Is It Time to Create Training Pathways Allowing Earlier Subspecialization within the "House of Orthopaedics"?: AOA Critical Issues.

ABSTRACT: The ability to train an orthopaedic resident in all aspects of orthopaedics in 5 years has become increasingly difficult due to the growth in knowledge and techniques, work-hour restrictions, and reduced resident autonomy. It has become nearly universal for our residents to complete at least 1 subspecialty fellowship prior to entering practice. In some subspecialties, the skills necessary to practice competently have become difficult to master. Simply adding to the current length of training may not address these issues effectively and would add to the economic cost of residency training. Novel training pathways that allow residents to focus earlier and in greater depth on their intended subspecialty while maintaining general orthopaedic competencies can be created without lengthening training. It is time to initiate discussions about these possibilities.

Treatment of metastatic placental site trophoblastic tumor with surgery, chemotherapy, immunotherapy and coil embolization of multiple pulmonary arteriovenous fistulate.

Placental Site Trophoblastic Tumor (PSTT) is a rare malignancy that often presents with extensive disease and can be resistant to traditional treatments. We present the case of a woman with stage IV PSTT who was initially managed with neoadjuvant chemotherapy followed by tumor debulking. Adjuvant therapy was guided by further pathologic analysis that revealed high levels of staining for PD-L1 as well as the presence of tumor infiltrating lymphocytes (TILs). Subsequently, the patient was treated with traditional chemotherapy with the EP/EMA regimen with the addition of pembrolizumab. The patient's treatment course was complicated by the development of pulmonary arteriovenous malformations, autoimmune thyroiditis thought to be secondary to immunotherapy, and significant tinnitus secondary to platinum agents. Currently the patient is in follow up and remains in a complete remission.

Changes in awareness of cancer risk factors among adult New Zealanders (CAANZ): 2001 to 2015.

Behaviour change, specifically that which decreases cancer risk, is an essential element of cancer control. Little information is available about how awareness of risk factors may be changing over time. This study describes the awareness of cancer risk behaviours among adult New Zealanders in two cross-sectional studies conducted in 2001 and 2014/5.Telephone interviews were conducted in 2001 (n = 436) and 2014/5 (n = 1064). Participants were asked to recall things they can do to reduce their risk of cancer. They were then presented with a list of potential risk behaviours and asked if these could increase or decrease cancer risk.Most New Zealand adults could identify at least one action they could take to reduce their risk of cancer. However, when asked to provide specific examples, less than a third (in the 2014/5 sample) recalled key cancer risk reduction behaviours such as adequate sun protection, physical activity, healthy weight, limiting alcohol and a diet high in fruit. There had been some promising changes since the 2001 survey, however, with significant increases in awareness that adequate sun protection, avoiding sunbeds/solaria, healthy weight, limiting red meat and alcohol, and diets high in fruit and vegetables decrease the risk of developing cancer.

Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus-Reducing the Colostomy Rate.

PURPOSE: The aim of this study is to determine overall survival, disease-specific survival and stoma-free survival after treatment of squamous cell carcinoma of the anus with chemoradiotherapy followed by brachytherapy or electron boost in a recent cohort of patients. METHODS: Fifty-two patients (median age 62 years) were treated with radical chemoradiotherapy (mitomycin C, infusional 5-fluorouracil concurrently with conformal radical radiotherapy 45 Gy in 25 fractions over 5 weeks) followed by a radiotherapy boost between 1 December 2000 and 30 April 2011. Follow-up was to 30 November 2014. Thirty-six patients received a boost (15-20 Gy) over 2 days with 192Ir needle brachytherapy for anal canal tumours, and 16 patients received electron beam therapy (20 Gy in 10 fractions in 2 weeks) for anal margin tumours. A defunctioning stoma was only created prior to chemoradiotherapy for fistula or severe anal pain. RESULTS: The overall survival for the 36 patients treated with chemoradiotherapy followed by brachytherapy was 75 % (95 % CI, 61-89) at 5 years, the disease-specific survival was 91 % (95 % CI, 81-101 %), and the stoma-free survival was 97 % (95 % CI, 91-103 %) all at 5 years. For the 16 patients treated with an electron boost for anal margin tumours, the 5-year overall survival, disease-specific survival and stoma-free survival were 68 % (95 % CI, 44-92 %), 78 % (95 % CI, 56-100 %) and 80 % (95 % CI, 60-100 %), respectively. CONCLUSIONS: A very low stoma formation rate can be obtained with radical chemoradiotherapy followed by a brachytherapy boost for squamous cell carcinoma of the anal canal but not with an electron boost for anal margin tumours.

