Is the IROC H&N credentialing phantom an effective surrogate for different anatomical sites?: Using IROC's H&N phantom for various sites.

PURPOSE: The IROC head and neck phantom is used to credential institutions for IMRT delivery for all anatomical sites where delivery of modulated therapy is a primary challenge. This study evaluated how appropriate the use of this phantom is for varied clinical anatomy by evaluating how closely the IROC head and neck phantom described clinical dose errors from beam modeling compared to various anatomical sites. METHODS: The MLC offset, transmission, PDD and seven additional beam modeling parameters for a Varian accelerator were modified in RayStation to match community data at the 2.5, 25, 50, 75 and 97.5 percentile levels. Modifications were evaluated on 25 H&N phantom cases and 25 clinical cases (H&N, prostate, lung, mesothelioma, and brain), generating 2,000 plan perturbations. Differences in mean dose delivered to clinical target volumes (CTV) and organs at risk (OAR) were compared between phantom and clinical plans to assess the relationship between dose deviations in phantom versus clinical CTVs, and as a function of 18 different complexity metrics. RESULTS: Perturbations to MLC offset and transmission parameters demonstrated the greatest impact on dose accuracy for phantom and clinical plans (for all anatomic sites). The phantom demonstrated equivalent or greater sensitivity to these parameter perturbations when compared to clinical sites, largely aligning with treatment complexity. The mean MLC Gap best described the impact of errors in TPS beam modeling parameters in phantoms plan and clinical plans from various anatomical sites. CONCLUSION: When compared across various anatomical sites, the IROC H&N credentialing phantom exhibited similar or greater sensitivity to errors in the treatment planning system. As such, it is a suitable surrogate device for assessing institutional performance across various anatomical sites. If an institution successfully irradiates the phantom, that result confers confidence that IMRT to a wide range of anatomical sites can be successfully delivered by the institution.

A real-time contouring feedback tool for consensus-based contour training.

Purpose: Variability in contouring structures of interest for radiotherapy continues to be challenging. Although training can reduce such variability, having radiation oncologists provide feedback can be impractical. We developed a contour training tool to provide real-time feedback to trainees, thereby reducing variability in contouring. Methods: We developed a novel metric termed localized signed square distance (LSSD) to provide feedback to the trainee on how their contour compares with a reference contour, which is generated real-time by combining trainee contour and multiple expert radiation oncologist contours. Nine trainees performed contour training by using six randomly assigned training cases that included one test case of the heart and left ventricle (LV). The test case was repeated 30 days later to assess retention. The distribution of LSSD maps of the initial contour for the training cases was combined and compared with the distribution of LSSD maps of the final contours for all training cases. The difference in standard deviations from the initial to final LSSD maps, ΔLSSD, was computed both on a per-case basis and for the entire group. Results: For every training case, statistically significant ΔLSSD were observed for both the heart and LV. When all initial and final LSSD maps were aggregated for the training cases, before training, the mean LSSD ([range], standard deviation) was -0.8 mm ([-37.9, 34.9], 4.2) and 0.3 mm ([-25.1, 32.7], 4.8) for heart and LV, respectively. These were reduced to -0.1 mm ([-16.2, 7.3], 0.8) and 0.1 mm ([-6.6, 8.3], 0.7) for the final LSSD maps during the contour training sessions. For the retention case, the initial and final LSSD maps of the retention case were aggregated and were -1.5 mm ([-22.9, 19.9], 3.4) and -0.2 mm ([-4.5, 1.5], 0.7) for the heart and 1.8 mm ([-16.7, 34.5], 5.1) and 0.2 mm ([-3.9, 1.6],0.7) for the LV. Conclusions: A tool that uses real-time contouring feedback was developed and successfully used for contour training of nine trainees. In all cases, the utility was able to guide the trainee and ultimately reduce the variability of the trainee's contouring.

Our Experience Leading a Large Medical Physics Practice During the COVID-19 Pandemic.

