Timing of Urgent Inpatient Palliative Radiation Therapy.

PURPOSE: Urgent indications for palliative radiation therapy (RT) include malignant spinal cord compression, symptomatic brain metastases, pain, airway obstruction, and bleeding. Data on the timing of palliative RT in the inpatient setting are limited. We report our experience with inpatient palliative RT at a tertiary academic center and evaluate the effect of a dedicated inpatient palliative RT nurse practitioner (NP) on treatment timelines. METHODS AND MATERIALS: We performed a retrospective, single-institution review of 219 inpatients consulted for RT to sites of metastatic disease between May 2012 and May 2018. We compared time-to-treatment intervals before and after integrating an NP for palliative RT in August 2017. RESULTS: The median age of the 219 patients receiving RT was 61 years (interquartile range [IQR], 51-69 years). The most frequent indications were symptomatic brain metastases (73 patients [33%]), pain (61 patients [28%]), and cord/cauda compression (48 patients [22%]). The median time from consultation request to consult was 1 day (IQR, 0-2 days), and the median time from consultation request to first RT fraction was 3 days (IQR, 2-6 days). The median time from consultation request to RT was shorter for cord compression (2 [IQR, 1-4] days) than for pain (5 [IQR, 2-7] days) (P = .001) or symptomatic brain metastases (3 [IQR, 1-6] days; P = .037). With an NP, patients were more likely to undergo same-day consultation and simulation (75% vs 60%; P = .045), which was associated with shorter median duration from consultation to initiation of RT (1 [IQR, 0-3] days vs 4 [IQR, 2-7] days; P <.001). After the integration of an NP for palliative RT, patients had a higher median Karnofsky Performance Score (70 [IQR, 60-80] vs 50 [IQR, 40-60]; P < .001) and were more likely to complete their prescribed RT course (93% vs 82%; P = .05). CONCLUSIONS: Time from consultation request to RT is necessarily short for urgent inpatient palliative RT. Advanced practice providers may facilitate and potentially expedite treatment, with significantly shorter times to treatment among patients who undergo same-day consultation and simulation.

High-dose-rate interstitial brachytherapy for vaginal endometrial cancer recurrence after prior surgery and radiotherapy.

PURPOSE: Characterize the clinical outcomes of endometrial cancer vaginal recurrences after previous surgery and radiation therapy treated with reirradiation including image-guided interstitial high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: A single-institution retrospective study identifying women receiving reirradiation for vaginal recurrence of endometrial cancer between 2004 and 2017. RESULTS: Twenty-three women had vaginal recurrences of endometrial cancer, median 13.7 months (range 3.5-104.9) from initial radiation. All received reirradiation with interstitial HDR brachytherapy, and seven also received external beam radiation. Median reirradiation EQD2_10 was 48 Gy (range 24.0-68.81), and median cumulative EQD2_10 was 106.25 Gy (range 62.26-122.0). Median follow-up after reirradiation was 40.2 months (range 4.5-112.7). At 3 years, overall survival was 56%, cancer-specific survival was 61%, and disease-free survival was 46%. 14 patients experienced disease recurrence; 10 including distant sites, one at a regional node only. Three patients experienced local recurrences, two of whom did not complete the prescribed course of reirradiation. The overall crude local control rate was 87%. Three patients experienced Grade 3 vaginal toxicity. There was no bladder or rectal toxicity with Grade >2. CONCLUSIONS: Reirradiation including interstitial HDR brachytherapy is a promising option for vaginal recurrences of endometrial cancer after prior radiation, with high rate of local control and acceptable toxicity. However, distant failure is common. Further studies are needed to determine cumulative radiation dose limits and the role of systemic therapy in this scenario.

Improved Tumor Control Related to Radiotherapy Technological Development for Hypopharyngeal Cancer.

