Intrafraction motion analysis in online adaptive radiotherapy for esophageal cancer.

Intrafraction motion during magnetic resonance (MR)-guided dose delivery of esophageal cancer tumors was retrospectively analyzed. Deformable image registration of cine-MR series resulted in gross tumor volume motion profiles in all directions, which were subsequently filtered to isolate respiratory and drift motion. A large variability in intrafraction motion patterns was observed between patients. Median 95% peak-to-peak motion was 7.7 (3.7 - 18.3) mm, 2.1 (0.7 - 5.7) mm and 2.4 (0.5 - 5.6) mm in cranio-caudal, left-right and anterior-posterior directions, relatively. Furthermore, intrafraction drift was generally modest (<5mm). A patient specific approach could lead to very small margins (<3mm) for most patients.

Planning target volume margin assessment for online adaptive MR-guided dose-escalation in rectal cancer on a 1.5 T MR-Linac.

PURPOSE: This study assessed the margins needed to cover tumor intrafraction motion during an MR-guided radiotherapy (MRgRT) dose-escalation strategy in intermediate risk rectal cancer. METHODS: Fifteen patients with rectal cancer were treated with neoadjuvant short-course radiotherapy, 5x5 Gy, according to an online adaptive workflow on a 1.5 T MR-linac. Per patient, 26 3D T2 weighted MRIs were made; one reference scan preceding treatment and five scans per treatment fraction. The primary tumor was delineated on each scan as gross tumor volume (GTV). Target coverage margins were assessed by isotropically expanding the reference GTV until more than 95% of the voxels of the sequential GTVs were covered. A margin with a coverage probability threshold of 90% was defined as adequate. Intra- and interfraction margins to cope with the movement of the GTV in the period between scans were calculated to indicate the target volume margins. Furthermore, the margin needed to cover GTV movement was calculated for different time intervals. RESULTS: The required margins to cover inter- and intrafraction GTV motion were 17 mm and 6 mm, respectively. Analysis based on time intervals between scans showed smaller margins were needed for adequate GTV coverage as time intervals became shorter, with a 4 mm margin required for a procedure of 15 min or less. CONCLUSION: The shorter the treatment time, the smaller the margins needed to cover for the GTV movement during an online adaptive MRgRT dose-escalation strategy for intermediate risk rectal cancer. When time intervals between replanning and the end of dose delivery could be reduced to 15 min, a 4 mm margin would allow adequate target coverage.

Systematic review of the impact of appropriate versus inappropriate initial antibiotic therapy on outcomes of patients with severe bacterial infections.

We investigated the impact of appropriate versus inappropriate initial antimicrobial therapy on the clinical outcomes of patients with severe bacterial infections as part of a systematic review and meta-analyses assessing the impact of delay in appropriate antimicrobial therapy. Literature searches of MEDLINE and Embase, conducted on 24 July 2018, identified studies published after 2007 reporting the impact of delay in appropriate antibiotic therapy for hospitalised adult patients with bacterial infections. Results were statistically pooled for outcomes including mortality, hospital length of stay (LOS) and treatment failure. Subgroup analyses were explored by site of infection where data permitted. Inclusion criteria were met by 145 studies, of which 114 reported data on the impact of appropriate versus inappropriate initial therapy. In the pooled analysis, rates of mortality were significantly in favour of appropriate therapy [odds ratio (OR) = 0.44, 95% CI 0.38-0.50]. Across eight studies, LOS was shorter with appropriate therapy compared with inappropriate therapy [mean difference (MD) -2.54 days (95% CI -5.30 to 0.23)], but not significantly so. The incidence of treatment failure was significantly lower in patients who received appropriate therapy compared with patients who received inappropriate therapy (six studies: OR = 0.33, 95% CI 0.16-0.66) as was mean hospital costs (four studies: MD -7.38 thousand US$ or Euros, 95% CI -14.14 to -0.62). Initiation of appropriate versus inappropriate antibiotics can reduce mortality, reduce treatment failure and decrease LOS, highlighting the importance of broad­spectrum empirical therapy and rapid diagnostics for early identification of the causative pathogen. [Study registration: PROSPERO: CRD42018104669].

