Can Peer Assessment Impact Self-efficacy During Small-Group Learning?

INTRODUCTION: While studies report positive correlations between students' perceptions of the learning environment and their reported self-efficacy, the role of peer assessment is poorly understood in this context. This study examines the process and impact of peer assessment on self-efficacy and perceptions of the learning environment during a small-group discussion-based course required of first-year medical students. METHODS: After spending time in small-group learning, students completed three peer assessments and reviewed three assessments of themselves. Analysis of the peer assessments included thematic coding of comments and word counts. Prior to and following the assessment period, students completed a survey including the Generalized Self-efficacy (GSE) Scale, and six locally-developed questions regarding the learning environment and perceptions of peer assessment. We performed paired-sample t tests to determine whether there were differences between the pre- and post-peer assessment surveys. The SUNY Upstate Institutional Review Board reviewed the study and determined it to be exempt. RESULTS: Peer assessment narratives referred most commonly to students' participation style and the need for greater participation. Word counts ranged widely. A paired sample t test indicated that the difference between pre and post peer assessment GSE scores was significant (P=.009), but the effect size was small (d=0.32). Perceptions of the learning environment did not change after the peer assessments. CONCLUSION: Peer assessment offers a potential strategy for enhancing self-efficacy in medical school small-group learning environments and requires few resources to implement, relative to the potential benefits.

"The stakes could not be higher": A mixed methods study of parental social media use in pediatric oncology.

BACKGROUND: To describe how parents and families of children with cancer evaluate the benefits and risks of using social media (SM) and how they navigate disagreements between oncologists' advice and information found on SM. PROCEDURE: Parents of children who had been previously diagnosed with cancer, and who had used SM for a purpose related to that child's health were recruited through SM sites and nonprofit organizations across the United States and were invited to complete questionnaires about their experiences using SM; a subset of participants also completed a follow-up in-depth interview. Open-ended responses and interviews were analyzed using thematic analysis. RESULTS: Ninety parents completed written questionnaires; 21 completed follow-up interviews. Seventy percent reported experiencing a situation in which information shared on SM conflicted with information provided by their child's oncologist. Although 86% reported that they discussed the conflicting information with the oncologist and 70% described the oncologist's response as positive, 78% also described ongoing negative feelings about the experience. Parents described openness to discussing SM, honesty, transparency, and humility regarding the limits of medicine, and shared decision-making regarding information found on SM as increasing their trust in their oncologist. CONCLUSIONS: Parents offered valuable insights regarding their experiences navigating SM, including eight recommendations for how pediatricians might approach discussing parental SM use. Future studies will evaluate the utility of these recommendations for pediatric clinicians.

Qualitative insights into how men with low-risk prostate cancer choosing active surveillance negotiate stress and uncertainty.

BACKGROUND: Active surveillance is a management strategy for men diagnosed with early-stage, low-risk prostate cancer in which their cancer is monitored and treatment is delayed. This study investigated the primary coping mechanisms for men following the active surveillance treatment plan, with a specific focus on how these men interact with their social network as they negotiate the stress and uncertainty of their diagnosis and treatment approach. METHODS: Thematic analysis of semi-structured interviews at two academic institutions located in the northeastern US. Participants include 15 men diagnosed with low-risk prostate cancer following active surveillance. RESULTS: The decision to follow active surveillance reflects the desire to avoid potentially life-altering side effects associated with active treatment options. Men on active surveillance cope with their prostate cancer diagnosis by both maintaining a sense of control over their daily lives, as well as relying on the support provided them by their social networks and the medical community. Social networks support men on active surveillance by encouraging lifestyle changes and serving as a resource to discuss and ease cancer-related stress. CONCLUSIONS: Support systems for men with low-risk prostate cancer do not always interface directly with the medical community. Spousal and social support play important roles in helping men understand and accept their prostate cancer diagnosis and chosen care plan. It may be beneficial to highlight the role of social support in interventions targeting the psychosocial health of men on active surveillance.

Cognitive and Affective Representations of Active Surveillance as a Treatment Option for Low-Risk Prostate Cancer.