OBJECTIVES/HYPOTHESIS: Squamous cell carcinoma of the hypopharynx (SCCHP) is associated with worse survival compared to other head and neck subsites. This report quantifies the impact of technological improvements in radiotherapy (RT) on outcomes over 6 decades. METHODS: Patients with SCCHP receiving curative-intent treatment between 1962 and 2015 were retrospectively reviewed. Kaplan-Meier analyses of freedom from local recurrence (FFLR), progression-free survival (PFS), and overall survival (OS) were compared across treatment eras and radiation techniques. Multivariable Cox proportional hazards modeling was performed to specify the effect of RT technique. RESULTS: One hundred thirty-four patients had a median follow-up of 17 months (IQR = 9-38). There were no differences in staging or use of surgery over time, but use of chemotherapy concurrent with RT increased (P < .001) beginning in the 2000s. The 24-month FFLR using two-dimensional RT (2D-RT), three-dimensional conformal RT (3D-CRT), and intensity-modulated RT (IMRT) was 52%, 55%, and 80%, respectively; 24-month PFS was 39%, 46%, and 73%, respectively; and 24-month OS was 27%, 40%, and 68%, respectively. OS (P = .01), PFS (P = .03), and FFLR (P = 0.02) were improved with IMRT over 2D-RT, and FFLR appeared to be improved over 3D-CRT (P = .06). Controlling for chemotherapy use and other major variables, IMRT produced a strong influence over FFLR (adjusted hazard ratio [HR] = 0.2, 95% confidence interval [CI]: 0.0-1.2, P = .08) and a benefit in OS (adjusted HR = 0.1, 95% CI: 0.0-0.4, P = .005). CONCLUSIONS: Across 6 decades, patient and tumor characteristics remained similar whereas use of chemoradiation increased and IMRT was adopted. The introduction of IMRT was associated with improved FFLR, PFS, and OS, and a reduction in acute toxicity as compared to earlier radiation technologies. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E452-E458, 2021.

Reirradiation of recurrent high-grade glioma and development of prognostic scores for progression and survival.

BACKGROUND: Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores. METHODS: A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients. RESULTS: Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively. CONCLUSIONS: Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.

Phase I study of dose escalation to dominant intraprostatic lesions using high-dose-rate brachytherapy.

PURPOSE: Radiation dose escalation for prostate cancer improves biochemical control but is limited by toxicity. Magnetic resonance spectroscopic imaging (MRSI) can define dominant intraprostatic lesions (DIL). This phase I study evaluated dose escalation to MRSI-defined DIL using high-dose-rate (HDR) brachytherapy. MATERIAL AND METHODS: Enrollment was closed early due to low accrual. Ten patients with prostate cancer (T2a-3b, Gleason 6-9, PSA < 20) underwent pre-treatment MRSI, and eight patients had one to three DIL identified. The eight enrolled patients received external beam radiation therapy to 45 Gy and HDR brachytherapy boost to the prostate of 19 Gy in 2 fractions. MRSI images were registered to planning CT images and DIL dose-escalated up to 150% of prescription dose while maintaining normal tissue constraints. The primary endpoint was genitourinary (GU) toxicity. RESULTS: The median total DIL volume was 1.31 ml (range, 0.67-6.33 ml). Median DIL boost was 130% of prescription dose (range, 110-150%). Median urethra V120 was 0.15 ml (range, 0-0.4 ml) and median rectum V75 was 0.74 ml (range, 0.1-1.0 ml). Three patients had acute grade 2 GU toxicity, and two patients had late grade 2 GU toxicity. No patients had grade 2 or higher gastrointestinal toxicity, and no grade 3 or higher toxicities were noted. There were no biochemical failures with median follow-up of 4.9 years (range, 2-8.5 years). CONCLUSIONS: Dose escalation to MRSI-defined DIL is feasible. Toxicity was low but incompletely assessed due to limited patients' enrollment.

Influence of respiratory motion management technique on radiation pneumonitis risk with robotic stereotactic body radiation therapy.

