David R. W. Hodgson

A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma

Renal cell carcinoma (RCC) has previously been described as being less responsive to radiotherapy (RT) than other tumor types. The authors conducted a prospective study to assess the effect of RT on symptoms and quality of life (QOL) in patients with metastatic RCC.

Characteristics and Outcomes of Breast Cancer in Women With and Without a History of Radiation for Hodgkin's Lymphoma: A Multi-Institutional, Matched Cohort Study

PURPOSE To compare characteristics and outcomes of breast cancer in women with and without a history of radiation therapy (RT) for Hodgkins lymphoma (HL). PATIENTS AND METHODS Women with breast cancer diagnosed from 1980 to 2006 after RT for HL were identified from eight North American hospitals and were matched three-to-one with patients with sporadic breast cancer by age, race, and year of breast cancer diagnosis. Information on patient, tumor and treatment characteristics, and clinical outcomes was abstracted from medical records. RESULTS A total of 253 patients with breast cancer with a history of RT for HL were matched with 741 patients with sporadic breast cancer. Median time from HL to breast cancer diagnosis was 18 years. Median age at breast cancer diagnosis was 42 years. Breast cancer after RT for HL was more likely to be detected by screening, was more likely to be diagnosed at an earlier stage, and was more likely to be bilateral at diagnosis. HL survivors had an increased risk of metachronous contralateral breast cancer (adjusted hazard ratio [HR], 4.3; 95% CI, 1.7 to 11.0) and death as a result of any cause (adjusted HR, 1.9; 95% CI, 1.1 to 3.3). Breast cancer-specific mortality was also elevated, but this difference was not statistically significant (adjusted HR, 1.6; 95% CI, 0.7 to 3.4). CONCLUSION In women with a history of RT for HL, breast cancer is diagnosed at an earlier stage, but these women are at greater risk for bilateral disease and are more likely to die as a result of causes other than breast cancer. Our findings support close follow-up for contralateral tumors in these patients and ongoing primary care to manage comorbid conditions.

Long-term outcome in stage I and II follicular lymphoma following treatment with involved field radiation therapy alone

6521 Background: Patients with localized follicular lymphoma (FL) are usually treated with radiation therapy (RT). The aim of this study was to assess the long-term overall survival (OS), local disease control and pattern of relapse after involved-field RT in stage I/II FL Methods: 669 patients with stage I and II FL were seen between 1968 and 1999. The records on these patients were systematically collected in an institutional database. The analysis focused on the outcome of treatment in terms of OS, relapse and local disease control in those initially treated with involved-field RT alone (n=460). Median RT dose was 35 Gy (16.0 -47.5 Gy) given over 3-4 wks Results: In 460 patients treated with RT alone, the median age at diagnosis was 59 yrs (17 - 86 yrs); median follow-up duration was 12.5 yrs (range 1.1 -32.2 yrs). The clinical stage was: stage IA: 337 pts, stage IIA: 115 pts, IB: 2 pts and IIB: 5 pts. Histology was: follicular grade 1: 35%, grade 2: 38%, and grade 3: 27%. 75% had nodal disease alone, and 25% presented with extranodal disease. 43% had Karnofsky performance status (KPS) of 100% and 55% KPS of 90%. OS at 5 and 10 yrs were 79% and 62% and DFS 56% and 41%, respectively. Local disease control was excellent; 450 patients achieved complete response and only 5.5% relapsed in radiation fields. Most relapses occurred in distant sites. The cumulative incidence rates for relapse at 5, 10, 15, 20, and 25 yrs were 38%, 48%, 54%, 56%, and 56% respectively. For those at risk of relapse, the probability of relapse between 5 and 10 yrs was only 11%, for 10-15 yrs 6%, and beyond 15 yrs, 2%. CONCLUSIONS Involved-field radiation therapy provides excellent local control in stage I and II follicular lymphomas. Long-term clinical disease control is observed in over 40% of pts. While 30% of all relapses occur after 5 years, risk of very late relapse is low. Long-term follow-up is recommended. No significant financial relationships to disclose.

A tRNA aminoacylation system for non-natural amino acids based on a programmable ribozyme.