Tumor volume regression during neoadjuvant chemoradiotherapy for esophageal cancer: a prospective study with weekly MRI.

Background: Neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer causes tumor regression during treatment. Tumor regression can induce changes in the thoracic anatomy, with smaller target volumes and displacement of organs at risk (OARs) surrounding the tumor as a result. Adaptation of the radiotherapy treatment plan according to volumetric changes during treatment might reduce radiation dose to the OARs, while maintaining adequate target coverage. Data on the magnitude of the volumetric changes and its impact on the thoracic anatomy is scarce. The aim of this study was to assess the volumetric changes in the primary tumor during nCRT for esophageal cancer based on weekly MRI scans.Material and methods: In this prospective study, patients with adeno- or squamous cell carcinoma of the esophagus treated with neoajduvant chemoradiotherapy according to the CROSS regimen (carboplatin + paclitaxel + 23 × 1.8 Gy) were included. Of each patient, six sequential MRI scans were acquired: one prior to nCRT, and five in each subsequent week during nCRT. Tumor volumes were delineated on the transversal T2 weighted images by two radiation oncologists. Volumetric changes were analyzed using linear mixed effects models.Results: A total of 170 MRI scans from 29 individual patients were included. The mean (± standard deviation (SD)) tumor volume at baseline was 45 cm3 (± 23). Tumor volume regression started after the first week of nCRT with a significant decrease in tumor volumes every subsequent week. A decrease to 42 cm3 (91% of initial volume), 38 cm3 (81%), 35 cm3 (77%), and 32 cm3 (72%) was observed in the second, third, fourth and fifth week of nCRT, respectively.Conclusion: Based on weekly MRI scanning during nCRT for esophageal cancer, a considerable decrease in tumor volume was observed during treatment. Volume regression and consequential anatomical changes suggest the possible benefit of adaptive radiotherapy.

A Systematic Review of the Effect of Delayed Appropriate Antibiotic Treatment on the Outcomes of Patients With Severe Bacterial Infections.

BACKGROUND: Patients with severe bacterial infections often experience delay in receiving appropriate treatment. Consolidated evidence of the impact of delayed appropriate treatment is needed to guide treatment and improve outcomes. RESEARCH QUESTION: What is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections? STUDY DESIGN AND METHODS: Literature searches of MEDLINE and Embase, conducted on July 24, 2018, identified studies published after 2007 reporting the impact of delayed appropriate therapy on clinical outcomes for hospitalized adult patients with bacterial infections. Where appropriate, results were pooled and analyzed with delayed therapy modeled three ways: delay vs no delay in receiving appropriate therapy; duration of delay; and inappropriate vs appropriate initial therapy. This article reports meta-analyses on the effect of delay and duration of delay. RESULTS: The eligibility criteria were met by 145 studies, of which 37 contributed data to analyses of effect of delay. Mortality was significantly lower in patients receiving appropriate therapy without delay compared with those experiencing delay (OR, 0.57; 95% CI, 0.45-0.72). Mortality was also lower in the no-delay group compared with the delay group in subgroups of studies reporting mortality at 20 to 30 days, during ICU stay, or in patients with bacteremia (OR, 0.57 [95% CI, 0.43-0.76]; OR, 0.47 [95% CI, 0.27-0.80]; and OR, 0.54 [95% CI, 0.40-0.75], respectively). No difference was found in time to appropriate therapy between those who died and those who survived (P = .09), but heterogeneity between studies was high. INTERPRETATION: Avoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections. CLINICAL TRIAL REGISTRATION: PROSPERO; No.: CRD42018104669; URL: www.crd.york.ac.uk/prospero/.

A value-based healthcare approach: Health-related quality of life and psychosocial functioning in women with Turner syndrome.