PURPOSE: To provide a series of suggestions for other Medical Physics practices to follow in order to provide effective radiation therapy treatments during the COVID-19 pandemic. METHODS AND MATERIALS: We reviewed our entire Radiation Oncology infrastructure to identify a series of workflows and policy changes that we implemented during the pandemic that yielded more effective practices during this time. RESULTS: We identified a structured list of several suggestions that can help other Medical Physics practices overcome the challenges involved in delivering high quality radiotherapy services during this pandemic. CONCLUSIONS: Our facility encompasses 4 smaller Houston Area Locations (HALs), a main campus with 8 distinct services based on treatment site (ie. Thoracic, Head and Neck, Breast, Gastrointestinal, Gynecology, Genitourinary, Hematologic Malignancies, Melanoma and Sarcoma and Central Nervous System/Pediatrics), a Proton Center facility, an MR-Linac, a Gamma Knife clinic and an array of brachytherapy services. Due to the scope of our services, we have gained experience in dealing with the rapidly changing pandemic effects on our clinical practice. Our paper provides a resource to other Medical Physics practices in search of workflows that have been resilient during these challenging times.

Implementation of a stereotactic body radiotherapy program for unresectable pancreatic cancer in an integrated community academic radiation oncology satellite network.

With increasing interest in stereotactic body radiotherapy (SBRT) for unresectable pancreatic cancer, quality improvement (QI) initiatives to develop integrated clinical workflows are crucial to ensure quality assurance (QA) when introducing this challenging technique into radiation practices. MATERIALS/METHODS: In 2017, we used the Plan, Do, Study, Act (PDSA) QI methodology to implement a new pancreas SBRT program in an integrated community radiation oncology satellite. A unified integrated information technology infrastructure was used to virtually integrate the planned workflow into the community radiation oncology satellite network (P - Plan/D - Do). This workflow included multiple prospective quality assurance (QA) measures including multidisciplinary evaluation, prospective scrutiny of radiation target delineation, prospective radiation plan evaluation, and monitoring of patient outcomes. Institutional review board approval was obtained to retrospectively study and report outcomes of patients treated in this program (S - Study). RESULTS: There were 12 consecutive patients identified who were treated in this program from 2017 to 2020 with a median follow-up of 27 months. The median survival was 13 months, median local failure free survival was 12 months and median progression free survival was 6 months from SBRT. There were no acute or late Common Terminology Criteria for Adverse Effects (CTCAE) version 5 toxicities ≥ Grade 3. CONCLUSION: We report the successful implementation of a community pancreas SBRT program involving multiple prospective QA measures, providing the groundwork to safely expand access to pancreas SBRT in our community satellite network (A - Act).

Prospective Comparison of Toxicity and Cosmetic Outcome After Accelerated Partial Breast Irradiation With Conformal External Beam Radiotherapy or Single-Entry Multilumen Intracavitary Brachytherapy.