Smoke-free policies in New Zealand public tertiary education institutions.

The Framework Convention on Tobacco Control mandates the creation of smoke-free environments to protect non-smokers from second-hand smoke and reduce demand for tobacco. We aimed to examine the extent and nature of smoke-free campus policies at tertiary education institutions throughout New Zealand, and examine the policy development process. Stage one comprised an audit and content analysis of smoke-free policies. In stage two, semi-structured telephone interviews were conducted to investigate the process of developing and implementing policies. Qualitative content analysis was undertaken on interview notes. Policies were identified for most institutions (n = 26/29), though varied widely in nature. Only nine mandated 100% smoke-free campuses without exceptions and few prohibited the sale of tobacco on campus, or connections with the tobacco industry. During interviews (n = 22/29), cited barriers to developing a 100% smoke-free policy included enforcement challenges and anticipated opposition from staff and students. However, participants from institutions with 100% smoke-free policies reported having encountered few challenges. Varying levels of compliance with 100% smoke-free policies were reported yet, overall, these policies were viewed as being effective. Smoke-free campus policies could be strengthened to better reflect a completely tobacco-free organization. Other institutions and workplaces could use these findings to develop 100% smoke-free policies.

Suppression of adrenomedullin contributes to vascular leakage and altered epithelial repair during asthma.

BACKGROUND: The anti-inflammatory peptide, adrenomedullin (AM), and its cognate receptor are expressed in lung tissue, but its pathophysiological significance in airway inflammation is unknown. OBJECTIVES: This study investigated whether allergen-induced airway inflammation involves an impaired local AM response. METHODS: Airway AM expression was measured in acute and chronically sensitized mice following allergen inhalation and in airway epithelial cells of asthmatic and nonasthmatic patients. The effects of AM on experimental allergen-induced airway inflammation and of AM on lung epithelial repair in vitro were investigated. RESULTS: Adrenomedullin mRNA levels were significantly (P < 0.05) reduced in acute ovalbumin (OVA)-sensitized mice after OVA challenge, by over 60% at 24 h and for up to 6 days. Similarly, reduced AM expression was observed in two models of chronic allergen-induced inflammation, OVA- and house dust mite-sensitized mice. The reduced AM expression was restricted to airway epithelial and endothelial cells, while AM expression in alveolar macrophages was unaltered. Intranasal AM completely attenuated the OVA-induced airway hyperresponsiveness and mucosal plasma leakage but had no effect on inflammatory cells or cytokines. The effects of inhaled AM were reversed by pre-inhalation of the putative AM receptor antagonist, AM ((22-52)) . AM mRNA levels were significantly (P < 0.05) lower in human asthmatic airway epithelial samples than in nonasthmatic controls. In vitro, AM dose-dependently (10(-11) -10(-7) M) accelerated experimental wound healing in human and mouse lung epithelial cell monolayers and stimulated epithelial cell migration. CONCLUSION: Adrenomedullin suppression in T(H) 2-related inflammation is of pathophysiological significance and represents loss of a factor that maintains tissue integrity during inflammation.

Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study.

