A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy.

PURPOSE: To compare health-related quality of life (QoL) in urinary, bowel, and sexual domains after combined external beam radiation therapy (EBRT) and either low-dose rate (LDR) or high-dose rate (HDR) prostate brachytherapy (BT). METHODS AND MATERIALS: Eligible men with intermediate or high-risk prostate cancer treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score, Index of Erectile Function, and Expanded Prostate Cancer Composite were collected at baseline, 1, 3, 6, and 12 months, every 6 months to 3 years and then annually along with prostate-specific antigen/testosterone. Fisher's exact test compared categorical variables and the Mann-Whitney U test Expanded Prostate Cancer Index Composite (EPIC) domain scores. RESULTS: From January 2014 to December 2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89 and 88 respectively for Genito-urinary; 92 and 93 for Gastro-intestinal. EPIC urinary scores decreased at 1 month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained more than the minimum clinically important difference out to 5 years. CONCLUSIONS: The patient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms.

MRI-defined treatment margins, urinary toxicity, and PSA response in LDR prostate brachytherapy.

PURPOSE: Implant quality metrics as measured by D90 and V100 do not address the adequacy of periprostatic margins. Relative margin deficiencies may relate to efficacy and margin excesses to post-implant toxicity. Our purpose is to determine MRI-defined treatment margins on prostate achieved with LDR brachytherapy. METHODS AND MATERIALS: Post implant CT and MR images from 487 consecutive patients who received LDR brachytherapy from 2010 to 14 were co-registered. Four prostate quadrants were defined; anterior-superior (AS), posterior-superior (PS), anterior-inferior (AI), posterior-inferior (PI). Dosimetric variables were measured for prostate, and for each quadrant with a 0-, 2-, 3-, and 5-mm margin, as well as for the membranous urethra defined on MRI. RESULTS: Prostate D90 (no margin) was associated with D90 to the volume enclosed by 2 mm, 3 mm and 5 mm margins (R2 = 0.9 - 1.0) with an average 7.1% decrease in dose per mm of margin. Mean D90 for PS, AI and PI quadrants were > 110% of prescription dose for margins of 2-, 3-, and 5-mm. AS quadrant mean D90s were generally lower (83.2% for 2 mm, 76.4% for 3 mm and 62.2% for 5 mm). Urethral strictures (n = 9) were associated with higher doses in the AI quadrant, and higher membranous urethral V125 (51 vs. 32%, p 0.013) and V150 (34.5 vs. 17.6%, p 0.01). CONCLUSIONS: Using MR-CT post implant dosimetry, margin coverage up to 5 mm was excellent with less margin coverage in the AS quadrant. Late ≥ grade 2 toxicity and urinary strictures are more likely to occur with relative margin excess in the anterior-inferior quadrant and higher doses caudal to the prostate apex. Within this analysis, there was no relationship between treatment margins, and PSA outcome.

Characteristics and Outcome of Extranodal NK/T-cell Lymphoma in North America: A Retrospective Multi-Institutional Experience.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinical data from non-Asian countries are lacking. It is unclear whether outcomes and disease natural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers. PATIENTS AND METHODS: We retrospectively identified patients with newly-diagnosed CD56 + ENKTL and studied disease characteristics and clinical outcomes. RESULTS: One hundred and twenty-one patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treated with combined modality therapy (CMT) (n = 53), chemotherapy alone (CT) (n = 14) or radiotherapy alone (RT) (n = 16).  Thirty-eight patients (31%) had stage III/IV disease and were treated with CMT (n = 12), CT (n = 23), or RT (n = 3).  The median follow-up for the entire cohort was 51 months. Patients with stage I/II disease, compared to those with stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs 19% (P = .03) and overall survival (OS) 59% vs. 29% (P= .004). Outcomes were similar for stage I/II patients who received CMT vs. RT alone with 2-year PFS (53% vs. 47%; P= .91) and OS (67% vs. 67%; P= .58). No significant differences in outcomes were noted based on race/ethnicity. CONCLUSIONS: This series represents a large experience of ENKTL treated at several major North American academic centers.  Our data are consistent with Asian studies: (1) majority of patients present with early-stage disease; (2) overall poor outcome regardless of race/ethnicity; (3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease.

