Lipase domain effector AGLIP1 in Rhizoctonia solani triggers necrotic killing in plants.

KEY MESSAGE: We highlight the emerging role of the R. solani novel lipase domain effector AGLIP1 in suppressing pattern-triggered immunity and inducing plant cell death. The dynamic interplay between plants and Rhizoctonia solani constitutes a multifaceted struggle for survival and dominance. Within this complex dynamic, R. solani has evolved virulence mechanisms by secreting effectors that disrupt plants' first line of defense. A newly discovered effector, AGLIP1 in R. solani, plays a pivotal role in inducing plant cell death and subverting immune responses. AGLIP1, a protein containing a signal peptide and a lipase domain, involves complex formation in the intercellular space, followed by translocation to the plant cytoplasm, where it induces cell death (CD) and suppresses defense gene regulation. This study provides valuable insights into the intricate molecular interactions between plants and necrotrophic fungi, underscoring the imperative for further exploration in this field.

Minimally Invasive Techniques for Facial Rejuvenation Utilizing Polydioxanone Threads.

Cosmetic procedures to combat the effects of aging are increasing in demand. Surgical interventions, such as rhytidectomy, have long been the standard method of providing a more youthful appearance. However, these procedures are costly, often require general anesthesia, and have potential risks such as scarring and prolonged recovery. A safe, effective, alternative to surgery is the nonsurgical thread-lift. Nevertheless, proper patient selection is critical for optimal outcomes and for patient and provider satisfaction. Over the past decade, these treatments have gained significant popularity for patients to achieve a more rejuvenated appearance with less complications and minimal downtime.

Minimally Invasive Techniques for Facial Rejuvenation Utilizing Polydioxanone Threads.

Cosmetic procedures to combat the effects of aging are increasing in demand. Surgical interventions, such as rhytidectomy, have long been the standard method of providing a more youthful appearance. However, these procedures are costly, often require general anesthesia, and have potential risks such as scarring and prolonged recovery. A safe, effective, alternative to surgery is the nonsurgical thread-lift. Nevertheless, proper patient selection is critical for optimal outcomes and for patient and provider satisfaction. Over the past decade, these treatments have gained significant popularity for patients to achieve a more rejuvenated appearance with less complications and minimal downtime.

Deployment of Brassica carinata A. Braun Derived Brassica juncea (L.) Czern. Lines for Improving Heterosis and Water Use Efficiency Under Water Deficit Stress Conditions.

Among Brassica species, Ethiopian mustard (Brassica carinata A. Braun) is known to tolerate most abiotic stresses, including drought. Drought caused by low and erratic rainfall in semi-arid regions consistently challenges rapeseed mustard productivity. Development of B. carinata-derived lines (CDLs) in Brassica juncea (L.) Czern. nuclear background, carrying genomic segments from B. carinata, are expected to tolerate moisture deficit stress conditions. The present study was, thus, aimed to establish the phenomenon "heterosis" for drought tolerance and water use efficiency by evaluating 105 hybrids developed from intermating 15 CDLs in half diallel fashion. Data on 17 seed yield and yield contributing traits were recorded under two different environments, viz., irrigated and rainfed conditions. Traits under study were found to be governed by both additive and non-additive types of gene action. Average degree of dominance was higher (>2) for yield and yield contributing traits, viz., secondary branches/plant, point to first siliqua on main shoot, total siliquae/plant, 1,000-seed weight, seed yield/plant, biological yield, harvest index, and seed yield/hectare under rainfed conditions, clearly indicating that higher productivity under drought conditions can be realised through the development of hybrids. Out of 15, highly significant general combining ability (GCA) effects for seven CDLs were observed under rainfed condition. Furthermore, nine and six hybrids expressed highly significant specific combining ability (SCA) effects and > 50% heterobeltiosis for yield contributing traits under rainfed and irrigated conditions, respectively. Water use efficiency (WUE) of parental CDLs and hybrids varied from 2.05 to 2.57 kg m-3 under rainfed, while 1.10 to 1.28 kg m-3 under irrigated conditions. Hybrids expressed higher WUE than parental lines under both water regimes. Furthermore, selection indices such as drought tolerance index (DTI) and mean relative performance (MRP) were identified to be efficient in the selection of productive CDLs and hybrids under drought conditions. Nine hybrids, identified as highly productive in the present study, can further be exploited for improving the yield of Indian mustard in drought-prone areas. Usefulness of interspecific hybridisation in the development of B. carinata-derived B. juncea lines for improving heterosis and WUE is, thus, well demonstrated through the present study.