PURPOSE: This study aimed to prospectively characterize toxicity and cosmesis after accelerated partial breast irradiation (APBI) with 3-dimensional conformal radiation therapy (CRT) or single-entry, multilumen, intracavitary brachytherapy. METHODS AND MATERIALS: A total of 281 patients with pTis, pT1N0, or pT2N0 (≤3.0 cm) breast cancer treated with segmental mastectomy were prospectively enrolled from December 2008 through August 2014. APBI was delivered using 3-dimensional CRT (n = 29) or with SAVI (n = 176), Contura (n = 56), or MammoSite (n = 20) brachytherapy catheters. Patients were evaluated at protocol-specified intervals, at which time the radiation oncologist scored cosmetic outcome, toxicities, and recurrence status using a standardized template. RESULTS: The median follow-up time is 41 months. Grade 1 seroma and fibrosis were more common with brachytherapy than with 3-dimensional CRT (50.4% vs 3.4% for seroma; P < .0001 and 66.3% vs 44.8% for fibrosis; P = .02), but grade 1 edema was more common with 3-dimensional CRT than with brachytherapy (17.2% vs 5.6%; P = .04). Grade 2 to 3 pain was more common with 3-dimensional CRT (17.2% vs 5.2%; P = .03). Actuarial 5-year rates of fair or poor radiation oncologist-reported cosmetic outcome were 9% for 3-dimensional CRT and 24% for brachytherapy (P = .13). Brachytherapy was significantly associated with inferior cosmesis on mixed model analysis (P = .003). Significant predictors of reduced risk of adverse cosmetic outcome after brachytherapy were D0.1cc (skin) ≤102%, minimum skin distance >5.1 mm, dose homogeneity index >0.54, and volume of nonconformance ≤0.89 cc. The 5-year ipsilateral breast recurrence was 4.3% for brachytherapy and 4.2% for 3-dimensional CRT APBI patients (P = .95). CONCLUSIONS: Brachytherapy APBI is associated with higher rates of grade 1 fibrosis and seroma than 3-dimensional CRT but lower rates of grade 1 edema and grade 2 to 3 pain than 3-dimensional CRT. Rates of radiation oncologist-reported fair or poor cosmetic outcomes are higher with brachytherapy. We identified dosimetric parameters that predict reduced risk of adverse cosmetic outcome after brachytherapy-based APBI. Ipsilateral breast recurrence was equivalent for brachytherapy and 3-dimensional CRT.

Lower mean heart dose with deep inspiration breath hold-whole breast irradiation compared with brachytherapy-based accelerated partial breast irradiation for women with left-sided tumors.

PURPOSE: For left-sided breast cancer, radiation to the heart is a concern. We present a comparison of mean heart and coronary artery biologically effective dose (BED) between accelerated partial breast irradiation (APBI) and whole breast irradiation with deep inspiration breath-hold technique (DIBH-WBI). METHODS AND MATERIALS: A total of 100 patients with left-sided, early-stage breast cancer were identified. Fifty underwent single-entry catheter-based APBI and 50 underwent DIBH-WBI. The heart, left anterior descending/interventricular branch, left main, and right coronary artery were delineated. BEDs were calculated from APBI treatment plans (34 Gy in 3.4 Gy twice daily fractions) and for 4 separate plans generated for each DIBH-WBI patient: 50 Gy in 25 fractions (50/25), 50/25 + 10/5 boost, 40/15, and 40/15 + 10/5 boost. RESULTS: BED to the heart and coronary vessels were statistically significantly higher with APBI than with any of the DIBH-WBI dose/fractionation schedules. CONCLUSIONS: For women with left-sided early-stage breast cancer, DIBH-WBI resulted in statistically significantly lower mean BED to the heart and coronary vessels compared with APBI. This is likely due to increased physical separation between the heart and tumor bed afforded by the DIBH-WBI technique. Long-term assessment of late effects in these tissues will be required to determine whether these differences are clinically significant.

Contralateral breast dose from partial breast brachytherapy.

The purpose of this study was to determine the dose to the contralateral breast during accelerated partial breast irradiation (APBI) and to compare it to external beam-published values. Thermoluminescent dosimeter (TLD) packets were used to measure the dose to the most medial aspect of the contralateral breast during APBI simulation, daily quality assurance (QA), and treatment. All patients in this study were treated with a single-entry, multicatheter device for 10 fractions to a total dose of 34 Gy. A mark was placed on the patient's skin on the medial aspect of the opposite breast. Three TLD packets were taped to this mark during the pretreatment simulation. Simulations consisted of an AP and Lateral scout and a limited axial scan encompassing the lumpectomy cavity (miniscan), if rotation was a concern. After the simulation the TLD packets were removed and the patients were moved to the high-dose-rate (HDR) vault where three new TLD packets were taped onto the patients at the skin mark. Treatment was administered with a Nucletron HDR afterloader using Iridium-192 as the treatment source. Post-treatment, TLDs were read (along with the simulation and QA TLD and a set of standards exposed to a known dose of 6 MV photons). Measurements indicate an average total dose to the contralateral breast of 70 cGy for outer quadrant implants and 181 cGy for inner quadrant implants. Compared to external beam breast tangents, these results point to less dose being delivered to the contralateral breast when using APBI.