Characteristics and Outcome of Extranodal NK/T-Cell Lymphoma in North America: A Retrospective Multi-Institutional Experience.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinicaldata from non-Asian countries are lacking. It is unclear whether outcomes and diseasenatural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers. PATIENTS AND METHODS: We retrospectively identified patients with newly-diagnosedCD56 + ENKTL and studied disease characteristics and clinical outcomes. RESULTS: 121 patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treatedwith combined modality therapy (CMT) (n=53), chemotherapy alone (CT) (n=14) orradiotherapy alone (RT) (n=16). Thirty-eight patients (31%) had stage III/IV diseaseand were treated with CMT (n=12), CT (n=23), or RT (n=3). The median follow-up forthe entire cohort was 51 months. Patients with stage I/II disease, compared to thosewith stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs19% (p=0.03) and overall survival (OS) 59% vs 29% (p=0.004). Outcomes were similarfor stage I/II patients who received CMT vs RT alone with 2-year PFS (53% vs 47%;p=0.91) and OS (67% vs 67%; p=0.58). No significant differences in outcomes werenoted based on race/ethnicity. CONCLUSIONS: This series represents a large experience of ENKTL treated at several major North American academic centers. OUR DATA ARE CONSISTENT WITH ASIAN STUDIES: 1) majority of patients present with early-stage disease; 2) overall poor outcome regardless of race/ethnicity; 3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease.

Commissioning a four-dimensional Computed Tomography Simulator for minimum target size due to motion in the Anterior-Posterior direction: a procedure and treatment planning recommendations.

The purpose of this work is to develop a procedure for commissioning four-dimensional computed tomography (4DCT) algorithms for minimum target reconstruction size, to quantify the effect of anterior-posterior (AP) motion artifacts on known object reconstruction for periodic and irregular breathing patterns, and to provide treatment planning recommendations for target sizes below a minimum threshold. A mechanical platform enabled AP motion of a rod and lung phantom during 4DCT acquisition. Static, artifact-free scans of the phantoms were first acquired. AP sinusoidal and patient breathing motion was applied to obtain 4DCT images. 4DCT reconstruction artifacts were assessed by measuring the apparent width and angle of the rod. Comparison of known tumor diameters and volumes between the static image parameters with the 4DCT image sets was used to quantify the extent of AP reconstruction artifact and contour deformation. Examination of the rod width, under sinusoidal motion, found it was best represented during the inhale and exhale phases for all periods and ranges of motion. From the gradient phases, the apparent width of the rod decreased with increasing amplitude and decreasing period. The rod angle appeared larger on the reconstructed images due to the presence of motion artifact. The apparent diameters of the spherical tumors on the gradient phases were larger/equivalent than the true values in the AP/LR direction, respectively, while the exhale phase consistently displayed the spheres at the approximately correct diameter. The Eclipse calculated diameter matched closely with the true diameter on the exhale phase and was found to be larger on the inhale, MIP, and Avg scans. The procedure detailed here may be used during the acceptance and commissioning period of a computed tomography simulator or retroactively when implementing a SBRT program to determine the minimum target size that can be reliably reconstructed.

Automated air kerma strength quality assurance of permanent seed implant prostate brachytherapy sources using vendor autoradiographs.

PURPOSE: To develop a novel quality assurance (QA) program to determine the air kerma strength (AKS) of brachytherapy seeds within preloaded needles using autoradiographs alone, without jeopardizing sterility or necessitating procedural changes either by the vendor or in the operating room. METHODS AND MATERIALS: Digital autoradiographs of QA seed orders and sterile preloaded needles were acquired. Regions of interest of each preloaded seed were determined through an iterative scanning process identifying changes from background levels to radioactivity exposure. Average exposure values through the center of each region of interest were fitted with a Gaussian curve and Full Width at Half Maximums (FWHMs) were calculated. The two-dimensional exposure-scaled FWHM (Exp2D) measurements for the QA seed orders were plotted against measured AKS values and related using a linear curve fit that was adjusted using the third-party assay average AKS and applied as a calibration curve to convert Exp2D to AKS. RESULTS: Estimated seed AKS was found to have a strong dependence on position within the holding tray because of imager positioning inconsistencies. Calculated seed AKS for patient-specific seed orders using the curve scaling factor varied from the nominal order AKS by 1.1 ± 0.9% and from the third-party assay measurements by 0.0 ± 0.4%. CONCLUSIONS: This work depicts a clinically useful tool to aid in QA of preloaded brachytherapy permanent seed implant needles without compromising sterility or increasing clinical workloads. With this procedure, each individual seed's AKS can be verified automatically before a patient's scheduled implant or retroactively when auditing patient records.