Radiation and Androgen Deprivation Therapy With or Without Docetaxel in the Management of Nonmetastatic Unfavorable-Risk Prostate Cancer: A Prospective Randomized Trial.

PURPOSE: Although docetaxel is not recommended when managing men with unfavorable-risk prostate cancer (PC) given negative or inconclusive results from previous randomized trials, unstudied benefits may exist. METHODS: Between September 21, 2005, and January 13, 2015, we randomly assigned 350 men 1:1 with T1c-4N0M0 unfavorable-risk PC to receive radiation therapy (RT) and androgen deprivation therapy (ADT) plus docetaxel (60 mg/m2 once every 3 weeks for three cycles before RT and 20 mg/m2 once weekly during RT) versus ADT + RT. We evaluated the treatment effect of adding docetaxel to ADT + RT on the primary end point of overall survival (OS) and the incidence of RT-induced cancers and explored whether the impact of the treatment effect on OS differed within prostate-specific antigen (PSA) subgroups (< 4, > 20 v 4-20 ng/mL) using the interaction test for heterogeneity adjusted for age and PC prognostic factors. RESULTS: After a median follow-up of 10.2 years, 89 men died (25.43%); of these, 42 from PC (47.19%). Although OS was not significantly increased in the docetaxel arm (the restricted mean survival time over 10 years was 9.11 v 8.82 years; P = .22), significantly fewer RT-induced cancers were observed (10-year estimates: 0.61% v 4.90%; age-adjusted hazard ratio of 0.13; 95% CI, 0.02 to 0.97; P = .046). The treatment effect of adding docetaxel to ADT + RT on OS significantly differed in men with a PSA < 4 ng/mL versus 4-20 ng/mL (adjusted hazard ratio: 0.27 and 1.51, respectively) because of less PC-specific mortality on the docetaxel arm (0.00% v 28.57%) among men with PSA < 4 ng/mL. CONCLUSION: Adding docetaxel to ADT + RT did not prolong OS in men with unfavorable-risk PC, but decreased RT-induced cancer incidence, and may prolong OS in the subgroup of men with a PSA < 4 ng/mL by reducing PC-specific mortality.

The price of progress: Funding and financing Alzheimer's disease drug development.

INTRODUCTION: Advancing research and treatment for Alzheimer's disease (AD) and the search for effective treatments depend on a complex financial ecosystem involving federal, state, industry, advocacy, venture capital, and philanthropy funding approaches. METHODS: We conducted an expert review of the literature pertaining to funding and financing of translational research and drug development for AD. RESULTS: The federal government is the largest public funder of research in AD. The National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, and National Center for Advancing Translational Science all fund aspects of research in AD drug development. Non-National Institutes of Health federal funding comes from the National Science Foundation, Veterans Administration, Food and Drug Administration, and the Center for Medicare and Medicaid Services. Academic Medical Centers host much of the federally funded basic science research and are increasingly involved in drug development. Funding of the "Valley of Death" involves philanthropy and federal funding through small business programs and private equity from seed capital, angel investors, and venture capital companies. Advocacy groups fund both basic science and clinical trials. The Alzheimer Association is the advocacy organization with the largest research support portfolio relevant to AD drug development. Pharmaceutical companies are the largest supporters of biomedical research worldwide; companies are most interested in late stage de-risked drugs. Drugs progressing into phase II and III are candidates for pharmaceutical industry support through licensing, mergers and acquisitions, and co-development collaborations. DISCUSSION: Together, the funding and financing entities involved in supporting AD drug development comprise a complex, interactive, dynamic financial ecosystem. Funding source interaction is largely unstructured and available funding is insufficient to meet all demands for new therapies. Novel approaches to funding such as mega-funds have been proposed and more integration of component parts would assist in accelerating drug development.

Assessment of Monte Carlo algorithm for compliance with RTOG 0915 dosimetric criteria in peripheral lung cancer patients treated with stereotactic body radiotherapy.