The ability to recognize tRNA identities is essential to the function of the genetic coding system. In translation aminoacyl-tRNA synthetases (ARSs) recognize the identities of tRNAs and charge them with their cognate amino acids. We show that an in vitro–evolved ribozyme can also discriminate between specific tRNAs, and can transfer amino acids to the 3′ ends of cognate tRNAs. The ribozyme interacts with both the CCA-3′ terminus and the anticodon loop of tRNAfMet, and its tRNA specificity is controlled by these interactions. This feature allows us to program the selectivity of the ribozyme toward specific tRNAs, and therefore to tailor effective aminoacyl-transfer catalysts. This method potentially provides a means of generating aminoacyl tRNAs that are charged with non-natural amino acids, which could be incorporated into proteins through cell-free translation.

Catabolism of Glutathione Conjugates in Arabidopsis thaliana ROLE IN METABOLIC REACTIVATION OF THE HERBICIDE SAFENER FENCLORIM

The safener fenclorim (4,6-dichloro-2-phenylpyrimidine) increases tolerance to chloroacetanilide herbicides in rice by enhancing the expression of detoxifying glutathione S-transferases (GSTs). Fenclorim also enhances GSTs in Arabidopsis thaliana, and while investigating the functional significance of this induction in suspension cultures, we determined that these enzymes glutathionylated the safener. The resulting S-(fenclorim)-glutathione conjugate was sequentially processed to S-(fenclorim)-γ-glutamyl-cysteine and S-(fenclorim)-cysteine (FC), the latter accumulating in both the cells and the medium. FC was then either catabolized to 4-chloro-6-(methylthio)-phenylpyrimidine (CMTP) or N-acylated with malonic acid. These cysteine derivatives had distinct fates, with the enzymes responsible for their formation being induced by fenclorim and FC. Fenclorim-N-malonylcysteine was formed from FC by the action of a malonyl-CoA-dependent N-malonyltransferase. A small proportion of the fenclorim-N-malonylcysteine then underwent decarboxylation to yield a putative S-fenclorim-N-acetylcysteine intermediate, which underwent a second round of GST-mediated S-glutathionylation and subsequent proteolytic processing. The formation of CMTP was catalyzed by the concerted action of a cysteine conjugate β-lyase and an S-methyltransferase, with the two activities being coordinately regulated. Although the fenclorim conjugates tested showed little GST-inducing activity in Arabidopsis, the formation of CMTP resulted in metabolic reactivation, with the product showing good enhancing activity. In addition, CMTP induced GSTs and herbicide-safening activity in rice. The bioactivated CMTP was in turn glutathione-conjugated and processed to a malonyl cysteine derivative. These results reveal the surprisingly complex set of competing catabolic reactions acting on xenobiotics entering the S-glutathionylation pathway in plants, which can result in both detoxification and bioactivation.

Report from the Rockefellar Foundation Sponsored International Workshop on reducing mortality and improving quality of life in long-term survivors of Hodgkin's disease: July 9–16, 2003, Bellagio, Italy

Abstract:  A workshop, sponsored by the Rockefellar Foundation, was held between 9 to 16 July, 2003 to devise strategies to reduce mortality and improve quality of life of long‐term survivors of Hodgkins disease. Participants were selected for their clinical and research background on late effects after Hodgkins disease therapy. Experts from both developed and developing nations were represented in the workshop, and efforts were made to ensure that the proposed strategies would be globally applicable whenever possible. The types of late complications, magnitude of the problem, contributing risk factors, methodology to assess the risk, and challenges faced by developing countries were presented. The main areas of late effects of Hodgkins disease discussed were as follows: second malignancy, cardiac disease, infection, pulmonary dysfunction, endocrine abnormalities, and quality of life. This report summarizes the findings of the workshop, recommendations, and proposed research priorities in each of the above areas.

Regulation of prokaryotic adenylyl cyclases by CO2.

The Slr1991 adenylyl cyclase of the model prokaroyte Synechocystis PCC 6803 was stimulated 2-fold at 20 mM total C(i) (inorganic carbon) at pH 7.5 through an increase in k(cat). A dose response demonstrated an EC50 of 52.7 mM total C(i) at pH 6.5. Slr1991 adenylyl cyclase was activated by CO2, but not by HCO3-. CO2 regulation of adenylyl cyclase was conserved in the CyaB1 adenylyl cyclase of Anabaena PCC 7120. These adenylyl cyclases represent the only identified signalling enzymes directly activated by CO2. The findings prompt an urgent reassessment of the activating carbon species for proposed HCO3--activated adenylyl cyclases.