Implementation of a Health Plan Program for Switching From Analogue to Human Insulin and Glycemic Control Among Medicare Beneficiaries With Type 2 Diabetes.

Importance: Prices for newer analogue insulin products have increased. Lower-cost human insulin may be effective for many patients with type 2 diabetes. Objective: To evaluate the association between implementation of a health plan-based intervention of switching patients from analogue to human insulin and glycemic control. Design, Setting, and Participants: A retrospective cohort study using population-level interrupted times series analysis of members participating in a Medicare Advantage and prescription drug plan operating in 4 US states. Participants were prescribed insulin between January 1, 2014, and December 31, 2016 (median follow-up, 729 days). The intervention began in February 2015 and was expanded to the entire health plan system by June 2015. Exposures: Implementation of a health plan program to switch patients from analogue to human insulin. Main Outcomes and Measures: The primary outcome was the change in mean hemoglobin A1c (HbA1c) levels estimated over three 12-month periods: preintervention (baseline) in 2014, intervention in 2015, and postintervention in 2016. Secondary outcomes included rates of serious hypoglycemia or hyperglycemia using ICD-9-CM and ICD-10-CM diagnostic codes. Results: Over 3 years, 14 635 members (mean [SD] age: 72.5 [9.8] years; 51% women; 93% with type 2 diabetes) filled 221 866 insulin prescriptions. The mean HbA1c was 8.46% (95% CI, 8.40%-8.52%) at baseline and decreased at a rate of -0.02% (95% CI, -0.03% to -0.01%; P <.001) per month before the intervention. There was an association between the start of the intervention and an overall HbA1c level increase of 0.14% (95% CI, 0.05%-0.23%; P = .003) and slope change of 0.02% (95% CI, 0.01%-0.03%; P < .001). After the completion of the intervention, there were no significant differences in changes in the level (0.08% [95% CI, -0.01% to 0.17%]) or slope (<0.001% [95% CI, -0.008% to 0.010%]) of mean HbA1c compared with the intervention period (P = .09 and P = 0.81, respectively). For serious hypoglycemic events, there was no significant association between the start of the intervention and a level (2.66/1000 person-years [95% CI, -3.82 to 9.13]; P = .41) or slope change (-0.66/1000 person-years [95% CI, -1.59 to 0.27]; P = .16). The level (1.64/1000 person-years [95% CI, -4.83 to 8.11]; P = .61) and slope (-0.23/1000 person-years [95% CI, -1.17 to 0.70]; P = .61) changes in the postintervention period were not significantly different compared with the intervention period. The baseline rate of serious hyperglycemia was 22.33 per 1000 person-years (95% CI, 12.70-31.97). For the rate of serious hyperglycemic events, there was no significant association between the start of the intervention and a level (4.23/1000 person-years [95% CI, -8.62 to 17.08]; P = .51) or slope (-0.51/1000 person-years [95% CI, -2.37 to 1.34]; P = .58) change. Conclusions and Relevance: Among Medicare beneficiaries with type 2 diabetes, implementation of a health plan program that involved switching patients from analogue to human insulin was associated with a small increase in population-level HbA1c.

Unexpected Seed Migration in Prostate Brachytherapy Implants Coincident with Change in Seed Stranding Product.

