Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 µg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.

Radiological protection for pregnant women at a large academic medical Cancer Center.

PURPOSE: Most radiation protection programs, regulations and guidance apply specific restrictions to the occupational exposure of pregnant workers. The aim of this study was to compile data from the declared pregnant woman (DPW) radiation protection program over more than 5years at a large, high-volume, comprehensive oncology academic/medical institution and to evaluate for effectiveness against existing regulations and guidance. METHODS: A retrospective review was performed of the data collected as part of the DPW radiation protection program from January 2010 through May 2016, including the number of declared pregnancies, worker category, personal and fetal dosimetry monitoring measurements, workplace modifications, as well as the monthly and total recorded badge results during the entire pregnancy. RESULTS: 245 pregnancies were declared. The mean monthly fetal radiation dosimetry result was 0.009mSv with a median of 0.005mSv and a maximum of 0.39mSv. The mean total dose over the entire pregnancy was estimated to be 0.08mSv with a median of 0.05mSv and a maximum of 0.89mSv. Only 8 (3.2%) of the 245 declared pregnancies required that workplace modifications be implemented for the worker. CONCLUSIONS: The implementation of a declared pregnancy and fetal assessment program, careful planning, an understanding of the risks, and minimization of radiation dose by employing appropriate radiation safety measures as needed, can allow medical staff to perform procedures and normal activities without incurring significant risks to the conceptus, or significant interruptions of job activities for most medical workers.

Intraoperative high-dose rate of radioactive phosphorus 32 brachytherapy for diffuse recalcitrant conjunctival neoplasms: a retrospective case series and report of toxicity.

IMPORTANCE: Adjunct treatments for conjunctival malignancies are needed when standard therapy provides limited benefits or fails. OBJECTIVE: To describe the results of patients with diffuse conjunctival neoplasms treated with radioactive phosphorus 32 (32P)-impregnated flexible film. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series between January 1, 2010, and January 1, 2013, was conducted at Memorial Sloan-Kettering Cancer Center, a tertiary referral center. The study was conducted on 7 eyes of 6 patients treated for diffuse conjunctival squamous cell carcinoma, sebaceous carcinoma, or lymphoma that had recurrent or residual disease after primary treatment. INTERVENTIONS: Patients underwent mapping biopsies and detailed conjunctival drawings to delineate the pathologic extent of the disease. The brachytherapy film used for treatment was the RIC Conformal Source Model 100 (RIC-100, RI Consultants). The RIC-100 is a flexible, thin (approximately 0.5-mm) film made of a polymer chemically bound to 32P. The radioactive 32P film was placed intraoperatively, allowed to stay in place until the prescription dose was reached, and then removed. The median dose at the prescription point (1 mm from the surface of the film) was 15 Gy (range, 5-17 Gy). MAIN OUTCOMES AND MEASURES: Patients were tested for best-corrected visual acuity, recurrence-free survival, and adverse events scored by using the Adult Comorbidity Evaluation-27 scale. RESULTS: Between 2010 and 2013, 7 eyes of 6 patients were treated. The median age of patients was 70 years. All patients had a recurrent or persistent neoplasm. Four patients with squamous cell carcinoma, 1 with sebaceous carcinoma, and 1 with metachronous bilateral lymphomas were treated. The median treatment time was 19 minutes (range, 10-52 minutes). The median follow-up was 24.9 months (range, 3.1-38.2 months). Recurrence-free survival 24 months after brachytherapy was 75% (95% CI, 19-89.1). Two moderate adverse events and 1 severe adverse event occurred. Visual acuity was stable or improved in 5 of the 7 eyes (ie, better than 20/70 in the 5 patients who retained their treated eye). CONCLUSIONS AND RELEVANCE: Our results show the use of an intraoperative high-dose rate of 32P brachytherapy in selected cases of recalcitrant diffuse conjunctival neoplasms. This technique offers a novel adjunct in the treatment of these cancers. Further follow-up and study are warranted.

Activity thresholds for patient instruction and release for positron emission tomography radionuclides.

The use of unconventional or novel radionuclides for positron emission tomography (PET) is becoming more prevalent in both nuclear medicine diagnosis and therapy. Many of these radionuclides are produced in cyclotrons or are further eluted from generators. Although half-lives from many of these unconventional PET radionuclides are considered relatively short (minutes to hours, but some are days) and the intent of their use is often as a diagnostic imaging agent, patient release criteria and patient radiation safety instruction regulatory requirements are based on estimated dose to a member of the public. This paper reviews a method referenced routinely for patient release criteria as found in U.S. Nuclear Regulatory Commission guidance, estimates fundamental quantities used in the method, compares estimated quantities with the published literature, and calculates release and patient radiation safety instruction criteria for several novel PET radionuclides used in nuclear medicine. It should be recognized that some quantities of novel PET radionuclides in use today reach the threshold for patient safety instruction using conservative model procedures for patient release.