Benefits of early diagnosis and treatment remain debatable for men with low-risk prostate cancer. Active surveillance (AS) is an alternative to treatment. The goal of AS is to identify patients whose cancer is progressing rapidly while avoiding treatment in the majority of patients. The purpose of this study was to explore cognitive and affective representations of AS within a clinical environment that promotes AS a viable option for men with low-risk prostate cancer. Participants included patients for whom AS and active treatment were equally viable options, as well as practitioners who were involved in consultations for prostate cancer. Data were generated from semistructured interviews and audits of consultation notes and were analyzed using thematic analysis. Nineteen patients and 16 practitioners completed a semistructured interview. Patients generally viewed AS as a temporary strategy that was largely equated with inaction. There was variation in the degree to which inaction was viewed as warranted or favorable. Patient perceptions of AS were generally malleable and able to be influenced by information from trusted sources. Encouraging slow deliberation and multiple consultations may facilitate greater understanding and acceptance of AS as a viable treatment option for low-risk prostate cancer.

Total inhibition of (1)O2-induced oxidative damage to guanine bases of DNA/RNA by turmeric extracts.

The guanine base of nucleic acids is known to be very reactive towards degradation by (1)O2-induced oxidative stress. Oxidative reactions of DNA are linked to many human diseases including cancer. Among the various forms of reactive O2 species (OH, (1)O2 or O2(-)), the oxidative stress caused by (1)O2 is of particular physiologic importance because of its selectively long life in aqueous medium and its ability to diffuse through a cell membrane. In this study we investigated the degradation of a model compound guanosine (Guo) by (1)O2, which was generated by riboflavin-induced photosensitization and by molybdate ion catalyzed disproportionation of H2O2. We observed the remarkable ability of an aqueous and alcoholic extracts of Turmeric (Curcuma longa) as an extraordinary scavenger of (1)O2 to completely inhibit the degradation of Guo. The alcoholic extracts were more effective in their antioxidant activity than the corresponding water extract. This naturally occurring antioxidant offers a most economical supplement to protect biologically significant molecules from the oxidative stress induced by (1)O2.

Candidate gene studies in hypodontia suggest role for FGF3.

INTRODUCTION: The majority of tooth agenesis cases are mild (hypodontia) and typically not associated with the gene mutations linked to oligodontia. From this, we hypothesise that most cases of tooth agenesis fit a polygenic mode of inheritance, where several genes with small effects cause a variety of varying phenotypes. MATERIALS AND METHODS: In this study, we looked at 18 not typically studied genes in this condition, to ascertain their contribution to hypodontia. Our study subjects consisted of 167 patients with hypodontia and their parents from two cohorts (one from Brazil and one from Turkey). An additional 465 DNA samples (93 cases with hypodontia and 372 controls without family history for tooth agenesis or oral clefts) from Brazil were also available for this study. Ninety-three single nucleotide polymorphisms that maximally represent the linkage disequilibrium structure of the genes for the 18 genes were selected and genotyped using Taqman chemistry. Chi square was used to test if genotype distributions were in Hardy-Weinberg equilibrium, and 24 markers that were in Hardy-Weinberg equilibrium and had allele frequencies higher than 5 % in a panel of 50 CEPH samples were further tested. Association between hypodontia and genetic variants was tested with the transmission disequilibrium test within the programme Family-Based Association Test (FBAT) and by using Chi square and Fisher's exact tests. Alpha at a level of 0.05 was used to report results. RESULTS: Results suggest possible associations between several genes and hypodontia in the three populations. In the Turkish cohort (n = 51 parent-affected child trios) the most significant results were as follows: FGF3 rs1893047, p = 0.08; GLI3 rs929387, p = 0.03; GLI3 haplotype rs929387-rs846266, p = 0.002; and PAX9 rs2073242, p = 0.03. In the Brazilian cohort (n = 116 parent-affected child trios), the results were as follows: DLX1 rs788173, p = 0.07; FGF3 rs12574452, p = 0.03; GLI2 rs1992901, p = 0.03; and PITX2 rs2595110, p = 0.01. The second Brazilian cohort also suggested that FGF3 (rs12574452, p = 0.01) is associated with hypodontia and added EDAR (rs17269487, p = 0.04), LHX6 (rs989798, p = 0.02), and MSX1 (rs12532, p = 0.003). CONCLUSION: Our results suggest that several genes are potentially associated with hypodontia and their individual contributions may be modest. Hence, these cases may not be explained by inactivating mutations such as many oligodontia cases segregating in a Mendelian fashion but rather are influenced by one or more susceptibility alleles in multiple small effect genes.

Indole peroxygenase activity of indoleamine 2,3-dioxygenase.