OBJECTIVE: As part of the value-based healthcare programme in our hospital, a set of patient-reported outcome measures was developed together with patients and implemented in the dedicated Turner Syndrome (TS) outpatient clinic. This study aims to investigate different aspects of health-related quality of life (HR-QoL) and psychosocial functioning in women with TS in order to establish new possible targets for therapy. DESIGN/PARTICIPANTS: A comprehensive set of questionnaires (EQ-5D, PSS-10, CIS-20, Ferti-QoL, FSFI) was developed and used to capture different aspects of HR-QoL and psychosocial functioning in a large cohort of adult women with Turner syndrome. All consecutive women, ≥18 years, who visited the outpatient clinic of our tertiary centre were eligible for inclusion. RESULTS: Of the eligible 201 women who were invited to participate, 177 women (age 34 ± 12 years, mean ± SD) completed at least one of the validated questionnaires (88%). Women with TS reported a lower health-related quality of life (EQ-5D: 0.857 vs 0.892, P = .003), perceived more stress (PSS-10:14.7 vs 13.3; P = .012) and experienced increased fatigue (CIS-20: P < .001) compared to the general Dutch population. A relationship between noncardiac comorbidities (eg diabetes, orthopaedic complaints) and HR-QoL was found (R = .508). CONCLUSIONS: We showed that TS women suffer from impaired HR-QoL, more perceived stress and increased fatigue compared to healthy controls. A relationship between noncardiac comorbidities and HR-QoL was found. Especially perceived stress and increased fatigue can be considered targets for improvement of HR-QoL in TS women.

Optimal timing for prediction of pathologic complete response to neoadjuvant chemoradiotherapy with diffusion-weighted MRI in patients with esophageal cancer.

OBJECTIVE: This study was conducted in order to determine the optimal timing of diffusion-weighted magnetic resonance imaging (DW-MRI) for prediction of pathologic complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. METHODS: Patients with esophageal adenocarcinoma or squamous cell carcinoma who planned to undergo nCRT followed by surgery were enrolled in this prospective study. Patients underwent six DW-MRI scans: one baseline scan before the start of nCRT and weekly scans during 5 weeks of nCRT. Relative changes in mean apparent diffusion coefficient (ADC) values between the baseline scans and the scans during nCRT (ΔADC(%)) were compared between pathologic complete responders (pCR) and non-pCR (tumor regression grades 2-5). The discriminative ability of ΔADC(%) was determined based on the c-statistic. RESULTS: A total of 24 patients with 142 DW-MRI scans were included. pCR was observed in seven patients (29%). ΔADC(%) from baseline to week 2 was significantly higher in patients with pCR versus non-pCR (median [IQR], 36% [30%, 41%] for pCR versus 16% [14%, 29%] for non-pCR, p = 0.004). The ΔADC(%) of the second week in combination with histology resulted in the highest c-statistic for the prediction of pCR versus non-pCR (0.87). The c-statistic of this model increased to 0.97 after additional exclusion of patients with a small tumor volume (< 7 mL, n = 3) and tumor histology of the resection specimen other than adenocarcinoma or squamous cell carcinoma (n = 1). CONCLUSION: The relative change in tumor ADC (ΔADC(%)) during the first 2 weeks of nCRT is the most predictive for pathologic complete response to nCRT in esophageal cancer patients. KEY POINTS: • DW-MRI during the second week of neoadjuvant chemoradiotherapy is most predictive for pathologic complete response in esophageal cancer. • A model including ΔADCweek 2was able to discriminate between pathologic complete responders and non-pathologic complete responders in 87%. • Improvements in future MRI studies for esophageal cancer may be obtained by incorporating motion management techniques.

Anti-HER2 CD4+ T-Helper Type 1 Immune Response is Superior to Breast MRI for Assessing Response to Neoadjuvant Therapy in Patients with HER2-Positive Breast Cancer.

BACKGROUND: In human epidermal growth factor 2-positive breast cancer (HER2+BC), neoadjuvant chemotherapy and anti-HER2-targeted therapy (nCT) achieves a complete pathologic response (pCR) in 40-67% of patients. Posttreatment magnetic resonance imaging (pMRI) is considered the gold standard, with high specificity but lower sensitivity for assessing response. The authors previously determined that anti-HER2Th1 immune response is associated with pathologic response after nCT in HER2+BC patients. This study contrasted pMRI with anti-HER2Th1 response for assessing pCR in HER2+BC. METHODS: A retrospective review of HER2+BC patients at the authors' institution was performed. Original pMRI reports were collected, and images were reviewed by a breast radiologist blinded to pCR and immune response. The post-nCT imaging-based tumor response was assessed by Response Evaluation Criteria in Solid Tumors. The anti-HER2Th1 response was determined by ex vivo stimulation of peripheral blood mononuclear cells with six major histocompatibility complex (MHC) class 2-derived HER2 peptides via enzyme-linked immunospot (ELISPOT). Posttreatment MRI and anti-HER2Th1 responses were cross-tabulated with pCR. Standard diagnostic metrics were computed. RESULTS: For 30 patients, pMRI and anti-HER2Th1 immune response were measured, with 13 patients (43.3%) achieving pCR. The mean anti-HER2Th1 response in pCR was 167 (range 53-418), and