PURPOSE: This study was undertaken to determine if significant seed migration occurred when our institution changed seed products by comparing patterns of seed migration in implants containing different stranding material. METHODS AND MATERIALS: Day 0 and Day 30 CT scans were registered by the contoured prostate center of mass. An implant reconstruction program identified seeds on CT according to the pre-plan, enabling one-to-one correspondence between Day 0 and Day 30 seeds. Significant seed migration was defined by review of seeds that migrated > 2 cm outside the prostate or appearance in unexpected locations.   Results: Twenty-five (149, 16.8%) new strands displayed movement > 2 cm between Day 0 and Day 30 compared with just 2/118 (1.7%) of the standard strands. Six out of 26 (23%) patients with new strands displayed significant migration compared with 2/13 (14%) of patients with standard strands. In the six patients with new strands and significant migration, a mean of four strands (17%, range: 2-8 per patient) migrated significantly with 65% due to whole strand migration, 25% due to strand breakage, and 10% strand clumping. In the control group, only two strands (2%) migrated significantly, both due to strand breakage. Despite the greater seed movement with the new strands, Day 0 and Day 30 dosimetry was acceptable. CONCLUSION: In this short report, we identified that a change to a new strand type was associated with unexpected significant seed movement compared to our typical strands. Since seed movement can arise from unexpected causes, it is important to maintain quality assurance practices when a change in technique or infrastructure is instituted.

The role of radiation therapy in the treatment of metastatic castrate-resistant prostate cancer.

In the setting of castrate-resistant prostate cancer, patients present with a variety of symptoms, including bone metastases, spinal cord compression and advanced pelvic disease. Fortunately, a variety of radiotherapeutic options exist for palliation. This article focuses on these options, including both external beam radiotherapy and radiopharmaceuticals.

Salvage low-dose-rate permanent seed brachytherapy for locally recurrent prostate cancer: Association between dose and late toxicity.

PURPOSE: Rates of late toxicity are higher for salvage treatment of local recurrence after prior radiotherapy. We present our experience with salvage prostate brachytherapy (BT) for local recurrence after definitive external beam radiotherapy with attention to the relationship between dose and late toxicity. METHODS AND MATERIALS: From 2005 to 2012, 18 patients with biopsy proven locally recurrent prostate cancer and negative staging received low-dose-rate BT with a prescribed dose of 130-144 Gy. Toxicities were graded using Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Median followup is 31.5 months (range, 12-104). International Prostate Symptom Scores peaked at 3 months (median, 21/35), returning to baseline by 24 months. Urinary catheterization rate was 33% (median duration, 14 days; range, 1-90 days). Late Grade 3/4 genitourinary toxicity occurred in 1 patient each, one of whom also had Grade 3 late gastrointestinal toxicity; urethral strictures developed in three others. These 5 patients with late toxicity had higher dose to the prostate (isodose enclosing 90% [D90] median, 151 Gy; range, 135-185 Gy) compared with those without late complications (median, 134 Gy; range, 105-165; p < 0.04). Acute gastrointestinal toxicity Grade <3 occurred in 44%. Four patients (22%) experienced biochemical failure. CONCLUSION: Salvage low-dose-rate prostate BT can provide durable biochemical control. Care should be taken to select patients with higher likelihood of organ-confined disease. The goal of planning should be to treat the recurrent disease to an adequate dose with careful attention to maintain a conservative D90.

Deformable image registration for defining the postimplant seroma in permanent breast seed implant brachytherapy.

PURPOSE: To demonstrate the benefit of deformable image registration (DIR) to define postimplant seromas in permanent breast seed implants (PBSIs) by adapting preimplant seromas to postimplant images. METHODS AND MATERIALS: Planning and Day 0 CT scans from 15 consecutive PBSI patients were included. Seromas were contoured on the preimplant CTs. After implant, DIR (MIM Maestro; MIM Software, Inc., Cleveland, OH) was used to adapt preimplant seromas to postimplant scans. Resulting seromas were evaluated for accuracy and adjusted if required, and pre- and postimplant seroma volumes were recorded and compared. DIR was validated by assessing the spatial correspondence of surgical clips pre- and postimplant in eight cases. Retrospectively, rigid registration was also investigated. RESULTS: Surgical clip location corresponded between pre- and postimplant images with a median agreement of <1.0 mm. The seroma defined using DIR was an acceptable rendering of the postimplant seroma in 9 of 15 cases, and in the remaining six cases, minor alterations (mean, 1.0 ± 0.2 mm) were made. Mean change in seroma volumes between preimplant and postimplant imaging was -6.1 ± 26.4%. Rigid registration exhibited unacceptable variability, with poor concordance in postimplant seroma between different observers (median conformity index, 26.5%; range, 0-52.7%). CONCLUSIONS: Deformable image registration can be used to adapt the preimplant seroma to postimplant PBSI images and is recommended for implant quality assurance in PBSI. Using deformable registration avoids uncertainties associated with poor seroma visualization and interobserver variability when rigid registration is performed. The accurate deformation of implanted surgical clips demonstrates the reliability of deformable image registration for PBSI.