The heme enzyme indoleamine 2,3-dioxygenase (IDO) was found to catalyze the oxidation of indole by H(2)O(2), with generation of 2- and 3-oxoindole as the major products. This reaction occurred in the absence of O(2) and reducing agents and was not inhibited by superoxide dismutase or hydroxyl radical scavengers, although it was strongly inhibited by L-Trp. The stoichiometry of the reaction indicated a one-to-one correspondence for the consumption of indole and H(2)O(2). The (18)O-labeling experiments indicated that the oxygen incorporated into the monooxygenated products was derived almost exclusively from H(2)(18)O(2), suggesting that electron transfer was coupled to the transfer of oxygen from a ferryl intermediate of IDO. These results demonstrate that IDO oxidizes indole by means of a previously unrecognized peroxygenase activity. We conclude that IDO inserts oxygen into indole in a reaction that is mechanistically analogous to the "peroxide shunt" pathway of cytochrome P450.

NADH oxidase activity of indoleamine 2,3-dioxygenase.

The heme enzyme indoleamine 2,3-dioxygenase (IDO) was found to oxidize NADH under aerobic conditions in the absence of other enzymes or reactants. This reaction led to the formation of the dioxygen adduct of IDO and supported the oxidation of Trp to N-formylkynurenine. Formation of the dioxygen adduct and oxidation of Trp were accelerated by the addition of small amounts of hydrogen peroxide, and both processes were inhibited in the presence of either superoxide dismutase or catalase. Anaerobic reaction of IDO with NADH proceeded only in the presence of a mediator (e.g. methylene blue) and resulted in formation of the ferrous form of the enzyme. We propose that trace amounts of peroxide previously proposed to occur in NADH solutions as well as solid NADH activate IDO and lead to aerobic formation of superoxide and the reactive dioxygen adduct of the enzyme.

Versatility of the Novalis system to deliver image-guided stereotactic body radiation therapy (SBRT) for various anatomical sites.

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) programs to treat brain tumors were implemented when we first acquired the Brainlab Novalis system in 2003. Two years later, we started an extra-cranial stereotactic radio-ablation or more appropriately a stereotactic body radiation therapy (SBRT) program using the Brainlab Novalis image-guided system at The Methodist Hospital in Houston, Texas. We hereby summarize our initial experience with this system in delivering image-guided SBRT to a total of 80 patients during our first year of clinical implementation, from February 2005 to January 2006. Over 100 lesions in more than 20 distinct anatomical sites were treated. These include all levels of spine from cervical, thoracic, lumbar, and sacral lesions. Spinal lesions encompass intramedullary, intradural, extradural, or osseous compartments. Also treated were lesions in other bony sites including orbit, clavicle, scapula, humerus, sternum, rib, femur, and pelvis (ilium, ischium, and pubis). Primary or metastatic lesions located in the head and neck, supraclavicular region, axilla, mediastinum, lung (both central and peripheral), abdominal wall, liver, kidney, para-aortic lymph nodes, prostate, and pelvis were also treated. In addition to primary radiotherapy, SBRT program using the Brainlab Novalis system allows re-irradiation for recurrence and "boost" after conventional treatment to various anatomical sites. Treating these sites safely and efficaciously requires knowledge in radiation tolerance, fraction size, total dose, biologically equivalent dose (BED), prior radiotherapy, detailed dose volume histograms (DVH) of normal tissues, and the radiosensitive/radioresistant nature of the tumor. Placement of radio-opaque markers (Visicoil, Radiomed) in anatomical sites not in close proximity to bony landmarks (e.g., kidney and liver) helps in measuring motion and providing image guidance during each treatment fraction. Tumor/organ motion data obtained using 4D-CT while the patient is immobilized in the body cast aids in planning treatment margin and determining the need for respiratory motion control, e.g., abdominal compressor, gating, or active breathing control. The inclusion of PET/CT to the Brainlab treatment planning system further refines the target delineation and possibly guides differential fraction size prescription and delivery. The majority of the patients tolerated the SBRT treatment well despite the longer daily treatment time when compared to that of conventional treatment. All patients achieved good pain relief after SBRT. Compared to conventional standard radiotherapy of lower daily fraction size, we observed that the patients achieved faster pain relief and possibly more durable symptom control. Very high local control with stable disease on imaging was observed post SBRT. Our initial experience shows that the Brainlab Novalis system is very versatile in delivering image-guided SBRT to various anatomical sites. This SBRT approach can be applied to either primary or metastatic lesions in the primary, "boost," or re-irradiation settings. The understanding of fraction size, total dose, BED, and DVH of normal tissues is very important in the treatment planning. Appropriate use of immobilization devices, radio-opaque markers for image-guidance, 4D-CT for tumor/organ motion estimates, and fusion of planning CT scans with biological/functional imaging will further improve the planning and delivery of SBRT, hopefully leading to better treatment outcome.

