Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3)

PURPOSE: Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. METHODS AND MATERIALS: A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. RESULTS: Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). CONCLUSION: In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy.     

177Lu-EDTMP: a viable bone pain palliative in skeletal metastasis

Designing ideal radiopharmaceuticals for use as bone pain palliatives require the use of a moderate energy beta() emitter as a radionuclide and a suitable polyaminophosphonic acid as a carrier molecule. Owing to its suitable decay characteristics [T(1/2) = 6.73 d, E((max)) = 497 keV, E() = 113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production in adequate specific activity and radionuclidic purity using a moderate flux reactor, 177Lu could be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study was therefore, oriented toward the preparation and biologic evaluation of 177Lu complex of ethylenediaminetetramethylene phosphonic acid (EDTMP) in various animal models, with an aim to prepare a viable radiopharmaceutical for bone pain palliation. 177Lu was produced with a specific activity of approximately 12 GBq/mg (approximately 324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural Lu2O3 targeted at a thermal neutron flux of approximately 6 x 10(13) n/cm(2).s for 21 days. 177Lu-EDTMP complex was prepared in high-yield and excellent radiochemical purity (>99%), using EDTMP synthesized and characterized in-house. The complex exhibited excellent in vitro stability at room temperature. Biodistribution studies in Wistar rats showed a rapid skeletal accumulation of injected activity [(1.74 +/- 0.30)% per gram in femur at 3 hours postinjection] with a fast clearance from blood and minimal uptake in any of the major organs. Scintigraphic imaging studies carried out in normal Wistar rats, New Zealand white rabbits, as well as in Beagle dogs also demonstrated significant accumulation of the agent in the skeleton and almost no retention of activity in any other vital organs.     

A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression

Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP.     

Evaluation of seasonal variations in abundance of BTXE hydrocarbons and their ozone forming potential in ambient urban atmosphere of Dehradun (India)

In Dehradun, ambient volatile organic compounds (VOC) samples were collected for three seasons viz. summer, winter and monsoon (during period 2012–2013) to investigate seasonal variations at five different sampling sites. The samples were quantified for aromatic VOCs by gas chromatography (GC-FID) to monitor benzene, toluene, m, p-xylene, o-xylene and ethylbenzene. BTXE comprise an important group of VOCs mostly prevalent in a typical urban environment. They were monitored because they are known to cause impacts on climate, health and on vegetation. Toluene was found to be the most abundant VOC among the measured ones in the atmosphere of Dehradun. The maximum mean concentration of VOCs was observed in winters and lowest during summers for BE species. Toluene ambient concentration was rather found to register highest during winters and lowest in monsoons. Kruskal–Wallis test showed statistically significant differences seasonally (p?<?0.05). High toluene to benzene T/B (>1) observed ratio indicates vehicular emission as their major source. BTEX were also evaluated for their ozone-forming potential (OFP). Toluene and xylenes were found as the highest contributing hydrocarbons towards ozone forming potential among BTXE.     

Technique and preliminary results of interstitial irradiation for primary brain tumors

We have conducted a phase-I clinical trial of CT guided stereotactic implantation of Ir¹⁹² in the treatment of malignant astrocytomas. During the past year, 16 patients have been implanted with two to four catheters in the residual enhancing portion of their tumor. These patients represent 50% of our total experience with the CT compatible Leksell frame. Each catheter contains three to six high intensity (2.0 to 2.5 mg Ra equivalent) seeds with 0.5 cm separation between the sources. The total activity of Ir¹⁹² per implant has been 30–65 mg radium equivalent. In the 16 patients, 49 catheters have been placed, an average of three targets calculated per patient and no targets have been missed. The radiation exposure to personnel has been surveyed in detail and drops off to less than 2 mr/h six feet from the patient when our custombuilt radiation shield is employed. We have reserved permanent implantation of I¹²⁵ for patients with tumors in unusual locations (e.g. pineal) or for individuals with slowly growing non-gliomatous lesions (i.e. meningioma). The tumor volumes have ranged from 12–120 cm³. Unique aspects of our implant procedure include the use of a Leksell frame already adapted to the GE-8800 scanner, the use of pre- and post-implant computerized treatment planning programs to determine the dose distribution profiles and the use of adjustable metal collars crimped to the outer catheters to provide ease of insertion, uniform pre-implant catheter length, and protection against source migration. Two of our patients have suffered from subacute radiation reactions, primarily due to delayed cerebral edema and both of these cases have largely resolved. We believe that it is technologically feasible to deliver 5000 rads to the tumor periphery in 50 h without undue patient toxicity or environmental radiation hazard. The system we have been studying is fully compatible with the simultaneous use of mechanical cytoreduction, chemotherapy and interstitial hyperthermia.     

A case-control study of reproductive risk factors associated with cervical cancer

Using the logistic-regression technique, a hospital-based case-control study of 177 married women with invasive squamous-cell cervical cancer and 149 hospital-visiting controls enabled evaluation of selected reproductive factors as risks. Early age at marriage was found to be the single best predictor of the disease status. However, those who married late but gave birth to a large number of children were generally found to be suffering from cervical cancer. The results support the hypothesis that it is not so much parity per se that enhances the risk, but the rapidity of multiple pregnancies that matters. Logistic analysis also revealed the independent influence of birth interval on the risk of cervical cancer. These findings warrant serious consideration in future studies, given the obvious implications for prevention. Other implications for the prevention of cervical cancer are briefly discussed. © 1994 Wiley-Liss, Inc.