BACKGROUND: While Parkinson disease (PD) is consistently associated with impaired olfaction, one study reported better olfaction among Parkin mutation carriers than noncarriers. Whether olfaction differs between Parkin mutation heterozygotes and carriers of 2 Parkin mutations (compound heterozygotes) is unknown. OBJECTIVE: To assess the relationship between Parkin genotype and olfaction in PD probands and their unaffected relatives. METHODS: We administered the University of Pennsylvania Smell Identification Test (UPSIT) to 44 probands in the Consortium on Risk for Early-Onset Parkinson Disease study with PD onset ≤50 years (10 Parkin mutation heterozygotes, 9 compound heterozygotes, 25 noncarriers) and 80 of their family members (18 heterozygotes, 2 compound heterozygotes, 60 noncarriers). In the probands, linear regression was used to assess the association between UPSIT score (outcome) and Parkin genotype (predictor), adjusting for covariates. Among family members without PD, we compared UPSIT performance in heterozygotes vs noncarriers using generalized estimating equations, adjusting for family membership, age, gender, and smoking. RESULTS: Among probands with PD, compound heterozygotes had higher UPSIT scores (31.9) than heterozygotes (20.1) or noncarriers (19.9) (p < 0.001). These differences persisted after adjustment for age, gender, disease duration, and smoking. Among relatives without PD, UPSIT performance was similar in heterozygotes (32.5) vs noncarriers (32.4), and better than in heterozygotes with PD (p = 0.001). CONCLUSION: Olfaction is significantly reduced among Parkin mutation heterozygotes with PD but not among their heterozygous relatives without PD. Compound heterozygotes with PD have olfaction within the normal range. Further research is required to assess whether these findings reflect different neuropathology in Parkin mutation heterozygotes and compound heterozygotes.

Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model.

Different routes for the in vivo administration of synthetic siRNA complexes targeting lung tumors were compared, and siRNA complexes were administered for the inhibition of hypoxia-inducible factor (HIF-1alpha and HIF-2alpha). Intravenous jugular vein injection of siRNA proved to be the most effective means of targeting lung tumor tissue in the Lewis lung carcinoma (LLC1) model. In comparison, intraperitoneal injection of siRNA was not suitable for targeting of lung tumor and intratracheal administration of siRNA exclusively targeted macrophages. Inhibition of HIF-1alpha and HIF-2alpha by siRNA injected intravenously was validated by immunohistofluorescent analysis for glucose-transporter-1 (GLUT-1), a well-established HIF target protein. The GLUT-1 signal was strongly attenuated in the lung tumors of mice treated with siRNA-targeting HIF-1alpha and HIF-2alpha, compared with mice treated with control siRNA. Interestingly, injection of siRNA directed against HIF-1alpha and HIF-2alpha into LLC1 lung tumor-bearing mice resulted in prolonged survival. Immunohistological analysis of the lung tumors from mice treated with siRNA directed against HIF-1alpha and HIF-2alpha displayed reduced proliferation, angiogenesis and apoptosis, cellular responses, which are known to be affected by HIF. In conclusion, intravenous jugular vein injection of siRNA strongly targets the lung tumor and is effective in gene inhibition as demonstrated for HIF-1alpha and HIF-2alpha.

The impact of depressive symptoms in early Parkinson disease.

BACKGROUND: Depressive disorders may affect up to 50% of patients with Parkinson disease (PD) and are associated with increased disability and reduced quality of life. No previous study has systematically examined the impact of depressive symptoms in early, untreated PD. METHODS: We administered the 15-item Geriatric Depression Scale (GDS-15) as part of two NIH-sponsored phase II clinical trials in PD, enrolling 413 early, untreated PD subjects. We used linear mixed models to examine the relationship of depressive symptoms, measured by the GDS-15, with motor function and activities of daily living (ADLs), as measured by the Unified PD Rating Scale (UPDRS). A time-dependent Cox model was used to examine the effect of demographic and clinical outcome measures as predictors of investigator-determined time to need for symptomatic therapy for PD. RESULTS: A total of 114 (27.6%) subjects screened positive for depression during the average 14.6 months of follow-up. Forty percent of these subjects were neither treated with antidepressants nor referred for further psychiatric evaluation. Depression, as assessed by the GDS-15, was a significant predictor of more impairment in ADLs (p < 0.0001) and increased need for symptomatic therapy of PD (hazard ratio = 1.86; 95% CI 1.29, 2.68). CONCLUSIONS: Clinically important depressive symptoms are common in early Parkinson disease (PD), but are often not treated. Depressive symptoms are an important contributor to disability and the decision to start symptomatic therapy for motor-related impairment in early PD, highlighting the broad importance of identifying and treating depression in this population.