Hydrophobic interactions in complexes of antimicrobial peptides with bacterial polysaccharides.

Biofilms of Pseudomonas aeruginosa are responsible for chronic lung infections in cystic fibrosis patients, where they are characterized by overproduction of the exopolysaccharide alginate and are recalcitrant to treatment with conventional antibiotics. Cationic antimicrobial peptides (CAPs) are potential alternatives for the treatment of multi-drug-resistant P. aeruginosa. However, alginate in P. aeruginosa biofilms has been proposed to bind these peptides through hydrophobic interactions, consequently reducing their activity [Chan et al., J Biol Chem 2004; 279: 38749-38754]. Here we perform biophysical analyses of the interactions of alginate with a series of novel peptide antibiotics (alpha-CAPs) of prototypic sequence KK-AAAXAAAAAXAAWAAXAAA-KKKK (where X = Phe, Trp or Leu). The hydrophobic interaction interface in alginate was investigated by examining (i) the effects of polysaccharide composition with respect to D-mannuronate and L-guluronate content; (ii) glycan chain length; (iii) alpha-CAP Trp fluorescence; and (iv) 1-anilinonaphthalene-8-sulfonate fluorescence. The results show that, while M and G residues produce equivalent effects, hydrophobic interactions between alginate and alpha-CAPs require a minimal glycan chain length. Peptide interactions with alginate are deduced to be mediated by hydrophobic microdomains comprised of pyranosyl C-H groups that are inducible upon formation of alpha-CAP-alginate complexes due to charge neutralization between the two species.

Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase.

Lung cancer cells elaborate the immunosuppressive and antiapoptotic mediator prostaglandin E(2) (PGE(2)), a product of cyclooxygenase-2 (COX-2) enzyme activity. Because peroxisome proliferator-activated receptor (PPAR)gamma ligands, such as thiazolidinediones (TZDs), inhibit lung cancer cell growth, we examined the effect of the TZDs pioglitazone and rosiglitazone on PGE(2) levels in non-small-cell lung cancer (NSCLC) A427 and A549 cells. Both TZDs inhibited PGE(2) production in NSCLC cells via a COX-2 independent pathway. To define the mechanism underlying COX-2 independent suppression of PGE(2) production, we focused on other enzymes responsible for the synthesis and degradation of PGE(2). The expression of none of the three prostaglandin synthases (microsomal PGES1, PGES2 and cystosolic PGES) was down-regulated by the TZDs. It is noteworthy that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that produces biologically inactive 15-ketoprostaglandins from active PGE(2), was induced by TZDs. The TZD-mediated suppression of PGE(2) concentration was significantly inhibited by small interfering RNA to 15-PGDH. Studies using dominant-negative PPARgamma overexpression or 2-chloro-5-nitrobenzanilide (GW9662; a PPARgamma antagonist) revealed that the suppressive effect of the TZDs on PGE(2) is PPARgamma-independent. Together, these findings indicate that it is possible to use a clinically available pharmacological intervention to suppress tumor-derived PGE(2) by enhancing catabolism rather than blocking synthesis.

Lymphoscintigraphy does not enhance sentinel node identification or alter management of patients with early breast cancer.