The purpose of the study was to evaluate Monte Carlo-generated dose distributions with the X-ray Voxel Monte Carlo (XVMC) algorithm in the treatment of peripheral lung cancer patients using stereotactic body radiotherapy (SBRT) with non-protocol dose-volume normalization and to assess plan outcomes utilizing RTOG 0915 dosimetric compliance criteria. The Radiation Therapy Oncology Group (RTOG) protocols for non-small cell lung cancer (NSCLC) currently require radiation dose to be calculated using tissue density heterogeneity corrections. Dosimetric criteria of RTOG 0915 were established based on superposition/convolution or heterogeneities corrected pencil beam (PB-hete) algorithms for dose calculations. Clinically, more accurate Monte Carlo (MC)-based algorithms are now routinely used for lung stereotactic body radiotherapy (SBRT) dose calculations. Hence, it is important to determine whether MC calculations in the delivery of lung SBRT can achieve RTOG standards. In this report, we evaluate iPlan generated MC plans for peripheral lung cancer patients treated with SBRT using dose-volume histogram (DVH) normalization to determine if the RTOG 0915 compliance criteria can be met. This study evaluated 20 Stage I-II NSCLC patients with peripherally located lung tumors, who underwent MC-based SBRT with heterogeneity correction using X-ray Voxel Monte Carlo (XVMC) algorithm (Brainlab iPlan version 4.1.2). Total dose of 50 to 54 Gy in 3 to 5 fractions was delivered to the planning target vol-ume (PTV) with at least 95% of the PTV receiving 100% of the prescription dose (V100% ≥ 95%). The internal target volume (ITV) was delineated on maximum intensity projection (MIP) images of 4D CT scans. The PTV included the ITV plus 5 mm uniform margin applied to the ITV. The PTV ranged from 11.1 to 163.0 cc (mean = 46.1 ± 38.7 cc). Organs at risk (OARs) including ribs were delineated on mean intensity projection (MeanIP) images of 4D CT scans. Optimal clinical MC SBRT plans were generated using a combination of 3D noncoplanar conformal arcs and nonopposing static beams for the Novalis-TX linear accelerator consisting of high-definition multileaf collimators (HD-MLCs: 2.5 mm leaf width at isocenter) and 6 MV-SRS (1000 MU/min) beam. All treatment plans were evaluated using the RTOG 0915 high- and intermediate-dose spillage criteria: conformity index (R100%), ratio of 50% isodose volume to the PTV (R50%), maximum dose 2 cm away from PTV in any direction (D2cm), and percent of normal lung receiving 20Gy (V20) or more. Other OAR doses were documented, including the volume of normal lung receiving 5 Gy (V5) or more, dose to < 0.35 cc of spinal cord, and dose to 1000 cc of total normal lung tissue. The dose to < 1 cc, < 5 cc, < 10 cc of ribs, as well as maximum point dose as a function of PTV, prescription dose, and a 3D distance from the tumor isocenter to the proximity of the rib contour were also examined. The biological effective dose (BED) with α/ß ratio of 3 Gy for ribs was analyzed. All 20 patients either fully met or were within the minor deviation dosimetric compliance criteria of RTOG 0915 while using DVH normalization. However, only 5 of the 20 patients fully met all the criteria. Ten of 20 patients had minor deviations in R100% (mean = 1.25 ± 0.09), 13 in R50% (mean = 4.5 ± 0.6), and 11 in D2cm (mean = 61.9 ± 8.5). Lung V20, dose to 1000 cc of normal lung, and dose to < 0.35 cc of spinal cord were met in accordance with RTOG criteria in 95%, 100%, and 100%, respectively, with exception of one patient who exhibited the largest PTV (163 cc) and experienced a minor deviation in lung V20 (mean = 4.7±3.4%). The 3D distance from the tumor isocenter to the proximal rib contour strongly correlated with maximum rib dose. The average values of BED3Gy for maximum point dose and dose to < 1 cc of ribs were higher by a factor of 1.5 using XVMC compared to RTOG 0915 guidelines. The preliminary results for our iPlan XVMC dose analyses indicate that the majority (i.e., 75% of patient population) of our patients had minor deviations when compared to the dosimetric guidelines set by RTOG 0915 protocol. When using an exclusively sophisticated XVMC algorithm and DVH normalization, the RTOG 0915 dosimetric compliance criteria such as R100%, R50%, and D2cm may need to be revised. On average, about 7% for R100%, 13% for R50%, and 14% for D2cm corrections from the mean values were necessary to pass the RTOG 0915 compliance criteria. Another option includes rescaling of the prescription dose. No further adjustment is necessary for OAR dose tolerances including normal lung V20 and total normal lung 1000 cc. Since all the clinical MC plans were generated without compromising the target coverage, rib dose was on the higher side of the protocol guidelines. As expected, larger tumor size and proximity to ribs correlated to higher absolute dose to ribs. These patients will be clinically followed to determine whether delivered MC-computed dose to PTV and the ribs dose correlate with tumor control and severe chest wall pain and/or rib fractures. In order to establish new specific MC-based dose parameters, further dosimetric studies with a large cohort of MC lung SBRT patients will need to be conducted.