PURPOSE/OBJECTIVES: For lung stereotactic body radiation therapy (SBRT), real-time tumor tracking (RTT) allows for less radiation to normal lung compared to the internal target volume (ITV) method of respiratory motion management. To quantify the advantage of RTT, we examined the difference in radiation pneumonitis risk between these two techniques using a normal tissue complication probability (NTCP) model. MATERIALS/METHOD: 20 lung SBRT treatment plans using RTT were replanned with the ITV method using respiratory motion information from a 4D-CT image acquired at the original simulation. Risk of symptomatic radiation pneumonitis was calculated for both plans using a previously derived NTCP model. Features available before treatment planning that identified significant increase in NTCP with ITV versus RTT plans were identified. RESULTS: Prescription dose to the planning target volume (PTV) ranged from 22 to 60 Gy in 1-5 fractions. The median tumor diameter was 3.5 cm (range 2.1-5.5 cm) with a median volume of 14.5 mL (range 3.6-59.9 mL). The median increase in PTV volume from RTT to ITV plans was 17.1 mL (range 3.5-72.4 mL), and the median increase in PTV/lung volume ratio was 0.46% (range 0.13-1.98%). Mean lung dose and percentage dose-volumes were significantly higher in ITV plans at all levels tested. The median NTCP was 5.1% for RTT plans and 8.9% for ITV plans, with a median difference of 1.9% (range 0.4-25.5%, pairwise P < 0.001). Increases in NTCP between plans were best predicted by increases in PTV volume and PTV/lung volume ratio. CONCLUSIONS: The use of RTT decreased the risk of radiation pneumonitis in all plans. However, for most patients the risk reduction was minimal. Differences in plan PTV volume and PTV/lung volume ratio may identify patients who would benefit from RTT technique before completing treatment planning.

Salvage high-dose-rate brachytherapy and external beam radiotherapy for isolated vaginal recurrences of endometrial cancer with no prior adjuvant therapy.

PURPOSE: To evaluate clinical outcomes for isolated vaginal recurrence of endometrial cancer without adjuvant therapy treated with salvage external beam radiation therapy (EBRT) and high-dose-rate CT-based inverse-planned brachytherapy. METHODS AND MATERIALS: Thirty women were included in this retrospective study. Median time to first recurrence was 16.7 months, and median age at recurrence was 73 years. Initial grade was 1 or 2 in 19 patients (63%), and 2009 FIGO stage IA in 19 patients. All patients received pelvic EBRT in 1.8 Gy daily fractions to a total of 45 or 50.4 Gy. Interstitial brachytherapy was used in 27 patients (90%). The median total EQD2 dose was 68.3 Gy. Kaplan-Meier estimates of overall survival (OS), cause-specific survival (CSS), progression free survival (PFS), locoregional failure-free survival, and distant failure-free survival (DFFS) were calculated. RESULTS: Median follow-up was 76.4 months for vital status and 57.7 months for disease status after salvage therapy. The 5-year OS, CSS, PFS, locoregional failure-free survival, and DFFS after salvage therapy were 77%, 83%, 75%, 87%, and 86%. Initial high-grade disease was prognostic for OS, CSS, and DFFS (5-year OS 95% vs. 29%, p = 0.005). Initial stage beyond IA was prognostic for CSS, PFS, and DFFS (5-year CSS 93% vs. 74%, p = 0.025). CONCLUSIONS: Salvage EBRT and high-dose-rate brachytherapy resulted in a high rate of locoregional control. Initial high-grade and advanced stage disease were associated with greater distant failure and cancer-related mortality after salvage therapy.

Effect of the Maximum Dose on White Matter Fiber Bundles Using Longitudinal Diffusion Tensor Imaging.