Radiation safety considerations for the use of ²²³RaCl2 DE in men with castration-resistant prostate cancer.

The majority of patients with late stage castration-resistant prostate cancer (CRPC) develop bone metastases that often result in significant bone pain. Therapeutic palliation strategies can delay or prevent skeletal complications and may prolong survival. An alpha-particle based therapy, radium-223 dichloride (²²³RaCl2), has been developed that delivers highly localized effects in target areas and likely reduces toxicity to adjacent healthy tissue, particularly bone marrow. Radiation safety aspects were evaluated for a single comprehensive cancer center clinical phase 1, open-label, single ascending-dose study for three cohorts at 50, 100, or 200 kBq kg⁻¹ body weight. Ten patients received administrations, and six patients completed the study with 1 y follow-up. Dose rates from patients administered ²²³Ra dichloride were typically less than 2 µSv h⁻¹ MBq⁻¹ on contact and averaged 0.02 µSv h⁻¹ MBq⁻¹ at 1 m immediately following administration. Removal was primarily by fecal excretion, and whole body effective half-lives were highly dependent upon fecal compartment transfer, ranging from 2.5-11.4 d. Radium-223 is safe and straightforward to administer using conventional nuclear medicine equipment. For this clinical study, few radiation protection limitations were recommended post-therapy based on facility evaluations. Specific precautions are dependent on local regulatory authority guidance. Subsequent studies have demonstrated significantly improved overall survival and very low toxicity, suggesting that ²²³Ra may provide a new standard of care for patients with CRPC and bone metastases.

Phase I pharmacokinetic and biodistribution study with escalating doses of ²²³Ra-dichloride in men with castration-resistant metastatic prostate cancer.

PURPOSE: ²²³Ra-Dichloride (²²³Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent. METHODS: Ten patients received either 50, 100, or 200 kBq of ²²³Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed. RESULTS: Pharmacokinetic studies showed rapid clearance of ²²³Ra from the vasculature, with a median of 14% (range 9-34%), 2% (range 1.6-3.9%), and 0.5% (range 0.4-1.0%) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52% of administered ²²³Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4% of administered ²²³Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients. CONCLUSION: ²²³Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.

Fears, feelings, and facts: interactively communicating benefits and risks of medical radiation with patients.

OBJECTIVE: As public awareness of medical radiation exposure increases, there has been heightened awareness among patients and physicians of the importance of holistic benefit-and-risk discussions in shared medical decision making. CONCLUSION: We examine the rationale for informed consent and risk communication, draw on the literature on the psychology of radiation risk communication to increase understanding, examine methods commonly used to communicate radiation risk, and suggest strategies for improving communication about medical radiation benefits and risk.

Influence of Triplet Instabilities in TDDFT.

Singlet and triplet vertical excitation energies from time-dependent density functional theory (TDDFT) can be affected in different ways by the inclusion of exact exchange in hybrid or Coulomb-attenuated/range-separated exchange-correlation functionals; in particular, triplet excitation energies can become significantly too low. To investigate these issues, the explicit dependence of excitation energies on exact exchange is quantified for four representative molecules, paying attention to the effect of constant, short-range, and long-range contributions. A stability analysis is used to verify that the problematic TDDFT triplet excitations can be understood in terms of the ground state triplet instability problem, and it is proposed that a Hartree-Fock stability analysis should be used to identify triplet excitations for which the presence of exact exchange in the TDDFT functional is undesirable. The use of the Tamm-Dancoff approximation (TDA) significantly improves the problematic triplet excitation energies, recovering the correct state ordering in benzoquinone; it also affects the corresponding singlet states, recovering the correct state ordering in naphthalene. The impressive performance of the TDA is maintained for a wide range of molecules across representative functionals.

Unconventional nuclides for radiopharmaceuticals.

Rapid and widespread growth in the use of nuclear medicine for both diagnosis and therapy of disease has been the driving force behind burgeoning research interests in the design of novel radiopharmaceuticals. Until recently, the majority of clinical and basic science research has focused on the development of 11C-, 13N-, 15O-, and 18F-radiopharmaceuticals for use with positron emission tomography (PET) and 99mTc-labeled agents for use with single-photon emission computed tomography (SPECT). With the increased availability of small, low-energy cyclotrons and improvements in both cyclotron targetry and purification chemistries, the use of "nonstandard" radionuclides is becoming more prevalent. This brief review describes the physical characteristics of 60 radionuclides, including beta+, beta-, gamma-ray, and alpha-particle emitters, which have the potential for use in the design and synthesis of the next generation of diagnostic and/or radiotherapeutic drugs. As the decay processes of many of the radionuclides described herein involve emission of high-energy gamma-rays, relevant shielding and radiation safety issues are also considered. In particular, the properties and safety considerations associated with the increasingly prevalent PET nuclides 64Cu, 68Ga, 86Y, 89Zr, and 124I are discussed.