Surface mold brachytherapy for nonmelanoma skin cancer: Canadian patterns of practice.

PURPOSE: We sought to describe the use of surface mold brachytherapy (SMBT) for nonmelanoma skin cancer in Canada. METHODS AND MATERIALS: A list of Canadian Association of Radiation Oncologists membership and provincial registries were used for a preliminary survey to identify radiation oncologists and physicists involved in the practice of SMBT. A detailed survey was sent electronically to individuals involved in treating with SMBT. RESULTS: Of 41 centers in Canada, 39 responded, with 7 centers indicating use of SMBT. Seven radiation oncologists and 5 physicists from 6 of 7 treating centers responded to the detailed survey, with an overall 75% individual response rate (12/16). General agreement was found regarding indications for SMBT which included irregular or curved surfaces, avoidance of deep structures, and requirement for small fields. There was consensus regarding some contraindications for SMBT such as tumor depth and size. Hypofractionated schedules were used in 5 of 6 centers and doses ranged from 50 Gy in 5 fractions once per week to 30 Gy in 10 fractions twice a day over 5 days. The most common dosimetric parameters for plan evaluation included D90, D95, D100, and maximum skin dose. CONCLUSIONS: A minority of Canadian centers practice SMBT. In centers practicing SMBT, general agreement exists on general indications for its use. Given the wide variation in dose and fractionation used and the rarity of the indication a phase 2 Canadian protocol would be invaluable.

Brachytherapy practice across Canada: A survey of workforce and barriers.

PURPOSE: To determine the current use of brachytherapy, characteristics of the brachytherapy workforce, and barriers to development and maintenance of brachytherapy programs across Canada. METHODS AND MATERIALS: A survey was designed to inquire about the use of brachytherapy and was sent to all Canadian radiation oncologists. RESULTS: Of the 116 respondents, we identified 80 radiation oncologists from 33 of 41 responding centers who currently or in the past have practiced brachytherapy. Responses were received from 30% overall and 80% of provinces. Approximately 58% of the respondents treat in one site with brachytherapy, whereas 12% treat in three or more sites. Gynecologic (GYN) and genitourinary are the most commonly treated sites (49% of respondents). For all sites, there was a large range in the number of patients treated with brachytherapy by each radiation oncologist per year (i.e., cervix: 1-50). Approximately 49% of the respondents have discontinued practicing brachytherapy for a certain site, most commonly head and neck (28%), GYN (25%), and bronchus (24%). The most common reasons include reassignment or lack of a local program. The most common reasons why brachytherapy is not used for sites other than GYN and prostate include lack of infrastructure and insufficient training of radiation oncologists rather than insufficient patient numbers or lack of evidence for a benefit of brachytherapy. CONCLUSIONS: Within its limitations, our study suggests a mismatch between demand and availability of brachytherapy programs across Canada. In light of finite resources, a rational approach to investment in brachytherapy is needed and this must be based on a formal audit of brachytherapy demand and use.

Systematic review of dose-volume parameters in the prediction of esophagitis in thoracic radiotherapy.