PURPOSE: Previous efforts to decrease neurocognitive effects of radiation focused on sparing isolated cortical structures. We hypothesize that understanding temporal, spatial, and dosimetric patterns of radiation damage to whole-brain white matter (WM) after partial-brain irradiation might also be important. Therefore, we carried out a study to develop the methodology to assess radiation therapy (RT)-induced damage to whole-brain WM bundles. METHODS AND MATERIALS: An atlas-based, automated WM tractography analysis was implemented to quantify longitudinal changes in indices of diffusion tensor imaging (DTI) of 22 major WM fibers in 33 patients with predominantly low-grade or benign brain tumors treated by RT. Six DTI scans per patient were performed from before RT to 18 months after RT. The DTI indices and planned doses (maximum and mean doses) were mapped onto profiles of each of 22 WM bundles. A multivariate linear regression was performed to determine the main dose effect as well as the influence of other clinical factors on longitudinal percentage changes in axial diffusivity (AD) and radial diffusivity (RD) from before RT. RESULTS: Among 22 fiber bundles, AD or RD changes in 12 bundles were affected significantly by doses (P<.05), as the effect was progressive over time. In 9 elongated tracts, decreased AD or RD was significantly related to maximum doses received, consistent with a serial structure. In individual bundles, AD changes were up to 11.5% at the maximum dose locations 18 months after RT. The dose effect on WM was greater in older female patients than younger male patients. CONCLUSIONS: Our study demonstrates for the first time that the maximum dose to the elongated WM bundles causes post-RT damage in WM. Validation and correlative studies are necessary to determine the ability and impact of sparing these bundles on preserving neurocognitive function after RT.

Diffusion tensor imaging predicts cognitive function change following partial brain radiotherapy for low-grade and benign tumors.

PURPOSE/OBJECTIVES: Radiation injury to parahippocampal cingulum white matter is associated with cognitive decline. Diffusion tensor imaging (DTI) detects micropathologic changes in white matter. Increased radial diffusion (RD) and decreased axial diffusion (AD) correspond to demyelination and axonal degeneration/gliosis respectively. We aimed to develop a predictive model for radiation-induced cognitive changes based upon DTI changes. MATERIALS/METHODS: Twenty-seven adults with benign or low-grade tumors received partial brain radiation therapy (RT) to a median dose of 54Gy. Patients underwent DTI before RT, during RT, and at the end of RT. Cognitive testing was performed before RT, and 6 and 18months after RT. Parahippocampal cingulum white matter was contoured to obtain mean values of AD and RD. RESULTS: By univariate analysis, decreasing AD and increasing RD during RT predicted declines in verbal memory and verbal fluency. By multivariate analysis, baseline neurocognitive score was the only clinical variable predicting verbal memory change; no clinical variables predicted verbal fluency change. In a multivariate model, increased RD at the end of RT significantly predicted decline in verbal fluency 18months after RT. CONCLUSIONS: Imaging biomarkers of white matter injury contributed to predictive models of cognitive function change after RT.

Targeting epidermal growth factor receptor for head and neck squamous cell carcinoma: still lost in translation?

The epidermal growth factor receptor (EGFR) is preferentially expressed in head and neck squamous cell carcinoma (HNSCC), and is a promising therapeutic target. Yet other than cetuximab, no agent targeting EGFR has been approved for this disease, and none has shown benefit over the standard of care. Several randomized trials of antibody and small molecule agents have found no new indication for these agents, despite their initial promise. In this review, we examine the major clinical evidence and discuss potential future developments of translational science in this area, including use of these agents in risk-stratified subgroups, inhibition of downstream/parallel targets, and combination with immunotherapy.

A Radiation-Induced Hippocampal Vascular Injury Surrogate Marker Predicts Late Neurocognitive Dysfunction.

PURPOSE: We aimed to develop a hippocampal vascular injury surrogate marker for early prediction of late neurocognitive dysfunction in patients receiving brain radiation therapy (RT). METHODS AND MATERIALS: Twenty-seven patients (17 males and 10 females, 31-80 years of age) were enrolled in an institutional review board-approved prospective longitudinal study. Patients received diagnoses of low-grade glioma or benign tumor and were treated by (3D) conformal or intensity-modulated RT with a median dose of 54 Gy (50.4-59.4 Gy in 1.8-Gy fractions). Six dynamic-contrast enhanced MRI scans were performed from pre-RT to 18-month post-RT, and quantified for vascular parameters related to blood-brain barrier permeability, K(trans), and the fraction of blood plasma volume, Vp. The temporal changes in the means of hippocampal transfer constant K(trans) and Vp after starting RT were modeled by integrating the dose effects with age, sex, hippocampal laterality, and presence of tumor or edema near a hippocampus. Finally, the early vascular dose response in hippocampi was correlated with neurocognitive dysfunction at 6 and 18 months post-RT. RESULTS: The mean K(trans) Increased significantly from pre-RT to 1-month post-RT (P<.0004), which significantly depended on sex (P<.0007) and age (P<.00004), with the dose response more pronounced in older females. Also, the vascular dose response in the left hippocampus of females correlated significantly with changes in memory function at 6 (r=-0.95, P<.0006) and 18-months (r=-0.88, P<.02) post-RT. CONCLUSIONS: The early hippocampal vascular dose response could be a predictor of late neurocognitive dysfunction. A personalized hippocampus sparing strategy may be considered in the future.