Commissioning results of an automated treatment planning verification system.

A dose calculation verification system (VS) was acquired and commissioned as a second check on the treatment planning system (TPS). This system reads DICOM CT datasets, RT plans, RT structures, and RT dose from the TPS and automatically, using its own collapsed cone superposition/convolution algorithm, computes dose on the same CT dataset. The system was commissioned by extracting basic beam parameters for simple field geometries and dose verification for complex treatments. Percent depth doses (PDD) and profiles were extracted for field sizes using jaw settings 3 × 3 cm2 - 40 × 40 cm2 and compared to measured data, as well as our TPS model. Smaller fields of 1 × 1 cm2 and 2 × 2 cm2 generated using the multileaf collimator (MLC) were analyzed in the same fashion as the open fields. In addition, 40 patient plans consisting of both IMRT and VMAT were computed and the following comparisons were made: 1) TPS to the VS, 2) VS to measured data, and 3) TPS to measured data where measured data is both ion chamber (IC) and film measurements. Our results indicated for all field sizes using jaw settings PDD errors for the VS on average were less than 0.87%, 1.38%, and 1.07% for 6x, 15x, and 18x, respectively, relative to measured data. PDD errors for MLC field sizes were less than 2.28%, 1.02%, and 2.23% for 6x, 15x, and 18x, respectively. The infield profile analysis yielded results less than 0.58% for 6x, 0.61% for 15x, and 0.77% for 18x for the VS relative to measured data. Analysis of the penumbra region yields results ranging from 66.5% points, meeting the DTA criteria to 100% of the points for smaller field sizes for all energies. Analysis of profile data for field sizes generated using the MLC saw agreement with infield DTA analysis ranging from 68.8%-100% points passing the 1.5%/1.5 mm criteria. Results from the dose verification for IMRT and VMAT beams indicated that, on average, the ratio of TPS to IC and VS to IC measurements was 100.5 ± 1.9% and 100.4 ± 1.3%, respectively, while our TPS to VS was 100.1 ± 1.0%. When comparing the TPS and VS to film measurements, the average percentage pixels passing a 3%/3mm criteria based gamma analysis were 96.6 ± 4.2% and 97 ± 5.6%, respectively. When the VS was compared to the TPS, on average 98.1 ± 5.3% of pixels passed the gamma analysis. Based upon these preliminary results, the VS system should be able to calculate dose adequately as a verification tool of our TPS.

Use of a newly developed delivery device for percutaneous introduction of multiple lead configurations for spinal cord stimulation.

OBJECTIVE: The Epiducer lead delivery system is a novel lead delivery device that can be used to percutaneously implant S-Series paddle leads (St. Jude Medical, Plano, TX, USA) as well as multiple percutaneous leads obviating the need for laminectomy and/or multiple needle sticks, respectively. This study evaluates the safety and usage of the Epiducer lead delivery system. METHODS: An Institutional Review Board-approved observational data collection study was conducted to evaluate usage patterns of the Epiducer system. In addition to the number and frequency of different lead configurations, the following procedural aspects of the surgery were recorded during the evaluation: angle of entry, distance from entry to final lead placement, and physician feedback. Descriptive statistics on adverse events, procedural aspects, and patient outcomes were compiled. RESULTS: Data were collected from 163 patients across 25 investigational sites. Physicians successfully implanted patients using the Epiducer during 89% of the procedures. Seven possible lead configurations were implanted. There were 96% and 92% of physicians "satisfied" or "very satisfied" with accessing the epidural space and placing multiple leads with the Epiducer delivery system, respectfully. Eighty-nine percent of physicians were "satisfied" or "very satisfied" with implanting an S-Series paddle lead using the Epiducer delivery system. Ninety-five percent of physicians were "satisfied" or "very satisfied" with the Epiducer delivery system overall. Ten patients (6%) experienced adverse events. CONCLUSION: Results suggest that the Epiducer delivery system allows for the safe and successful percutaneous implantation of paddle leads and/or multiple lead configurations. Furthermore, physicians are satisfied with the Epiducer delivery system.

