plague.