Response-driven imaging biomarkers for predicting radiation necrosis of the brain.

Radiation necrosis is an uncommon but severe adverse effect of brain radiation therapy (RT). Current predictive models based on radiation dose have limited accuracy. We aimed to identify early individual response biomarkers based upon diffusion tensor (DT) imaging and incorporated them into a response model for prediction of radiation necrosis. Twenty-nine patients with glioblastoma received six weeks of intensity modulated RT and concurrent temozolomide. Patients underwent DT-MRI scans before treatment, at three weeks during RT, and one, three, and six months after RT. Cases with radiation necrosis were classified based on generalized equivalent uniform dose (gEUD) of whole brain and DT index early changes in the corpus callosum and its substructures. Significant covariates were used to develop normal tissue complication probability models using binary logistic regression. Seven patients developed radiation necrosis. Percentage changes of radial diffusivity (RD) in the splenium at three weeks during RT and at six months after RT differed significantly between the patients with and without necrosis (p = 0.05 and p = 0.01). Percentage change of RD at three weeks during RT in the 30 Gy dose-volume of the splenium and brain gEUD combined yielded the best-fit logistic regression model. Our findings indicate that early individual response during the course of RT, assessed by radial diffusivity, has the potential to aid the prediction of delayed radiation necrosis, which could provide guidance in dose-escalation trials.

Uncertainty in assessment of radiation-induced diffusion index changes in individual patients.

The purpose of this study is to evaluate repeatability coefficients of diffusion tensor indices to assess whether longitudinal changes in diffusion indices were true changes beyond the uncertainty for individual patients undergoing radiation therapy (RT). Twenty-two patients who had low-grade or benign tumors and were treated by partial brain radiation therapy (PBRT) participated in an IRB-approved MRI protocol. The diffusion tensor images in the patients were acquired pre-RT, week 3 during RT, at the end of RT, and 1, 6, and 18 months after RT. As a measure of uncertainty, repeatability coefficients (RC) of diffusion indices in the segmented cingulum, corpus callosum, and fornix were estimated by using test-retest diffusion tensor datasets from the National Biomedical Imaging Archive (NBIA) database. The upper and lower limits of the 95% confidence interval of the estimated RC from the test and retest data were used to evaluate whether the longitudinal percentage changes in diffusion indices in the segmented structures in the individual patients were beyond the uncertainty and thus could be considered as true radiation-induced changes. Diffusion indices in different white matter structures showed different uncertainty ranges. The estimated RC for fractional anisotropy (FA) ranged from 5.3% to 9.6%, for mean diffusivity (MD) from 2.2% to 6.8%, for axial diffusivity (AD) from 2.4% to 5.5%, and for radial diffusivity (RD) from 2.9% to 9.7%. Overall, 23% of the patients treated by RT had FA changes, 44% had MD changes, 50% had AD changes, and 50% had RD changes beyond the uncertainty ranges. In the fornix, 85.7% and 100% of the patients showed changes beyond the uncertainty range at 6 and 18 months after RT, demonstrating that radiation has a pronounced late effect on the fornix compared to other segmented structures. It is critical to determine reliability of a change observed in an individual patient for clinical decision making. Assessments of the repeatability and confidence interval of diffusion tensor measurements in white matter structures allow us to determine the true longitudinal change in individual patients.