Impact of neonatal NOS-1 inhibitor exposure on neurobehavioural measures and prefrontal-temporolimbic integration in the rat nucleus accumbens.

Nitric oxide (NO) is a gaseous neurotransmitter that plays a significant role in the establishment and refinement of functional neural circuits. Genetic and post-mortem studies have suggested that neuronal NO synthase (NOS-1) activity may be compromised in frontal and temporal lobes, and related structures, in schizophrenia. The goal of this study was to determine if there is a link between neonatal disruptions in NO signalling and disturbances in the development and function of prefrontal-temporolimbic circuits. Neonatal rats were injected on postnatal days PD3-5 with the selective NOS-1 inhibitor Nω-propyl-L-arginine (NPA) and tested in adulthood (≥PD60) or as juveniles (PD30). Adult rats treated with NPA as neonates exhibited increased amphetamine-induced locomotion compared to animals receiving vehicle as neonates, whereas this was not observed in juvenile rats treated with NPA as neonates. Adult rats exposed to NPA as neonates also exhibited deficits in social interaction and short-term recognition memory, as well as reduced brain weight, compared to vehicle-treated controls. Finally, neonatal NPA exposure increased the responsiveness of nucleus accumbens neurons to prefrontal cortical input and disrupted the modulation of cortico-accumbens circuits by hippocampal afferents that is normally observed in adult animals. These results show for the first time that neonatal inhibition of NOS-1 during a critical neurodevelopmental period leads to aberrant behaviours that manifest in adulthood, as well as electrophysiological abnormalities in prefrontal-temporolimbic circuits. Greater understanding of the role of NOS-1 in the development of these circuits will shed light on how developmental insults translate to pathophysiology associated with schizophrenia.

A new paradigm for calculating skin dose.

PURPOSE: Most institutions model breast epidermis with a surface contour and record the maximum dose on the external surface of the patient. The objective of this study was to compare the external surface contour (ext) model of the skin with our current volumetric model for skin for radiation treatment planning in accelerated partial breast irradiation brachytherapy. METHODS AND MATERIALS: A literature search was conducted to identify studies measuring breast epidermal thickness. Clinical plans were performed with a 2-mm contraction of the external surface contour. This 2-mm contraction of the external surface contour was used to approximate breast epidermis thickness. Then, the external surface contour was expanded 5mm outside the external contour of the patient for the second skin model. Maximum doses from the two models were recorded and compared. RESULTS: The average breast epidermal thickness from five studies was 1.68mm. Mean percent difference between skin and ext+5mm for balloon plans, strut plans, and all plans was 10.1%, 14.5%, and 12.5%, respectively. Differences in doses between the two skin models were statistically significant (p<0.0001). CONCLUSIONS: The volumetric skin model was validated because the average breast epidermal thickness was 1.68mm. The surface model for skin may underestimate the dose delivered to the epidermis by as much as 23.8%. The external surface contour method does not accurately represent the dermatologic skin thickness of the breast as the skin is modeled as a surface rather than a volume. These discrepancies may skew correlations of dose to skin and toxicity determinations.

On the feasibility of treating to a 1.5 cm PTV with a commercial single-entry hybrid applicator in APBI breast brachytherapy.