Less-restrictive, patient-specific radiation safety precautions can be safely prescribed after permanent seed implantation.

PURPOSE: To use radiation exposure rate measurements to determine patient-specific radiation safety instructions with the aim of reducing unnecessary precaution times and to evaluate potential doses to members of the public. METHODS AND MATERIALS: Radiation exposure rate measurements were obtained from 1279 patients with Stage T1-2 prostate cancer who underwent transperineal (125)I or (103)Pd seed implantation from January 1995 through July 2008. An algorithm was developed from these measurements to determine the required precaution times to maintain public effective doses below 50% of the limits for specific exposure situations. RESULTS: The median air kerma rates at 30 cm from the anterior skin surface were 4.9 microGy/h (range: 0.1-31.5) for (125)I and 1.5 microGy/h (range: 0.02-14.9) for (103)Pd. The derived algorithms depended primarily on the half-life T(p), the measured exposure rate at 30 cm, and specific exposure situation factors. For the typical (103)Pd patient, no radiation safety precautions are required. For the typical (125)I patient, no precautions are required for coworkers, nonpregnant adults who do not sleep with the patient, or nonpregnant adults who sleep with the patient. Typical (125)I patients should only avoid sleeping in the "spoon" position (i.e., in contact) with pregnant adults and avoid holding a child for long periods of time in the lap for about 2 months. CONCLUSIONS: The large number of cases available for this study permitted the development of an algorithm to simply determine patient-specific radiation safety instructions. The resulting precaution times are significantly less restrictive than those generally prescribed currently.

Feasibility of ex vivo FDG PET of the colon.

To facilitate future direct correlations between fluorine 18 fluorodeoxyglucose (FDG)-avid colonic lesions and immunohistochemical assay findings, the authors tested the feasibility of ex vivo FDG positron emission tomography (PET) of the colon resected from humans. In this institutional review board-approved, HIPAA-compliant study, the authors, after obtaining informed patient consent, injected FDG intraoperatively in five patients with neoplasms and imaged their resected colons approximately 3 hours later. The colon could be imaged during this fairly limited time interval, and polyps and cancers could be identified. No biologic tissue degradation occurred. The authors concluded that ex vivo FDG PET of the colon is feasible and, when combined with careful histologic and immunohistochemical analyses, may serve as a research tool to determine the mechanisms of the normal colonic uptake of FDG and the localization of FDG in polyps and cancers.

Clearance kinetics and external dosimetry of 131I-labeled murine and humanized monoclonal antibody A33 in patients with colon cancer: radiation safety implications.

The monoclonal antibody (mAb) A33 detects a membrane antigen that is expressed on greater than 95% of metastatic human colorectal cancers. Previous studies have shown excellent tumor-targeting of (131)I-labeled murine and humanized forms of the mAb. A retrospective analysis of whole-body clearance in the murine form was performed for comparison to the humanized form. Serial whole-body dose rate measurements were obtained for 55 treatments on 30 patients participating in phase I/II dose escalation studies of therapeutic (131)I-murine A33 mAb. Whole-body retention fractions over time were derived. Each treatment was fit with exponential curves to determine the effective half-lives and corresponding clearance fractions. There was a large variability in the calculated mono-exponential clearance effective half-life time, with a mean value of 36.5 h +/- 8.5 h. A bi-exponential fit of all combined data shows that 60% of the administered dose rapidly clears with a biological half-time of 23.9 h and 40% clears with a slower biological half-time of 101.2 h. The whole-body clearance proved to be more rapid in the murine form when compared with recent studies on the humanized form of radiolabeled A33 mAb. The variability in whole-body clearance reinforces the need for patient-specific tracer dosimetry for clinical care and radiation safety precautions. In addition, the slower clearance of the humanized form of the A33 mAb requires longer term radiation safety precautions than the earlier murine form. As other monoclonal antibodies progress from murine to humanized forms, radiopharmacokinetics should be evaluated for clinical and radiation safety implications.

Estimating radiation doses to the skin from interventional radiology procedures for a patient population with cancer.