PURPOSE: With dose escalation and increasing use of concurrent chemoradiotherapy, radiation esophagitis (RE) remains a common treatment-limiting acute side effect in the treatment of thoracic malignancies. The advent of 3DCT planning has enabled investigators to study esophageal dose-volume histogram (DVH) parameters as predictors of RE. The purpose of this study was to assess published dosimetric parameters and toxicity data systematically in order to define reproducible predictors of RE, both for potential clinical use, and to provide recommendations for future research in the field. MATERIALS AND METHODS: We performed a systematic literature review of published studies addressing RE in the treatment of lung cancer and thymoma. Our search strategy included a variety of electronic medical databases, textbooks and bibliographies. Both prospective and retrospective clinical studies were included. Information relating to the relationship among measured dosimetric parameters, patient demographics, tumor characteristics, chemotherapy and RE was extracted and analyzed. RESULTS: Eighteen published studies were suitable for analysis. Eleven of these assessed acute RE, while the remainder assessed both acute and chronic RE together. Heterogeneity of esophageal contouring practices, individual differences in information reporting and variability of RE outcome definitions were assessed. Well-described clinical and logistic modeling directly related V(35Gy), V(60Gy) and SA(55Gy) to clinically significant RE. CONCLUSIONS: Several reproducible dosimetric parameters exist in the literature, and these may be potentially relevant in the prediction of RE in the radiotherapy of thoracic malignancies. Further clarification of the predictive relationship between such standardized dosimetric parameters and observed RE outcomes is essential to develop efficient radiation treatment planning in locally advanced NSCLC in the modern concurrent chemotherapy and image-guided IMRT era.

The Winchester falls project: a randomised controlled trial of secondary prevention of falls in older people.

BACKGROUND: the mortality and morbidity of falls in older people is significant, with recurrent fallers being at an increased risk. The most effective way to reduce falls in this group is not clear. OBJECTIVE: to determine the effectiveness of two interventions, one based in primary care and the other in secondary care, at preventing further falls in recurrent fallers. DESIGN: cluster randomised controlled trial. PARTICIPANTS: sixty-five years or over, living in the community, two or more falls in the previous year and not presenting to an emergency department with index fall. SETTING: Mid Hampshire, UK. INTERVENTION: eighteen general practices were randomly allocated to one of three groups. The primary care group was assessed by nurses in the community, using a risk factor review and subsequent targeted referral to other professionals. The secondary care group received a multi-disciplinary assessment in a day hospital followed by identified appropriate interventions. The control group received usual care. Follow-up was for 1 year. RESULTS: five hundred and five participants were recruited. Follow-up was completed in 83% (421/505). The proportion of participants who fell again was significantly lower in the secondary care group (75%, 158/210) compared to the control group [84%, 133/159, adjusted odds ratio (OR) 0.52 (95% CI 0.35-0.79) P = 0.002]. The primary care group showed similar results to the control group [87%, 118/136, adjusted OR 1.17 (95% CI 0.57-2.37) P = 0.673]. CONCLUSION: a structured multi-disciplinary assessment of recurrent fallers significantly reduced the number experiencing further falls, but a community-based nurse-led assessment with targeted referral to other professionals did not.

The 'human revolution' in lowland tropical Southeast Asia: the antiquity and behavior of anatomically modern humans at Niah Cave (Sarawak, Borneo).

Recent research in Europe, Africa, and Southeast Asia suggests that we can no longer assume a direct and exclusive link between anatomically modern humans and behavioral modernity (the 'human revolution'), and assume that the presence of either one implies the presence of the other: discussions of the emergence of cultural complexity have to proceed with greater scrutiny of the evidence on a site-by-site basis to establish secure associations between the archaeology present there and the hominins who created it. This paper presents one such case study: Niah Cave in Sarawak on the island of Borneo, famous for the discovery in 1958 in the West Mouth of the Great Cave of a modern human skull, the 'Deep Skull,' controversially associated with radiocarbon dates of ca. 40,000 years before the present. A new chronostratigraphy has been developed through a re-investigation of the lithostratigraphy left by the earlier excavations, AMS-dating using three different comparative pre-treatments including ABOX of charcoal, and U-series using the Diffusion-Absorption model applied to fragments of bones from the Deep Skull itself. Stratigraphic reasons for earlier uncertainties about the antiquity of the skull are examined, and it is shown not to be an 'intrusive' artifact. It was probably excavated from fluvial-pond-desiccation deposits that accumulated episodically in a shallow basin immediately behind the cave entrance lip, in a climate that ranged from times of comparative aridity with complete desiccation, to episodes of greater surface wetness, changes attributed to regional climatic fluctuations. Vegetation outside the cave varied significantly over time, including wet lowland forest, montane forest, savannah, and grassland. The new dates and the lithostratigraphy relate the Deep Skull to evidence of episodes of human activity that range in date from ca. 46,000 to ca. 34,000 years ago. Initial investigations of sediment scorching, pollen, palynomorphs, phytoliths, plant macrofossils, and starch grains recovered from existing exposures, and of vertebrates from the current and the earlier excavations, suggest that human foraging during these times was marked by habitat-tailored hunting technologies, the collection and processing of toxic plants for consumption, and, perhaps, the use of fire at some forest-edges. The Niah evidence demonstrates the sophisticated nature of the subsistence behavior developed by modern humans to exploit the tropical environments that they encountered in Southeast Asia, including rainforest.