UNLABELLED: Lymphoscintigraphy (LS) is often performed before sentinel lymph node dissection (SLND) for breast cancer. The purpose of this study was to determine whether routine LS enhances rate of identification of sentinel nodes (SN), and if findings on LS alter either the SLND procedure or the subsequent patient management. METHODS: LS using technetium-99m sulfur colloid (99mTc) was performed in 136 consecutive patients undergoing SLND for invasive breast cancer. Three equal aliquots of 99mTc were injected peritumorally, and LS images were obtained at 60 to 120 min after 99mTc injection. Data were collected on the success of LS to visualize SN. Information regarding body mass index (BMI), biopsy type (core vs excisional), tumor location (medial vs lateral), and SN positivity were recorded and comparison was made with success of operative SN identification. In all SLND cases, 1% lymphazurin blue dye was used in addition to the 99mTc. RESULTS: LS failed to identify an SN in 9 of 136 cases (6.6%). Failed mappings did not correlate with biopsy type, tumor location, or SN positivity. There was a positive correlation between increased BMI and failed LS (p = <0.001). Failed LS did not predict operative SLND failure, as an SN was identified in 100% of cases (136/136), including the 9 with a failed LS. In 67% (6/9) of the failed LS, the SN was both hot and blue at operation. Internal mammary (IM) drainage was observed in 4% (6/136) of LS. Positive SN were found in 26% (35/136) of patients. Findings on LS did not affect adjuvant treatment decisions in any patient. CONCLUSIONS: There was a correlation between failed LS and BMI, but no correlation with biopsy type or tumor location. Drainage to extraaxillary sites was rare. LS findings did not enhance success of intraoperative identification of SN or alter the postoperative management of patients with early stage breast cancer.

Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer-interim report on PSA response and biopsy data.

PURPOSE: There is an evolving role for combining radiotherapy (RT) with gene therapy in the management of prostate cancer. However, the clinical results of this combined approach are much needed. The preliminary results addressing the safety of this Phase I-II study combining RT and gene therapy (adenovirus/herpes simplex virus-thymidine kinase gene/valacyclovir with or without hormonal therapy) in the treatment of prostate cancer have been previously reported. We now report the prostate-specific antigen (PSA) response and biopsy data. METHODS AND MATERIALS: This trial was composed of three separate arms. Arm A consisted of low-risk patients (Stage T1-T2a, Gleason score <7, pretreatment PSA <10 ng/mL) treated with combined RT-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated RT. They also received adenovirus/herpes simplex virus-thymidine kinase/valacyclovir gene therapy. Arm B consisted of high-risk patients (Stage T2b-T3, Gleason score >6, pretreatment PSA level >10 ng/mL) treated with combined RT-gene therapy and hormonal therapy (luteinizing hormone-releasing hormone agonist [30-mg Lupron, 4-month depot] and an antiandrogen [flutamide, 250 mg t.i.d. for 14 days]). Arm C consisted of patients with Stage D1 (positive pelvic lymph nodes) who received the same regimen as Arm B with the addition of 45 Gy to the pelvic lymphatics. PSA determination and biopsy were performed before, during, and after treatment. The American Society for Therapeutic Radiology and Oncology consensus definition (three consecutive rises in PSA level) was used to denote PSA failure. RESULTS: Fifty-nine patients (29 in Arm A, 26 in Arm B, and 4 in Arm C) completed the trial. The median age was 68 years (range, 39-85 years). The median follow-up for the entire group was 13.5 months (range, 1.4-27.8 months). Only Arm A patients were observed to have an increase in PSA on Day 14. The PSA then declined appropriately. All patients in Arm A (median follow-up, 13.4 months) and Arm B (median follow-up, 13.9 months) had biochemical control at last follow-up. Three patients in Arm C (with pretreatment PSA of 335, 19.6, and 2.5 ng/mL and a combined Gleason score of 8, 9, and 9 involving all biopsy cores) had biochemical failure at 3, 3, and 7.7 months. Two patients had distant failure in bone and 1 patient in the para-aortic lymph nodes outside the RT portal. Six to twelve prostate biopsies performed in these 3 patients revealed no evidence of residual carcinoma. In Arm A, biopsy showed no evidence of carcinoma in 66.7% (18 of 27), 92.3% (24 of 26), 91.7% (11 of 12), 100% (8 of 8), and 100% (6 of 6) at 6 weeks, 4 months, 12 months, 18 months, and 24 months after treatment, respectively. In Arm B, no evidence of carcinoma on biopsy was noted in 96% (24 of 25), 90.5% (19 of 21), 100% (14 of 14), 100% (7 of 7), and 100% (2 of 2), respectively, in the same interval after treatment. CONCLUSION: This is the first reported trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of RT by combining it with in situ gene therapy. The initial transient PSA rise in the Arm A patients may have been a result of local immunologic response or inflammation elicited by in situ gene therapy. Additional investigation to elucidate the mechanisms is needed. Hormonal therapy may have obliterated this rise in Arm B and C patients. The biopsy data were encouraging and appeared to show no evidence of malignancy earlier than historical data. Combined RT, short-course hormonal therapy, and in situ therapy appeared to provide good locoregional control but inadequate systemic control in patients with positive pelvic lymph nodes. Longer term use of hormonal therapy in addition to gene therapy and RT has been adopted for this group of patients to maximize both locoregional and systemic control.