Regional variation in brain white matter diffusion index changes following chemoradiotherapy: a prospective study using tract-based spatial statistics.

PURPOSE: There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in white matter changes following chemoradiotherapy. METHODS: Fourteen patients receiving two or three weeks of whole-brain radiation therapy (RT) ± chemotherapy underwent DTI pre-RT, at end-RT, and one month post-RT. Three diffusion indices were measured: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). We determined significant individual voxel changes of diffusion indices using tract-based spatial statistics, and mean changes of the indices within fourteen white matter structures of interest. RESULTS: Voxels of significant FA decreases and RD increases were seen in all structures (p<0.05), with the largest changes (20-50%) in the fornix, cingula, and corpus callosum. There were highly significant between-structure differences in pre-RT to end-RT mean FA changes (p<0.001). The inferior cingula had a mean FA decrease from pre-RT to end-RT significantly greater than 11 of the 13 other structures (p<0.00385). CONCLUSIONS: Brain white matter structures varied greatly in their response to chemoradiotherapy as measured by DTI changes. Changes in FA and RD related to white matter demyelination were prominent in the cingula and fornix, structures relevant to radiation-induced neurocognitive impairment. Future research should evaluate DTI as a predictive biomarker of brain chemoradiotherapy adverse effects.

Radiation therapy effects on white matter fiber tracts of the limbic circuit.

PURPOSE: To segment fiber tracts in the limbic circuit and to assess their sensitivity to radiation therapy (RT). METHODS: Twelve patients with brain metastases who had received fractionated whole brain radiation therapy to 30 Gy or 37.5 Gy were included in the study. Diffusion weighted images were acquired pre-RT, at the end of RT, and 1-month post-RT. The fornix, corpus callosum, and cingulum were extracted from diffusion weighted images by combining fiber tracking and segmentation methods based upon characteristics of the fiber bundles. Cingulum was segmented by a seed-based tractography, fornix by a region of interests (ROI)-based tractography, and corpus callosum by a level-set segmentation algorithm. The radiation-induced longitudinal changes of diffusion indices of the structures were evaluated. RESULTS: Significant decreases were observed in the fractional anisotropy of the posterior part of the cingulum, fornix, and corpus callosum from pre-RT to end of RT by -14.0%, -12.5%, and -5.2%, respectively (p < 0.001), and from pre-RT to 1-month post-RT by -11.9%, -12.8%, and -6.4%, respectively (p < 0.001). Moreover, significant increases were observed in the mean diffusivity of the corpus callosum and the posterior part of the cingulum from pre-RT to end of RT by 6.8% and 6.5%, respectively, and from pre-RT to 1-month post-RT by 8.5% and 6.3%, respectively. The increase in the radial diffusivity primarily contributed to the significant decrease in the fractional anisotropy, indicating that demyelination is the predominant radiation effect on the white matter structures. CONCLUSIONS: Our findings indicate that the fornix and the posterior part of the cingulum are significantly susceptible to radiation damage. We have developed robust computer-aided semiautomatic segmentation and fiber tracking tools to facilitate the ROI delineation of critical structures, which is important for assessment of radiation damage in a longitudinal fashion.

Diffusion tensor imaging of normal-appearing white matter as biomarker for radiation-induced late delayed cognitive decline.