Effects of solar particle event proton radiation on parameters related to ferret emesis.

The effectiveness of simulated solar particle event (SPE) proton radiation to induce retching and vomiting was evaluated in the ferret experimental animal model. The endpoints measured in the study included: (1) the fraction of animals that retched or vomited, (2) the number of retches or vomits observed, (3) the latency period before the first retch or vomit and (4) the duration between the first and last retching or vomiting events. The results demonstrated that γ ray and proton irradiation delivered at a high dose rate of 0.5 Gy/min induced dose-dependent changes in the endpoints related to retching and vomiting. The minimum radiation doses required to induce statistically significant changes in retching- and vomiting-related endpoints were 0.75 and 1.0 Gy, respectively, and the relative biological effectiveness (RBE) of proton radiation at the high dose rate did not significantly differ from 1. Similar but less consistent and smaller changes in the retching- and vomiting-related endpoints were observed for groups irradiated with γ rays and protons delivered at a low dose rate of 0.5 Gy/h. Since this low dose rate is similar to a radiation dose rate expected during a SPE, these results suggest that the risk of SPE radiation-induced vomiting is low and may reach statistical significance only when the radiation dose reaches 1 Gy or higher.

Effect of time interval between surgery and preoperative chemoradiotherapy with 5-fluorouracil or 5-fluorouracil and oxaliplatin on outcomes in rectal cancer.

BACKGROUND AND OBJECTIVES: Preoperative chemoradiotherapy for locally advanced rectal cancer is now considered "standard of care." However, the optimal time interval for resection after neoadjuvant therapy is unknown. METHODS: Between 11/90 and 11/04, 107 patients with rectal adenocarcinoma underwent preoperative chemo/RT at the University of Pennsylvania. Fifty-six percent had LAR and 40% had APR. Chemotherapy consisted of 5-FU/oxaliplatin in 28% and 5-FU in 72% of patients. All patients received preoperative RT. RESULTS: A longer time interval between chemo/RT and surgery was associated with tumor downstaging (OR 1.24, P = 0.02). A longer time interval was not associated with: nodal downstaging (OR 1.00, P = 0.98); pathologic complete response (PCR) (OR 0.97, P = 0.80); likelihood of performing an LAR (OR 0.90, P = 0.47); improved disease free survival (DFS), local control, or distant control (HR 1.05, P = 0.49; HR 1.14, P = 0.22; HR 1.06, P = 0.52, respectively). The PCR rate was 34.5% in the 5-FU/oxaliplatin/radiation group, and 13.7% in the 5-FU/radiation group. If patients with microscopic CR were excluded, then the PCR rate for 5FU/OX was 21.4% and for 5-FU was 12.2%. CONCLUSIONS: Time interval between surgery and chemo/RT appeared to have little effect on PCR or LAR rates. Patients receiving 5 FU/oxaliplatin/RT had a high PCR rate. A prospective randomized trial to test superiority of 5 FU/oxaliplatin is warranted.

Preliminary results of interstitial motexafin lutetium-mediated PDT for prostate cancer.

BACKGROUND AND OBJECTIVES: Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed extensive studies that demonstrate the feasibility of interstitial PDT for prostate cancer. Our preclinical and clinical experience is herein detailed. STUDY DESIGN/MATERIALS AND METHODS: We have treated 16 canines in preclinical studies, and 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed. RESULTS: We demonstrate the safe and comprehensive treatment of the prostate using PDT. However, there is significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate. CONCLUSIONS: PDT is an attractive option for the treatment of prostate adenocarcinoma. However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility. Our future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution.