Comparison of MRI pulse sequences in defining prostate volume after permanent implantation.

PURPOSE: To determine the relative value of three MRI pulse sequences in defining the prostate volume after permanent implantation. METHODS AND MATERIALS: A total of 45 patients who received a permanent 125I implant were studied. Two weeks after implantation, an axial CT scan (2 mm thickness) and T1-weighted, T1-weighted fat saturation, and T2-weighted axial MRI (3-mm) studies were obtained. The prostate volumes were compared with the initial ultrasound planning volumes, and subsequently the CT, T1-weighted, and T1-weighted fat saturation MRI volumes were compared with the T2-weighted volumes. Discrepancies in volume were evaluated by visual inspection of the registered axial images and the registration of axial volumes on the sagittal T2-weighted volumes. In a limited set of patients, pre- and postimplant CT and T2-weighted MRI studies were available for comparison to determine whether prostate volume changes after implant were dependent on the imaging modality. RESULTS: T1-weighted and T1-weighted fat saturation MRI and CT prostate volumes were consistently larger than the T2-weighted MRI prostate volumes, with a volume on average 1.33 (SD 0.24) times the T2-weighted volume. This discrepancy was due to the superiority of T2-weighted MRI for prostate definition at the following critical interfaces: membranous urethra, apex, and anterior base-bladder and posterior base-seminal vesicle interfaces. The differences in prostate definition in the anterior base region suggest that the commonly reported underdose may be due to overestimation of the prostate in this region by CT. The consistent difference in volumes suggests that the degree of swelling observed after implantation is in part a function of the imaging modality. In patients with pre- and postimplant CT and T2-weighted MRI images, swelling on the T2-weighted images was 1.1 times baseline and on CT was 1.3 times baseline, confirming the imaging modality dependence of prostate swelling. CONCLUSION: Postimplant T2-weighted MRI images provided superior prostate definition in all critical regions of the prostate compared with CT and the other MRI sequences tested. In addition to defining an optimal technique, these findings call two prior observations into question. Under dosing at the anterior base region may be overestimated because of poor definition of the prostate-bladder muscle interface. The swelling observed after implantation was lower on T2-weighted images as well, suggesting that a fraction of postimplant swelling is a function of the imaging modality. These findings have implications for preimplant planning and postimplant evaluation. As implant planning techniques become more conformal, and registration methods become more efficient, T2-weighted MRI after implantation will improve the accuracy of postimplant dosimetry.

Contemporary perspectives in tobacco cessation: what oncologists need to know.

Within the last 5 years there has been a large outgrowth of smoking cessation research, largely encouraged by the release of the 1996 Clinical Practice Guidelines for Treating Tobacco Use and Dependence. These federal guidelines published by the Agency for Healthcare Policy and Research offered comprehensive empirical evidence that tobacco cessation interventions are effective and encouraged routine implementation within medical settings. Since that time, numerous studies in tobacco cessation have augmented the state of knowledge regarding successful smoking intervention modalities. Unfortunately, approximately one-third of cancer-related deaths continue to be attributed to smoking behaviors. It is imperative that health care providers encourage and participate in the smoking cessation efforts of their patients and family members. This article provides a review of the current literature in smoking cessation and describes first-line therapies with proven effectiveness in tobacco cessation. Clinicians are encouraged to consistently screen for tobacco use and provide brief interventions utilizing behavioral counseling and pharmacotherapies to treat their patients' tobacco dependence.

Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.

PURPOSE: To assess long-term xerostomia in patients receiving parotid-sparing radiation therapy (RT) for head-and-neck cancer, and to find the patient and therapy-related factors that affect its severity. PATIENTS AND METHODS: From March 1994 through January 2000, 84 patients received comprehensive bilateral neck RT using conformal and multisegmental intensity-modulated RT (IMRT) aiming to spare the major salivary glands. Before RT and periodically through 2 years after the completion of RT, salivary flow rates from each of the major salivary glands were selectively measured. At the same time intervals, each patient completed an 8-item self-reported xerostomia-specific questionnaire (XQ). To gain a relative measure of the effect of RT on the minor salivary glands, whose output could not be measured, the surfaces of the oral cavity (extending to include the surface of the base of tongue) were outlined in the planning CT scans. The mean doses to the new organ ("oral cavity") were recorded. Forty-eight patients receiving unilateral neck RT were similarly studied and served as a benchmark for comparison. Factors predicting the XQ scores were analyzed using a random-effects model. RESULTS: The XQ was found to be reliable and valid in measuring patient-reported xerostomia. The spared salivary glands which had received moderate doses in the bilateral RT group recovered to their baseline salivary flow rates during the second year after RT, and the spared glands in the unilateral RT group, which had received very low doses, demonstrated increased salivary production beyond their pre-RT levels. The increase in the salivary flow rates during the second year after RT paralleled an improvement in xerostomia in both patient groups. The improvement in xerostomia was faster in the unilateral compared with the bilateral RT group, but the difference narrowed at 2 years. The major salivary gland flow rates had only a weak correlation with the xerostomia scores. Factors found to be independently associated with the xerostomia scores were the pre-RT baseline scores, the time since RT, and the mean doses to the major salivary glands (notably to the submandibular glands) and to the oral cavity. CONCLUSION: An improvement over time in xerostomia, occurring in tandem with rising salivary production from the spared major salivary glands, suggests a long-term clinical benefit from their sparing. The oral cavity mean dose, representing RT effect on the minor salivary glands, was found to be a significant, independent predictor of xerostomia. Thus, in addition to the major salivary glands, sparing the uninvolved oral cavity should be considered as a planning objective to further reduce xerostomia.

Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer.

PURPOSE: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose-volume histograms. The recurrences were classified as 1) "in-field," in which 95% or more of the recurrence volume (V(recur)) was within the 95% isodose; 2) "marginal," in which 20% to 95% of V(recur) was within the 95% isodose; or 3) "outside," in which less than 20% of V(recur) was within the 95% isodose. RESULTS: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68-90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared. CONCLUSIONS: The majority of local-regional recurrences after conformal and segmental IMRT were "in-field," in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.

Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.

PURPOSE: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to < or =25% pre-RT flow at 12 months. RESULTS: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of < or =26 Gy should be a planning goal if substantial sparing of the gland function is desired.

The effect of patient position and treatment technique in conformal treatment of prostate cancer.