Stimulation of Mammalian G-protein-responsive Adenylyl Cyclases by Carbon Dioxide

Carbon dioxide is fundamental to the physiology of all organisms. There is considerable interest in the precise molecular mechanisms that organisms use to directly sense CO2. Here we demonstrate that a mammalian recombinant G-protein-activated adenylyl cyclase and the related Rv1625c adenylyl cyclase of Mycobacterium tuberculosis are specifically stimulated by CO2. Stimulation occurred at physiological concentrations of CO2 through increased kcat. CO2 increased the affinity of enzyme for metal co-factor, but contact with metal was not necessary as CO2 interacted directly with apoenzyme. CO2 stimulated the activity of both G-protein-regulated adenylyl cyclases and Rv1625c in vivo. Activation of G-protein regulated adenylyl cyclases by CO2 gave a corresponding increase in cAMP-response element-binding protein (CREB) phosphorylation. Comparison of the responses of the G-protein regulated adenylyl cyclases and the molecularly, and biochemically distinct mammalian soluble adenylyl cyclase revealed that whereas G-protein-regulated enzymes are responsive to CO2, the soluble adenylyl cyclase is responsive to both CO2 and bicarbonate ion. We have, thus, identified a signaling enzyme by which eukaryotes can directly detect and respond to fluctuating CO2.

Children's Oncology Group's 2013 blueprint for research: Hodgkin lymphoma

In childhood Hodgkin lymphoma, estimated 5 years survival rates exceed 90%. Long‐term survival continues to decline from delayed toxicities. Key findings from recent Childrens Oncology Group trials include: (1) Radiotherapy selection may be based on early chemotherapy response assessed by both FDG‐PET and CT imaging, (2) A new prognostic factor score stratifies patients into risk categories; and (3) novel retrieval regimens were identified. A phase I/II trial is investigating Brentuximab vedotin (Bv) with gemcitabine in relapsed patients. A phase 3 trial will modify conventional chemotherapy and radiotherapy approaches through the addition of Bv, while incorporating translational biology to identify molecular targets. Pediatr Blood Cancer 2013; 60: 972–978.

Palliation by Low-Dose Local Radiation Therapy for Indolent Non-Hodgkin Lymphoma

PURPOSE The purpose of this study was to assess the efficacy of a 2×2 Gy (total dose, 4 Gy) palliative radiation therapy (RT) regimen for treating patients with indolent non-Hodgkin lymphoma (NHL) in terms of response rate, response duration, and symptom relief. METHODS AND MATERIALS A retrospective chart review was conducted. Between 2003 and 2007, 54 patients with NHL were treated to 85 anatomical sites with a 2×2 Gy palliative regimen. Local response was assessed by clinical and/or radiographic data. Symptoms before and after treatment for each site treated were obtained from clinical notes in patient medical records. Median follow-up time was 1.3 years. RESULTS For the 54 patients, the median age at time of treatment was 71.1 years old, and 57% of them were male. Of the 85 disease sites treated, 56% of sites had indolent histology, 28% of sites were diagnosed with chronic lymphocytic leukemia (CLL), 13% of sites had aggressive histology, and 2% of sites were shown to have other histology. Overall response rate (ORR) was 81% (49% complete response [CR], 32% partial response [PR]). The 2-year rate for freedom from local progression was 50% (95% CI, 37%-61%). The ORR for follicular lymphoma, Mucosa associated lymphoid tissue (MALT), and marginal zone lymphoma (MZL) histology was 88%, compared with a 59% rate for CLL histology (p=0.005). While the ORR was similar for tumors of different sizes, the CR rate for patients with tumors<5 cm tended to be higher than those with tumors>10 cm (CR rate of 57% vs. 27%, respectively; p=0.06). For the 48 sites with clearly documented symptoms at pretreatment, 92% of sites improved after low-dose RT. CONCLUSIONS Short-course low-dose palliative radiotherapy (2×2 Gy) is an effective treatment that results in high response rates for indolent non-Hodgkin lymphoma. This treatment regimen provides effective symptomatic relief for tumor bulk of all sizes.