Initial experience using intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma.

PURPOSE: To report our initial experience on the feasibility, toxicity, and tumor control using intensity-modulated radiotherapy (IMRT) for retreatment of recurrent nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: A total of 49 patients with locoregional recurrent carcinoma in the nasopharynx were treated with IMRT between January 2001 and February 2002 at the Sun Yat-Sen University Cancer Center, Guangzhou, China. The average time to the nasopharyngeal recurrence was 30.2 months after initial conventional RT. The median isocenter dose to the nasopharynx was 70 Gy (range 60.9-78.0) for the initial conventional RT. All patients were restaged at the time of recurrence according to the 1992 Fuzhou, China staging system on NPC. The number of patients with Stage I, II, III and IV disease was 4, 9, 10, and 26, respectively. T1, T2, T3, and T4 disease was found in 4, 9, 11, and 25 patients, respectively. N0, N1, N2, and N3 disease was found in 46, 2, 0, and 1 patient, respectively. Invasion of the nasal cavity, maxillary sinus, ethmoid sinus, sphenoid sinus, and cavernous sinus and erosion of the base of the skull was found in 8, 1, 3, 8, 15, and 20 patients, respectively. The gross tumor volume (GTV) was contoured according to the International Commission on Radiation Units and Measurements (ICRU) Report 62 guidelines. The critical structures were contoured, and the doses to critical structures were constrained according to ICRU 50 guidelines. The GTV in the nasopharynx and positive lymph nodes in the neck received a prescription dose of 68-70 Gy and 60 Gy, respectively. All patients received full-course IMRT. Three patients who had positive lymph nodes were treated with five to six courses of chemotherapy (cisplatin + 5-fluorouracil) after IMRT. RESULTS: The treatment plans showed that the percentage of GTV receiving 95% of the prescribed dose (V(95-GTV)) was 98.5%, and the dose encompassing 95% of GTV (D(95-GTV)) was 68.1 Gy in the nasopharynx. The mean dose to the GTV was 71.4 Gy. The average doses of the surrounding critical structures were much lower than the tolerable thresholds. At a median follow-up of 9 months (range 3-13), the locoregional control rate was 100%. Three cases (6.1%) of locoregional residual disease were seen at the completion of IMRT, but had achieved a complete response at follow-up. Three patients developed metastases at a distant site: two in the bone and one in the liver and lung at 13 months follow-up. Acute toxicity (skin, mucosa, and xerostomia) was acceptable according to the Radiation Therapy Oncology Group criteria. Tumor necrosis was seen toward the end of IMRT in 14 patients (28.6%). CONCLUSION: The improvement in tumor target coverage and significant sparing of adjacent critical structures allow the feasibility of IMRT as a retreatment option for recurrent NPC after initial conventional RT. This is the first large series using IMRT to reirradiate local recurrent NPC after initial RT failed. The treatment-related toxicity profile was acceptable. The initial tumor response/local control was also very encouraging. In contrast to primary NPC, recurrent NPC reirradiated with high-dose IMRT led to the shedding of tumor necrotic tissue toward the end of RT. More patients and longer term follow-up are warranted to evaluate late toxicity and treatment outcome.

Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme.