PURPOSE: To evaluate and determine whether 30 patients previously treated with the SAVI™ device could have been treated to a PTV_EVAL created with a 1.5 cm expansion. This determination was based upon dosimetric parameters derived from current recommendations and dose-response data. MATERIAL AND METHODS: Thirty patients were retrospectively planned with PTV_EVALs generated with a 1.5 cm expansion (PTV_EVAL_1.5). Plans were evaluated based on PTV_EVAL_1.5 coverage (V90, V95, V100), skin and rib maximum doses (0.1 cc maximum dose as a percentage of prescription dose), as well as V150 and V200 for the PTV_EVAL_1.5. The treatment planning goal was to deliver ≥90% of the prescribed dose to ≥90% of the PTV_EVAL_1.5. Skin and rib maximum doses were to be ≤125% of the prescription dose and preferably ≤100% of the prescription dose. V150 and V200 were not allowed to exceed 52.5 cc and 21 cc, respectively. Plans not meeting the above criteria were recomputed with a 1.25 cm expanded PTV_EVAL and re-evaluated. RESULTS: Based on the above dose constraints, 30% (9/30) of the patients evaluated could have been treated with a 1.5 cm PTV_EVAL. The breakdown of cases successfully achieving the above dose constraints by applicator was: 0/4 (0%) 6-1, 6/15 (40%) 8-1, and 3/11 (27%) 10-1. For these PTV_EVAL_1.5 plans, median V90% was 90.3%, whereas the maximum skin and rib doses were all less than 115.2% and 117.6%, respectively. The median V150 and V200 volumes were 39.2 cc and 19.3, respectively. The treated PTV_EVAL_1.5 was greater in volume than the PTV_EVAL by 41.7 cc, and 60 cc for the 8-1, and 10-1 applicators, respectively. All remaining plans (17) successfully met the above dose constraints to be treated with a 1.25 cm PTV_EVAL (PTV_EVAL_1.25). For the PTV_EVAL_1.25 plans, V90% was 93.7%, and the maximum skin and rib doses were all less than 109.2% and 102.5%, respectively. The median V150 and V200 volumes were 41.2 cc and 19.3, respectively. The treated PTV_EVAL_1.25 was greater in volume than the PTV_EVAL by 16 cc, 24.9 cc, and 33.5 cc for the 6-1, 8-1 and 10-1 applicators, respectively. CONCLUSIONS: It is dosimetrically possible to treat beyond the currently advised 1.0 cm expanded PTV_EVAL. Most patients should be able to be treated with a 1.25 cm PTV_EVAL and a select group with a 1.5 cm PTV_EVAL. Applicator size appears to determine the ability to expand to a 1.5 cm PTV_EVAL, as smaller devices were not as propitious in this regard. Further studies may identify additional patient groups that would benefit from this approach.

Behavioral sensitization to amphetamine is not accompanied by changes in glutamate receptor surface expression in the rat nucleus accumbens.

We examined whether behavioral sensitization to amphetamine is associated with redistribution of glutamate receptors (GluR) in the rat nucleus accumbens (NAc) or dorsolateral striatum (DLSTR). Following repeated amphetamine treatment and 21 days of withdrawal, surface and intracellular levels of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or NMDA receptor subunits were determined using a protein cross-linking assay. In contrast to our previous results in cocaine-sensitized rats, we did not observe redistribution of GluR1 or GluR2 to the cell surface in the NAc after amphetamine withdrawal, although a small increase in total GluR1 was found in the shell subregion. Nor did we observe activation of signaling pathways associated with cocaine-induced AMPA receptor trafficking or changes in NMDA receptor subunits. No significant changes were observed in the DLSTR. We also investigated the effect of administering a challenge injection of amphetamine to amphetamine-sensitized rats 24 h prior to biochemical analysis based on prior studies showing that cocaine challenge decreases AMPA receptor surface expression in the NAc of cocaine-sensitized rats. GluR1 and GluR2 were not significantly altered in either NAc or DLSTR, although a modest effect on GluR3 cannot be ruled out. Our results suggest that glutamate transmission in the NAc is dramatically different in rats sensitized to amphetamine versus cocaine.

Cortical cholinergic transmission and cortical information processing in schizophrenia.