PURPOSE: The relative value of prone versus supine positioning and axial versus nonaxial beam arrangements in the treatment of prostate cancer remains controversial. Two critical issues in comparing techniques are: 1) dose to critical normal tissues, and 2) prostate stabilization. METHODS AND MATERIALS: Ten patients underwent pretreatment CT scans in one supine and two prone positions (flat and angled). To evaluate normal tissue exposure, prostate/seminal vesicle volumes or prostate volumes were expanded 8 mm and covered by the 95% isodose surface by both 6-field axial and 4-field nonaxial techniques. A total of 280 dose-volume histograms (DVHs) were analyzed to evaluate dose to rectal wall and bladder relative to patient position and beam arrangement. A CT scan was repeated in each patient after 5 weeks of treatment. Prostate motion was assessed by comparing early to late scans by three methods: 1) center of mass shift, 2) superior pubic symphysis to anterior prostate distance, and 3) deviation of the posterior surface of the prostate. RESULTS: For prostate (P) or prostate/seminal vesicle (P/SV) treatments, prone flat was advantageous or equivalent to other positions with regard to rectal sparing. The mechanism of rectal sparing in the prone position may be related to a paradoxical retraction of the rectum against the sacrum, away from the P/SV. Although there was no clear overall preference for beam arrangement, substantial improvements in rectal sparing could be realized for individual patients. In this limited number of patients, there was no convincing evidence prostate position was stabilized by prone relative to supine position. CONCLUSIONS: Prone flat positioning was advantageous over other positions and beam arrangements in rectal sparing. This study suggests that patient position is a more critical a factor in conformal therapy than beam arrangement, and may improve the safety of dose escalation.

Quantification in patient urine samples of felbamate and three metabolites: acid carbamate and two mercapturic acids.

PURPOSE: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine. METHODS: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population. RESULTS: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured. CONCLUSIONS: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.

Optimization and clinical use of multisegment intensity-modulated radiation therapy for high-dose conformal therapy.

Intensity-modulated radiation therapy (IMRT) may be performed with many different treatment delivery techniques. This article summarizes the clinical use and optimization of multisegment IMRT plans that have been used to treat more than 350 patients with IMRT over the last 4.5 years. More than 475 separate clinical IMRT plans are reviewed, including treatments of brain, head and neck, thorax, breast and chest wall, abdomen, pelvis, prostate, and other sites. Clinical planning, plan optimization, and treatment delivery are summarized, including efforts to minimize the number of additional intensity-modulated segments needed for particular planning protocols. Interactive and automated optimization of segmental and full IMRT approaches are illustrated, and automation of the segmental IMRT planning process is discussed.

Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study.

PURPOSE: To analyze the failure patterns for patients with high-grade astrocytomas treated with high-dose conformal radiotherapy (CRT) using a quantitative technique to calculate the dose received by the CT- or MR-defined recurrence volume and to assess whether the final target volume margin used in the present dose escalation study requires redefinition before further escalation. METHODS AND MATERIALS: Between 4/89 and 10/95, 71 patients with high-grade supratentorial astrocytomas were entered in a phase I/II dose escalation study using 3-D treatment planning and conformal radiotherapy. All patients were treated to either 70 or 80 Gy in conventional daily fractions of 1.8-2.0 Gy. The clinical and planning target volumes (CTV, PTV) consisted of successively smaller volumes with the final PTV defined as the enhancing lesion plus 0.5 cm margin. As of 10/95, 47 patients have CT or MR evidence of disease recurrence/progression. Of the 47 patients, 36 scans obtained at the time of recurrence were entered into the 3-D radiation therapy treatment planning system. After definition of the recurrent tumor volumes, the recurrence scan dataset was registered with the pretreatment CT dataset so that the actual dose received by the recurrent tumor volumes during treatment could be accurately calculated and then analyzed dosimetrically using dose-volume histograms. Recurrences were divided into several categories: 1) "central," in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to high dose (95% of the prescription dose); 2) "in-field," in which 80% or more of Vrecur was within the D95 isodose surface; 3) "marginal," when between 20 and 80% of Vrecur was inside the D95 surface; 4) "outside," in which less than 20% of Vrecur was inside the D95 surface. RESULTS: In 29 of 36 patients, a solitary lesion was seen on recurrence scans. Of the 29 solitary recurrences, 26 were central, 3 were marginal, and none were outside. Multiple recurrent lesions were seen in seven patients: three patients had multiple central and/or in-field lesions only, three patients had central and/or in-field lesions with additional small marginal or outside lesions, and one patent had 6 outside and one central lesion. Since total recurrence volume was used in the final analysis, 6 of the 7 patients with multiple recurrent lesions were classified into centra/in-field category. CONCLUSION: Analysis of the 36 evaluable patients has shown that 32 of 36 patients (89%) failed with central or in-field recurrences, 3/36 (8%) had a significant marginal component to the recurrence, whereas only 1/36 (3%) could be clearly labeled as failing mainly outside the high-dose region. Seven patients had multiple recurrences, but only 1 of 7 had large-volume recurrences outside the high-dose region. This study shows that the great majority of patient recurrences that occur after high-dose (70 or 80 Gy) conformal irradiation are centrally located: only 1/36 patients (with 7 recurrent lesions) had more than 50% of the recurrence volume outside the region previously treated to high dose. Further dose escalation to 90 Gy (and beyond) thus seems reasonable, based on the same target volume definition criteria