PURPOSE: A pilot study was designed to evaluate the safety and efficacy of a novel regimen of hypofractionated intensity-modulated radiotherapy (RT) in the adjuvant treatment of primary glioblastoma multiforme (GBM). The rationale of the study was to combine the potential radiobiologic advantage of hypofractionation to GBM with a highly conformal radiotherapeutic technique. The study was designed to measure the acute and chronic morbidity of patients treated with this regimen, response of GBM to the treatment, overall survival, and time to disease progression after therapy completion. METHODS AND MATERIALS: Twenty eligible patients were accrued between February 1999 and May 2000 for the study. All patients had Karnofsky performance scores of >/=70. All patients were treated with intensity-modulated RT using the NOMOS Peacock system. A dose of 50 Gy was delivered in 5-Gy daily fractions within 2 weeks to enhancing primary disease, residual tumor, or surgical cavity. Simultaneously, 30 Gy was prescribed in 3-Gy daily fractions to surrounding edema. The time to progression was measured with serial neurologic examinations and MRI or CT scans after RT completion. Acute and late toxicity was graded using Radiation Therapy Oncology Group neurotoxicity scores. RESULTS: Of the 20 patients, 18 were evaluated for outcome. The median time to disease progression was 6 months after RT completion. The median overall survival was 7 months after treatment completion. All recurrences were within 2 cm of the operative bed. Neurotoxicity during therapy was minimal, with all patients experiencing Grade 0 or 1 toxicity. Late toxicity included 10 patients with Grade 0, 2 patients with Grade 2, and 3 patients with Grade 4 toxicity, manifesting as brain necrosis requiring surgical reexcision. The survival of the 3 patients with brain necrosis was 23, 20, and 9 months. Mortality in all cases was the result of tumor recurrence, with no mortality resulting from brain necrosis. CONCLUSION: This regimen of hypofractionated intensity-modulated RT did not improve the time to disease progression or overall survival compared with historical experience using conventional fractionation. However, the treatment duration was reduced from 6 weeks to 2 weeks, which may be of palliative benefit in certain subsets of patients. This treatment regimen demonstrated a greater incidence of brain necrosis requiring surgical intervention; however, the 3 patients experiencing this toxicity had longer survival times. Future investigation may be useful to determine which fraction size may be optimal for GBM when highly conformal RT is used in the adjuvant setting.

Roles of histidine residues in plant vacuolar H(+)-pyrophosphatase.

Vacuolar proton pumping pyrophosphatase (H(+)-PPase; EC 3.6.1.1) plays a pivotal role in electrogenic translocation of protons from cytosol to the vacuolar lumen at the expense of PP(i) hydrolysis. Alignment analysis on amino acid sequence demonstrates that vacuolar H(+)-PPase of mung bean contains six highly conserved histidine residues. Previous evidence indicated possible involvement of histidine residue(s) in enzymatic activity and H(+)-translocation of vacuolar H(+)-PPase as determined by using histidine specific modifier, diethylpyrocarbonate [J. Protein Chem. 21 (2002) 51]. In this study, we further attempted to identify the roles of histidine residues in mung bean vacuolar H(+)-PPase by site-directed mutagenesis. A line of mutants with histidine residues singly replaced by alanine was constructed, over-expressed in Saccharomyces cerevisiae, and then used to determine their enzymatic activities and proton translocations. Among the mutants scrutinized, only the mutation of H716 significantly decreased the enzymatic activity, the proton transport, and the coupling ratio of vacuolar H(+)-PPase. The enzymatic activity of H716A is relatively resistant to inhibition by diethylpyrocarbonate as compared to wild-type and other mutants, indicating that H716 is probably the target residue for the attack by this modifier. The mutation at H716 of V-PPase shifted the optimum pH value but not the T(1/2) (pretreatment temperature at which half enzymatic activity is observed) for PP(i) hydrolytic activity. Mutation of histidine residues obviously induced conformational changes of vacuolar H(+)-PPase as determined by immunoblotting analysis after limited trypsin digestion. Furthermore, mutation of these histidine residues modified the inhibitory effects of F(-) and Na(+), but not that of Ca(2+). Single substitution of H704, H716 and H758 by alanine partially released the effect of K(+) stimulation, indicating possible location of K(+) binding in the vicinity of domains surrounding these residues.

Rare case of metastatic prostate adenocarcinoma to the pituitary.

We report a rare case of metastatic prostate adenocarcinoma to the pituitary gland. The patient had lung and bone metastases when he presented with bitemporal hemianopsia. He was also receiving total androgen blockade at that time. Magnetic resonance imaging showed an intrasellar mass, and biopsy confirmed metastatic prostate cancer. Radiotherapy, in the form of intensity-modulated radiotherapy, was delivered to the intrasellar mass. The patient responded well to radiotherapy. The mechanisms of spread to the pituitary gland and treatment options, including intensity-modulated radiotherapy, are discussed.

Dosimetric predictors of xerostomia for head-and-neck cancer patients treated with the smart (simultaneous modulated accelerated radiation therapy) boost technique.