Models of the neuronal mediation of psychotic symptoms traditionally have focused on aberrations in the regulation of mesolimbic dopaminergic neurons, via their telencephalic afferent connections, and on the impact of abnormal mesolimbic activity for functions of the ventral striatum and its pallidal-thalamic-cortical efferent circuitry. Repeated psychostimulant exposure models major aspects of the sensitized activity of ventral striatal dopaminergic transmission that is observed in patients exhibiting psychotic symptoms. Based on neuroanatomical, neurochemical, and behavioral data, the hypothesis that an abnormally reactive cortical cholinergic input system represents a necessary correlate of a sensitized mesolimbic dopaminergic system is discussed. Moreover, the abnormal cognitive mechanisms that contribute to the development of psychotic symptoms are attributed specifically to the aberrations in cortical cholinergic transmission and to its consequences on the top-down regulation of sensory and sensory-associational input functions. Experimental evidence from studies demonstrating repeated amphetamine-induced sensitization of cortical cholinergic transmission and the ability of antipsychotic drugs to normalize the activity of cortical cholinergic inputs, and from experiments indicating the attentional consequences of manipulations that increase the excitability of cortical cholinergic inputs, supports this hypothesis. Relevant human neuropathological and psychopharmacological data are discussed, and the implications of an abnormally regulated cortical cholinergic input system for pharmacological treatment strategies are addressed. Given the role of cortical cholinergic inputs in gating cortical information processing, even subtle changes in the regulation of this cortexwide input system that represent a necessary transsynaptic consequence of sensitized mesolimbic dopaminergic transmission profoundly contribute to the neuronal mediation of psychotic symptoms.

Murine lung tumor measurement using respiratory-gated micro-computed tomography.

OBJECTIVE: The authors explored micro-computed tomography (micro-CT) to quantify lung tumor number and volume in a specific genetic mouse model for lung cancer. MATERIALS AND METHODS: The authors used K-ras mice, which develop lung adenomas and adenocarcinomas through somatic activation of the K-ras oncogene. Tumor number measured using micro-CT and were compared at necropsy (n = 38 mice). Tumor volume measurement precision (n = 39 mice) and accuracy (multiple tumors from a single mouse) were evaluated. Serial lung tumor volume was assessed in a pilot group (n = 8) of mice in vivo. RESULTS: Tumor number assessed at necropsy and using micro-CT were significantly correlated. Lung tumor volume measurements were both reproducible (2% operator variability) and accurate (6% average error). Strikingly, we observed both tumor growth and shrinkage within individual mice. CONCLUSION: Serial measurements provided evidence of tumor heterogeneity, an unexpected finding given the uniformity of the initiating genetic event. Micro-CT may become a powerful tool for murine lung cancer research in vivo.

Neurochemical correlates of sparing from motor deficits in rats depleted of striatal dopamine as weanlings.

The behavioral and neurochemical effects of striatal DA depletions were investigated in rats lesioned as weanlings (Day 27) or as adults (250-300 g). Administration of 6-OHDA into the medial forebrain bundle resulted in comparably large (> or = 95%) depletions of tissue levels of DA in both age groups. As expected, rats depleted of DA as adults exhibited marked deficits in motoric behavior and body weight regulation that persisted for the 8 days of postsurgical observation. In contrast, rats depleted of DA as weanlings were spared from such deficits, and their behavior closely resembled that of age-matched controls. Microdialysis studies revealed dialysate levels of striatal DA that paralleled these age-dependent behavioral differences. At a time when age-related behavioral differences were still quite pronounced (5-6 days postsurgery), basal DA levels were reduced by 80% of control values in rats lesioned as adults whereas basal DA levels in rats lesioned as weanlings were unchanged relative to their controls. Finally, adults depleted of striatal DA as weanlings were no more sensitive to the movement-impairing effects of intrastriatal sulpiride (3.0 or 10.0 micrograms/hemisphere) infusions than were control rats. These data suggest that weanlings compensate for large, but incomplete, denervation of striatal DA with markedly enhanced release and turnover from residual terminals. This developmental plasticity may prevent the occurrence of behavioral deficits soon after the lesion and also the supersensitivity to the challenging effects of DA antagonists as animals grow into adulthood.

Sensitization of cortical acetylcholine release by repeated administration of nicotine in rats.