Conformal and intensity modulated irradiation of head and neck cancer: the potential for improved target irradiation, salivary gland function, and quality of life.

PURPOSE: To develop techniques which facilitate sparing of the major salivary glands while adequately treating the targets in patients requiring comprehensive bilateral neck irradiation (RT). PATIENTS AND METHODS: Conformal and static, multisegmental intensity modulated (IMRT) techniques have been developed. The salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms. Subjective xerostomia questionnaires have been developed and validated. The pattern of local-regional recurrences has been examined using CT scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans and regenerating the dose distributions at the recurrence sites. RESULTS: Target coverage and dose homogeneity in IMRT treatment plans were found to be significantly better than standard RT plans. Significant parotid gland sparing was achieved. The relationships among dose, irradiated volume and saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean dose of 26 Gy was found to be the threshold for stimulated saliva. Subjective xerostomia was significantly reduced in patients irradiated with parotid sparing techniques, compared to patients with similar tumors treated with standard RT. The large majority of recurrences occurred inside high-risk targets. CONCLUSIONS: Tangible gains in salivary gland sparing and target coverage are being achieved and an improvement in some measures of quality of life is suggested by our findings. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to targets judged to be at highest risk may improve tumor control.

A brain tumor dose escalation protocol based on effective dose equivalence to prior experience.

PURPOSE: The current study describes the design of a dose escalation protocol for conformal irradiation of primary brain tumors that preserves the safe experience of a previous, sequential dose escalation scheme while enabling the delivery of substantially higher effective doses to a central target volume. METHODS AND MATERIALS: Normalized isoeffective composite dose distributions were formed for 20 patients treated on the original protocol (which specified three progressively smaller planning target volumes [PTVs]) using the linear quadratic model (here corrected to equivalent 2 Gy fractions using alpha/beta=10 Gy). These distributions were investigated and a new protocol was designed to preserve a similar level of efficacy and lack of toxicity for the outer volumes, but allowing a higher dose to the inner PTV. Treatment plans were then investigated to determine if the objectives of the new protocol were achievable. In particular, plans that simultaneously achieved all biological treatment planning objectives (all fields treated each day) were investigated. Finally, the success of the protocol design was demonstrated by analysis of the effective dose distributions of 10 patients treated using the new protocol. RESULTS: The composite normalized isoeffective minimum doses to the outer PTVs (PTV3 and PTV2) in the original protocol were close to 60 Gy and 75 Gy, respectively, and these values are specified as the minimum doses to those volumes for the new protocol. Homogeneity requirements to maintain equivalence for the outer target volume domains are: not more than 25% of [PTV3 exclusive of PTV2] >75 Gy; and not more than 50% of [PTV2 exclusive of PTV1] >85 Gy. Treatment plans using multiple noncoplanar arrangements of beams and static intensity modulation treat all volumes at each session. DVHs of the normalized isoeffective dose distributions reveal the equivalence of the new protocol plans to the sequential plans in the previous protocol as well as the ability to achieve a higher dose of 90 Gy to the isocenter of PTV1 (+/-5% homogeneity required). CONCLUSION: The ability to incorporate past experience through use of the linear quadratic model in the design of a new dose escalation protocol is demonstrated.