PURPOSE: To evaluate the predictors of xerostomia in the treatment of head-and-neck cancers treated with intensity-modulated radiation therapy (IMRT), using the simultaneous modulated accelerated radiation therapy (SMART) boost technique. Dosimetric parameters of the parotid glands are correlated to subjective salivary gland function. MATERIALS AND METHODS: Between January 1996 and June 2000, 30 patients with at least 6 months follow-up were evaluated for subjective xerostomia after being treated definitively for head-and-neck cancer with the SMART boost technique. Threshold limits for the ipsilateral and contralateral parotid glands were 35 Gy and 25 Gy, respectively. Dosimetric parameters to the parotid glands were evaluated. The median follow-up time was 38.5 months (mean 39.9 months). The results of the dosimetric parameters and questionnaire were statistically correlated. RESULTS: Xerostomia was assessed with a 10-question subjective salivary gland function questionnaire. The salivary gland function questionnaire (questions 1, 2, 3, 4, 6, and 9) correlated significantly with the dosimetric parameters (mean and maximum doses and volume and percent above tolerance) of the parotid glands. These questions related to overall comfort, eating, and abnormal taste. Questions related to thirst, difficulty with speech or sleep, and the need to carry water daily did not correlate statistically with the dosimetric parameters of the parotid glands. CONCLUSIONS: Questions regarding overall comfort, eating, and abnormal taste correlated significantly with the dosimetric parameters of the parotid glands. Questions related to thirst, difficulty with speech or sleep, and the need to carry water daily did not correlate statistically with the dosimetric parameters of the parotid glands. Dosimetric sparing of the parotid glands improved subjective xerostomia. IMRT in the treatment of head-and-neck cancer can be exploited to preserve the parotid glands and decrease xerostomia. This is feasible even with an accelerated treatment regimen like the SMART boost. More patients need to be evaluated using IMRT to identify relevant dosimetric parameters.

IMRT for prostate cancer: defining target volume based on correlated pathologic volume of disease.

PURPOSE: The intensity-modulated radiation therapy (IMRT) treatment planning system generates tightly constricted isodose lines. It is very important to define the margins that are acceptable in the treatment of prostate cancer to maximize the dose escalation and normal tissue avoidance advantages offered by IMRT. It is necessary to take into account subclinical disease and the potential for extracapsular spread. Organ and patient motion as well as setup errors are variables that must be minimized and defined to avoid underdosing the tumor or overdosing the normal tissues. We have addressed these issues previously. The purpose of the study was twofold: to quantify the radial distance of extracapsular extension in the prostatectomy specimens, and to quantify differences between the pathologic prostate volume (PPV), CT-based gross tumor volume (GTV), and planning target volume (PTV). MATERIALS AND METHODS: Two related studies were undertaken. A total of 712 patients underwent prostatectomy between August 1983 and September 1995. Pathologic assessment of the radial distance of extracapsular extension was performed. Shrinkage associated with fixation was accounted for with a linear shrinkage factor. Ten patients had preoperative staging studies including a CT scan of the pelvis. The GTV was outlined and volume determined from these CT scans. The PTV, defined as GTV with a 5-mm margin in all dimensions, was then calculated. The Peacock inverse planning system (NOMOS Corp., Sewickley, PA) was used. The PPV, GTV, and PTV were compared for differences and evaluated for correlation. RESULTS: Extracapsular extension (ECE) (i.e., prostatic capsular invasion level 3 [both focal and established]) was found in 299 of 712 patients (42.0%). Measurable disease extending radially outside the prostatic capsule (i.e., ECE level 3 established) was noted in 185 of 712 (26.0%). The median radial extension was 2.0 mm (range 0.50-12.00 mm) outside the prostatic capsule. As a group, 20 of 712 (2.8%) had extracapsular extension of more than 5 mm. In the volumetric comparison and correlation study of the GTV and PTV to the PPV, the average GTV was 2 times larger than the PPV. The average PTV was 4.1 times larger than the PPV. CONCLUSIONS: This is the largest series in the literature quantitatively assessing prostatic capsular invasion (i.e., the radial extracapsular extension). It is the first report of a comparison of PPV to CT-planned GTV and PTV. Using patient and prostate immobilization, 5 mm of margin to the GTV in this study provided sufficient coverage of the tumor volume based on data gathered from 712 patients. In the absence of prostate immobilization, additional margins of differing amounts depending on the technique employed would have to be placed to account for target, patient, and setup uncertainties. The large mean difference between CT-based estimates of the tumor volume and target volume (GTV+PTV) and PPV added further evidence for adequacy of tumor coverage. Target immobilization, setup error, and coverage of subclinical disease must be addressed carefully before successful implementation of IMRT to maximize its ability to escalate dose and to spare normal tissue simultaneously and safely.