High-resolution intravital NADH fluorescence microscopy allows measurements of tissue bioenergetics in rat ileal mucosa.

OBJECTIVES: NADH fluorescence microscopy has been used as an index of the metabolic state of tissue but is associated with various obstacles such as low spatial resolution and quenching effects of blood pigments that prevent reliable monitoring of tissue bioenergetics. The objective of this study was to develop a system to monitor tissue bioenergetics in vivo using NADH fluorescence microscopy in the rat ileal mucosa. MATERIALS AND METHODS: Using an inverted microscope with an epifluorescence unit and an intensified charge-coupled device camera, NADH fluorescence images were visualized. Fluorescence intensity was measured of beta-NADH solutions at varying concentration (n = 6) and pH (n = 3) and in ex vivo (n = 6) and in vivo (n = 6) preparations of ileal mucosa of Sprague-Dawley rats anesthetized with isoflurane. RESULTS: Intravital fluorescence microscopy reveals a map of the microcirculation that permits visualization of NADH fluorescence and intercapillary areas. The system was adjusted so a linear relationship between physiological concentrations of beta-NADH and fluorescence was achieved (r(2) = 0.98, p < .0001). Decreasing the pH of the solution had no effect on fluorescence intensity and fluorescence intensity in an anoxic ex vivo ileal segment was similar to that of the in vivo ileum after ischemia. Ischemia also resulted in spatial heterogeneity that was abolished by the addition of a 550-nm LP filter. CONCLUSIONS: With this system, intravital NADH fluorescence microscopy provides the high resolution necessary to reliably monitor tissue bioenergetics in the rat ileal mucosa.

Tissue bioenergetics and microvascular perfusion are impaired in rat ileal mucosa in normotensive sepsis.

OBJECTIVE: Sepsis is a systemic inflammatory response to a bacterial infection. Inflammation may result in injury to the small bowel and an increase in translocation of bacteria and toxins across the mucosal barrier, which may contribute to the progression of sepsis. Microcirculatory perfusion or cytopathic hypoxia may cause impairment of tissue bioenergetics and injury in sepsis. The objective of this study was to determine if sepsis is associated with microcirculatory hypoperfusion and impaired tissue bioenergetics in the ileal mucosa. MATERIALS AND METHODS: Sprague-Dawley rats were randomized to cecal ligation and perforation (sepsis group, n = 12) or control group (n = 14) and received arterial and venous catheters and fluid resuscitation. Following 24 h, rats were anesthetized with isoflurane and the ileum was prepared for intravital microscopy. Images of NADH fluorescence, which is an index of tissue bioenergetics, central arterial diameter, red cell velocity, red cell flux, and average intercapillary area, were recorded in 6-9 villi in each rat. RESULTS: Central arterial red cell flux (control 277 +/- 30 cell/s, sepsis 108 +/- 13 cells/s, p < .05), diameter (control 10.4 +/- 0.4 microm, sepsis 8.2 +/- 0.3 microm, p < .05) and red cell velocity (control 590 +/- 47 microm/s, sepsis 449 +/- 63 microm/s, p < .05) were decreased while average intercapillary area (control 815 +/- 171 microm(2), sepsis 1412 +/- 364 microm(2), p < .05) and NADH fluorescence (control 116 +/- 6 AIU, sepsis 154 +/- 9 AIU, p < .05) were increased at the villus tip in the sepsis group. CONCLUSION: Sepsis is associated with bioenergetic impairment and capillary hypoperfusion at the villus tip and a decrease in red cell flux in the central arteriole.