PURPOSE: To determine whether early assessment of cerebral white matter degradation can predict late delayed cognitive decline after radiotherapy (RT). METHODS AND MATERIALS: Ten patients undergoing conformal fractionated brain RT participated in a prospective diffusion tensor magnetic resonance imaging study. Magnetic resonance imaging studies were acquired before RT, at 3 and 6 weeks during RT, and 10, 30, and 78 weeks after starting RT. The diffusivity variables in the parahippocampal cingulum bundle and temporal lobe white matter were computed. A quality-of-life survey and neurocognitive function tests were administered before and after RT at the magnetic resonance imaging follow-up visits. RESULTS: In both structures, longitudinal diffusivity (λ(‖)) decreased and perpendicular diffusivity (λ(⊥)) increased after RT, with early changes correlating to later changes (p < .05). The radiation dose correlated with an increase in cingulum λ(⊥) at 3 weeks, and patients with >50% of cingula volume receiving >12 Gy had a greater increase in λ(⊥) at 3 and 6 weeks (p < .05). The post-RT changes in verbal recall scores correlated linearly with the late changes in cingulum λ(‖) (30 weeks, p < .02). Using receiver operating characteristic curves, early cingulum λ(‖) changes predicted for post-RT changes in verbal recall scores (3 and 6 weeks, p < .05). The neurocognitive test scores correlated significantly with the quality-of-life survey results. CONCLUSIONS: The correlation between early diffusivity changes in the parahippocampal cingulum and the late decline in verbal recall suggests that diffusion tensor imaging might be useful as a biomarker for predicting late delayed cognitive decline.

Expression of p16(INK4A) but not hypoxia markers or poly adenosine diphosphate-ribose polymerase is associated with improved survival in patients with pancreatic adenocarcinoma.

BACKGROUND: Pancreatic cancer is associated with mutations in the tumor suppressor gene cyclin-dependent kinase inhibitor 2A (p16(INK4A) ), a regulator of the cell cycle and apoptosis. This study investigates whether immunohistochemical expression of p16(INK4A) as well as hypoxia markers and poly adenosine diphosphate-ribose polymerase (PARP) correlates with survival in patients with resected pancreatic adenocarcinoma. METHODS: Seventy-three patients with pancreatic adenocarcinoma who underwent curative resection at Stanford University were included. From the surgical specimens, a tissue microarray was constructed using triplicate tissue cores from the primary tumor and used for immunohistochemical staining for the following markers: carbonic anhydrase IX, dihydrofolate reductase, p16(INK4A) , and PARP1/2. Staining was scored as either positive or negative and percentage positive staining. Staining score was correlated with overall survival (OS) and progression-free survival (PFS). RESULTS: Of the markers tested, only immunohistochemical expression of p16(INK4A) correlated with clinical outcome. On univariate analysis, p16(INK4A) expression in the tumor was associated with improved OS (P = .038) but not PFS (P = .28). The median survival for patients with positive versus negative p16(INK4A) staining was 28.8 months versus 18 months. On multivariate analysis, p16(INK4A) expression was associated with improved OS (P = .026) but not PFS (P = .25). Age (P = .0019) and number of nodes involved (P = .025) were also significant for OS. Adjuvant chemotherapy and margin status did not correlate with OS or PFS. CONCLUSIONS: Expression of p16(INK4A) is associated with improved OS in patients with resected pancreatic adenocarcinoma. Further investigation is needed for validation, given conflicting data in the published literature. .

Socioeconomic trends in hospitalization for multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a neurological disorder with a high burden on patient quality of life and medical rehabilitation services. Little is known about the acute hospitalization costs and characteristics. We examined the trends in MS hospitalizations from 1993 to 2006. METHODS: The Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project was searched using the ICD-9 code 340 (MS). Diagnostic, treatment and administrative data were analyzed using basic statistical software. RESULTS: A total of 288,454 hospital admissions with the primary diagnosis of MS occurred between 1993 and 2006, an average of 20,604 admissions annually. The percentage admitted from the emergency department (ED) increased from 19.4 to 60.0% during 1993-2006. The mean cost for each inpatient increased from USD 7,965 to 20,076. The percentage of discharges to home health care increased from 8.6 to 14.9%, and the percentage of discharges to nursing homes and rehabilitation services increased from 8.3 to 22.6%. In 2006, Medicaid patients were significantly more likely to be admitted from the ED (p < 0.001). Medicare payers were significantly more likely to be discharged to a nursing home/rehabilitation (p < 0.0001). CONCLUSION: National health insurance policies have made measurable effects on MS disease management. MS is becoming more expensive to treat acutely, and improved treatment modalities geared toward decreasing acute flare-ups may provide substantial cost savings by reducing ED visits, inpatient hospitalizations and the need for rehabilitation.