Reduction of endothelin-1 binding and inhibition of endothelin-1-mediated detrusor contraction by naftidrofuryl.

Endothelin-1 (ET-1) causes urinary bladder smooth muscle contraction and the endothelin receptors A and B (ET(A) and ET(B)) are both known to be present in the rabbit urinary bladder. Alterations in ET-1 signalling have been implicated in the pathophysiology of urinary tract disorders secondary to bladder outlet obstruction and also in diabetic cystopathy. Naftidrofuryl (Naf) (marketed under the trade name Praxilene) improves walking distance in patients with peripheral vascular disease, an effect which may be partially attributed to ET-1 antagonism. The purpose of this study is to assess whether Naf will reduce ET-1 binding in the rabbit detrusor muscle and to assess whether there is inhibition of ET-1-mediated detrusor contraction. Detrusor smooth muscle strips were mounted in organ baths and cumulative response curves were measured for ET-1-mediated contractions in the presence and absence of 10(-6) M Naf (therapeutic concentration). In addition, ET-1 was added to the detrusor strips in the presence of the ET(A) antagonist, BQ123, and the ET(B) antagonist, BQ788, to identify the receptor subtype functionally involved. Overall inhibition of [(125)I]ET-1 binding by Naf was assessed using autoradiography. Identification of receptor-subtype binding reduction was assessed using the radioligands [(125)I]PD151242 and [(125)I]BQ3020. Naf inhibited ET-1-mediated detrusor contractions significantly (P<0.04), e.g. at 10(-10) M ET-1, contraction was completely abolished by Naf. Autoradiography indicated that Naf competitively inhibited [(125)I]ET-1 binding in a dose-dependent manner (IC(50)=3x10(-7) M). All radioligand binding was reduced indicating binding of Naf to both ET(A) and ET(B) receptors. Naf reduces binding of ET-1 to rabbit detrusor ET(A) and ET(B) receptors and inhibits ET-1-induced detrusor contractions mediated by ET(A) receptors. Naf may have therapeutic potential in the treatment of bladder disorders secondary to bladder outlet obstruction and diabetes mellitus.

Interleukin-4 up-regulates mouse mammary tumor virus expression yet is not required for in vivo virus spread.

The mouse mammary tumor virus (MMTV) superantigen induces T-cell production of cytokines, such as interleukin-4, which in turn increase MMTV transcription. However, interleukin-4 is not required for in vivo virus spread, because mice lacking interleukin-4 or the STAT6 transcription factor showed wild-type infection of lymphoid and mammary tissue. In spite of this, mammary tumor incidence was decreased in STAT6 null mice.

Pediatric Crohn's disease: risk factors for postoperative recurrence.

OBJECTIVE: Postoperative recurrence of Crohn's disease in adults has been extensively studied; however, the course of Crohn's disease after surgery in children has not been well defined. The aim of this study was to examine the postoperative course of pediatric Crohn's disease and the factors that may predict early postoperative recurrence. METHODS: We identified 100 resective surgeries in 79 children with Crohn's disease seen at the Children's Hospital of Philadelphia between 1978 and 1996. A retrospective, multivariable analysis of factors potentially influencing postoperative clinical recurrence was performed. Preoperative and postoperative height measurements were compared, and z scores were computed for height-for-age. Two-tailed t test was used for the analysis. RESULTS: Clinical recurrence rates were 17% at 1 yr, 38% at 3 yr, and 60% at 5 yr. Patients with colonic Crohn's disease had a significantly shorter postoperative recurrence-free interval (median 1.2 yr) than patients with ileocecal (median 4.4 yr) or diffuse disease (median 3.0 yr) (p = 0.01). On multivariable analysis, a high Pediatric Crohn's Disease Activity Index at the time of surgery (p = 0.01) and preoperative use of 6-mercaptopurine (6-MP) (p < 0.005) were also independently associated with higher postoperative recurrence rates. There was a significant improvement in z scores for height (p = 0.04) after surgery. CONCLUSIONS: In children undergoing resective surgery for Crohn's disease, high rates of postoperative Crohn's disease recurrence are associated with severe disease at the time of surgery, colonic Crohn's disease, and the preoperative use of 6-MP. Patients who require preoperative use of 6-MP are likely to suffer from a more aggressive disease and would benefit from postoperative 6-MP prophylaxis. Height growth was improved after intestinal resection for Crohn's disease.