RATIONALE: The integrity of cortical cholinergic transmission is vital to attentional processing. A growing literature suggests that alterations in attentional processing accompany addictive drug use. This study examined the effects of acute and repeated administration of nicotine on cortical acetylcholine release. OBJECTIVES: The effects of repeated systemic nicotine administration on cortical acetylcholine (ACh) efflux in the frontal cortex were determined to test the hypothesis that repeated administration of nicotine results in a potentiated or sensitized increase in ACh efflux. METHODS: Animals were injected with nicotine (0.4 mg/kg, i.p.) or vehicle twice daily for 4 days. Cortical ACh efflux was measured using repeated microdialysis sampling on four occasions: on day 1, during the first exposure to nicotine or vehicle, on day 5 during a final exposure to nicotine, on day 8 during a nicotine challenge, and again on day 10 following saline administration. RESULTS: Acute nicotine administration on day 1 produced a 90% increase in cortical ACh efflux. Repeated exposure to nicotine resulted in a larger increase in cortical ACh efflux on day 5 (200%) and day 8 (210%) relative to ACh levels measured on day 1, and relative to animals that received vehicle during the initial treatment period. Cortical ACh efflux following acute nicotine administration was blocked by mecamylamine (1.0 mg/kg, i.p.). However, the sensitized efflux of cortical ACh on day 8 was only partially attenuated by mecamylamine (1.0 or 5.0 mg/kg, i.p.), suggesting a mecamylamine-insensitive component of the sensitized response to repeated nicotine administration. CONCLUSIONS: Repeated administration of nicotine results in a sensitized increase in cortical ACh release. Sensitized cortical ACh release may mediate, in part, the cognitive components of nicotine addiction.

Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats.

RATIONALE: The effects of non-competitive N-methyl- D-aspartate (NMDA) receptor antagonists model aspects of schizophrenic symptomatology. Because effects on both cortical cholinergic transmission and attentional processes have been hypothesized to represent components of the properties of psychotogenic drugs, the present study investigated the effects of ketamine on the activity of cortical cholinergic inputs and attentional performance. OBJECTIVE: To determine the effects of acute and repeated ketamine administration on cortical acetylcholine release and performance of rats in an operant task designed to assess sustained attention performance. METHODS: Experiment 1 assessed the effects of ketamine (2.0-20.0 mg/kg, i.p.) on medial prefrontal acetylcholine release using in vivo microdialysis. In experiment 2, animals were pretreated with 2.0 mg/kg or 25.0 mg/kg ketamine for 7 days. Cortical acetylcholine release was assessed in these rats following the subsequent administration of a 'challenge' dose of 2.0 mg/kg on days 1, 8, and 15 following completion of the pretreatment regimen. Experiment 3 assessed the effects of acute ketamine administration (2.0, 4.0, and 8.0 mg/kg, i.p.) on sustained attention performance. In experiment 4, animals trained in the sustained attention task were pretreated with 25.0 mg/kg ketamine or vehicle for 7 days. In these animals, the performance effects of 2.0 mg/kg ketamine administered 1, 8, or 15 days after completion of the pretreatment regimen were assessed. RESULTS: The acute administration of ketamine dose dependently increased cortical acetylcholine release by up to 250% above baseline and for over 40 min following the highest dose of ketamine. Pretreatment with 2.0 mg or 25.0 mg/kg did not robustly alter the effects of subsequent ketamine administration on cortical acetylcholine release. In animals performing the sustained attention task, administration of the highest dose of ketamine resulted in high levels of errors of omission, while the administration of the two smaller doses did not affect performance. Pretreatment with 25.0 mg/kg disrupted the attentional performance during the pretreatment period, but it did not affect the baseline performance thereafter. Furthermore, ketamine pretreatment did not systematically alter the performance effects of subsequent ketamine administration. CONCLUSIONS: The robust stimulation of cortical acetylcholine release represents a potent component of the pharmacological effects of ketamine. The effects of acute ketamine on attentional performance were limited to high rates of omissions. Repeated ketamine administration 'sensitized' neither cortical acetylcholine release nor attentional performance. These effects of repeated ketamine differ substantially from those of another major psychotogenic drug, amphetamine, and thus support the view that ketamine and amphetamine model fundamentally different aspects of schizophrenia.