PURPOSE: To estimate the peak radiation skin doses for interventional radiology cases performed at a cancer center, identify procedure types likely to result in skin doses exceeding the American College of Radiology's 3 Gy follow-up level, and determine a kerma area product (P(KA)) for use in monitoring. MATERIALS AND METHODS: A single-center retrospective study was performed to estimate doses from consecutive procedures performed during 2006. Of 6,598 procedures, 3,925 (60%) had P(KA) recorded and were included. Forty-three procedure types are represented. RESULTS: The median estimated peak skin dose was 39 mGy (third quartile, 205 mGy). In 2.6% of the cases, the estimated skin dose exceeded 3 Gy. No procedures resulted in skin doses greater than 15 Gy, and 94% of the cases resulted in skin doses less than 1 Gy. Procedure types with instances of skin doses greater than 1 Gy included hepatic, portal, and other arterial embolizations; diagnostic arteriography; biliary drainages; stent placements and catheter exchanges; nephrostomy/nephroureterostomy; urinary catheter exchanges; inferior vena cava filters; foreign body retrieval; abscess drainage; catheter exchange; and fistulography. Hepatic embolizations, nonhepatic arterial embolizations, and biliary drain/stent procedures were most likely to result in skin doses greater than 1 Gy. Significant variations in skin dose were noted within the same procedure type. No patients were noted to have developed any sequelae from radiation. CONCLUSIONS: It is unlikely that typical cases in an oncologic interventional radiology practice would exceed the Joint Commission's "reviewable sentinel event" skin dose level of 15 Gy. A P(KA) trigger of 300 Gy cm(2) could be used in the authors' clinic to identify follow-up requirements.

Tl-201 stress tests and homeland security.

BACKGROUND: This study estimates the length of time a patient might trigger security radiation detection devices after thallium 201 cardiac imaging. The US Department of Homeland Security is supporting the purchase and deployment of radiation detection pagers and portal monitors. Concurrently, there are an increasing number of cardiac perfusion imaging studies being performed using Tl-201. Therefore there is a higher probability that patients who have undergone nuclear medicine procedures could trigger alarms resulting in security questions. METHODS AND RESULTS: The length of time patients could trigger such devices is estimated based on the radiopharmacokinetics of Tl-201 and potential radioactive contaminants as well as the capabilities of current sensitive radiation detection devices, assuming the radioactive sources are distributed in and attenuated by the patient. It is estimated that patients may trigger portable pager devices for up to 33 days and may trigger portal detectors for up to 51 days after studies using Tl-201. This is much longer than length of time for a patient to trigger such alarms after technetium 99m myocardial imaging tests, which is potentially up to 6 days. CONCLUSIONS: It should be standard practice for patients to be issued information cards that indicate the potential time for triggering security radiation detectors after diagnostic cardiac procedures involving the use of Tl-201 or other radiopharmaceuticals.

Whole-body clearance kinetics and external dosimetry of 131I-3F8 monoclonal antibody for radioimmunotherapy of neuroblastoma.

The purpose of this retrospective study was to evaluate the whole-body clearance kinetics of I-3F8 monoclonal antibody, an anti-ganglioside 2 antibody, used in the treatment of pediatric patients with late-stage neuroblastoma (NB). Serial whole-body dose rate measurements were obtained on pediatric patients participating in phase I dose escalation studies of therapeutic I-3F8. Whole-body retention fractions were derived and fit for each treatment to exponential curves to determine both the effective half-lives and corresponding clearance fractions. 27 patients were administered I-3F8 over the course of cyclical administrations with a median administered activity of 2.5 GBq (range, 1-8.14 GBq), typically every 2-4 d for up to 9 treatment cycles. Based on whole-body dose rate measurements, there was a large variability in the calculated mono-exponential clearance effective half-life time, with a mean of 26.4 h (range, 12.4-45.5 h). The data from a subset of 12 treatments were fit to a bi-exponential curve with a rapid clearance component mean effective half-time of 16.9 h (range, 4.3-26 h) and a slower clearance component mean effective half-time of 65.5 h (range, 16.9-136 h). The use of whole-body dose rate measurements, obtained for patient-release and other radiation safety considerations, can be useful in estimating whole-body clearance kinetics for photon emitting radionuclide labeled mAbs and other therapeutic radiopharmaceuticals. In the case of I-3F8 for pediatric NB therapy, the demonstrated variability in effective half-time suggests the need for patient-specific tracer dosimetry for both optimization of treatment and radiation safety precaution decision-making.

Excited state dynamics and rapid internal conversion in a stable dipole molecule.

The excited singlet state of an azomethine ylide or 'stable dipole' exhibits an ultrafast radiationless relaxation after femtosecond laser excitation. These transients are observed before the excited state decays in an almost activationless manner, the barrier is 440 cm-1, to the ground state with a 1.5 ps lifetime. Cooling of the hot ground state is also apparent in the transient absorption data and in methanol decays with a 5.7 ps lifetime. The viscosity dependence of the fluorescence yield and lifetime in different solvents is small and far less pronounced than in triphenylmethane dyes. Surprisingly, the excited state decay is not due to twisting about the C-N bond of the ylide but it is caused by buckling of one of the rings as the nitrogen atom changes character from sp2 to sp3 hybridisation.