Locally recurrent malignant melanoma characteristics and outcomes: a single-institution study.

Despite improvements in the identification and treatment of melanoma, local recurrence continues to challenge the success of current melanoma therapy. A retrospective analysis of 1,996 patients presenting from 1990 to 1997 at the Pigmented Lesion Group of the University of Pennsylvania was performed to assess clinical characteristics and outcomes of locally recurrent melanoma. The cases were analyzed by chart and pathological slide review. A control group was identified for statistical comparison. The incidence of locally recurrent melanoma during the study period was 2.2%. Lentigo maligna melanoma (LMM) accounted for 37% of the local recurrences. Increased tumor thickness and microsatellites were associated with "early" local recurrence and decreased survival from time of recurrence. Nineteen percent of the local recurrences occurred more than 5 years after the initial definitive treatment. The preponderance of locally recurrent LMM suggests the need for refinements in the techniques of margin identification and surgical excision of LMM. Tumors with increased thickness and microsatellites should receive particularly close attention. Lastly, with nearly 20% of the local recurrences occurring more than 5 years after the initial date of treatment, the authors suggest extending the follow-up time for all melanoma lesions beyond 5 years.

p16(INK4a) expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation.

BACKGROUND & AIMS: p16(INK4a) is a cell cycle inhibitor and a major tumor-suppressor protein, but the regulation of p16(INK4a) is poorly understood and the physiologic settings in which it exerts its antiproliferative effects are unknown. A role for p16(INK4a) in intestinal neoplasia is suggested by the observation that the promoter region is methylated in a subset of human colon tumors. We examined the expression of the protein in specimens representing the full spectrum of neoplastic progression in the human colon and determined whether expressing cells showed evidence of cell cycle inhibition. METHODS: We studied p16(INK4a) expression by immunoprecipitation, immunoblotting, reverse-transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and immunofluorescence in matched normal and neoplastic colonic tissue from 70 patients. RESULTS: p16(INK4a) expression was very low in normal mucosa, with staining observed in rare epithelial cells at the base of crypts. A distinctly higher expression was found in 4 of 7 aberrant crypt foci, 32 of 36 adenomas, 18 of 28 primary carcinomas, and 5 of 5 metastatic carcinomas. Within each neoplasm p16(INK4a) staining was heterogeneous, with higher expression commonly seen in areas bordering normal tissue. p16(INK4a) staining correlated inversely with that of Ki67, cyclin A, and the retinoblastoma protein, suggesting that cell cycle progression was inhibited. CONCLUSIONS: These results suggest that p16(INK4a) expression begins in the earliest detectable stages of neoplastic progression in the human colon and exerts a continuous, piecemeal constraint on tumor growth.

Farnesyltransferase inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated HRAS.

Successful radiosensitization requires that tumor cells become more radiosensitive without causing an equivalent reduction in the survival of cells of the surrounding normal tissues. Since tumor cell radiosensitivity can be influenced by RAS oncogene activation, we have hypothesized that inhibition of oncogenic RAS activity would lead to radiosensitization of tumors with activated RAS. We previously showed in tissue culture that prenyltransferase treatment of cells with activated RAS resulted in radiosensitization, whereas treatment of cells with wild-type RAS had no effect on radiation survival. Here we ask whether the findings obtained in vitro have applicability in vivo. We found that treatment of nude mice bearing T24 tumor cell xenografts with farnesyltransferase inhibitors resulted in a significant and synergistic reduction in tumor cell survival after irradiation. The regrowth of T24 tumors expressing activated RAS was also significantly prolonged by the addition of treatment with farnesyltransferase inhibitors compared to the regrowth after irradiation alone. In contrast, there was no effect on the radiosensitivity of HT-29 tumors expressing wild-type RAS. These results demonstrate that specific radiosensitization of tumors expressing activated RAS oncogenes can be obtained in vivo.