Trade-Off between Treatment of Early Prostate Cancer and Incidence of Advanced Prostate Cancer in the Prostate Screening Era.

PURPOSE: Prostate specific antigen screening has led to the early detection of prostate cancer. However, there has also been concern about the over diagnosis and overtreatment of patients with indolent cancers. We performed a population based analysis to evaluate the trade-off between excess treatment and prevention. MATERIALS AND METHODS: We used the CDC (Centers for Disease Control and Prevention) Behavioral Risk Factor Surveillance System survey from 2001 to 2010 to determine rates of prostate specific antigen screening. We used the SEER database to identify all patients diagnosed with prostate cancer from 1988 (pre-prostate specific antigen screening) to 2010. Demographic, staging and treatment data were collected. Cases were classified as early (low/intermediate risk), high risk, node positive or metastatic disease. RESULTS: Prostate specific antigen screening rates in the last 2 years were 54% for men older than 40 years, including 71% for those older than 60, and did not vary during 2001 to 2010. Comparing 1988 and 2000 to 2010, per 100,000 men the incidence of early prostate cancer increased (61.7 to 113.7), while high risk cancer increased (20.7 to 28.2), node positive cancer decreased (3.7 to 1.8) and metastatic cancer decreased (13.6 to 6.2). The rate of definitive primary treatment (radical prostatectomy or radiation therapy) for men with early cancer increased from 47% to 67% (p <0.001). CONCLUSIONS: Prostate specific antigen screening has led to an additional diagnosis of 5.8 cases of early stage cancer and 3.9 cases receiving treatment for early cancer for every 1 less case of stage IV disease at initial diagnosis. This ratio represents the worst-case scenario for overtreatment and provides a quantitative basis for studying the effect of prostate specific antigen screening.

The role of radiotherapy in management of pancreatic cancer.

Pancreatic cancer is one of the leading causes of cancer death. The treatment options in pancreatic cancer remain limited. This review provides an overview of the role of radiotherapy (RT) alone or in combination with systemic treatment at different settings of treatment strategy. Neoadjuvant chemoradiotherapy (CRT) may downstage the borderline resectable disease and make resection possible, which could translate to a survival benefit. Although the benefit of adjuvant CRT remains controversial due to inconsistent outcome of randomized trials, in North America it is still a common recommendation of the treatment. For locally advanced pancreatic cancer, the treatment option could either be chemotherapy or chemoradiotherapy. By using advanced radiotherapy modalities, the toxicity of RT could be reduced and RT dose escalation becomes possible to improve locoregional control.

Mucosa-associated lymphoid tissue lymphoma and concurrent adenocarcinoma of the prostate.

Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the prostate is a rare disease that characteristically follows an indolent course. It is believed that infection or chronic inflammation may be triggers for malignant transformation in the prostate, but it is of unknown etiology. Reports of MALT lymphomas of the prostate with other concurrent primary prostate cancers are even more limited. We present the unique case of a 67-year-old male with concurrent adenocarcinoma of the prostate and primary MALT lymphoma of the prostate. The patient was treated with standard therapy for prostate adenocarcinoma, which would also treat a primary MALT lymphoma. He has been disease-free for over one year for both his primary malignancies. This case confirms that MALT lymphoma can arise concurrently with adenocarcinoma of the prostate.

Isolated post-traumatic right-sided diaphragmatic hernia.

A 3-yr-old boy presented with respiratory distress of 2 days duration. There was a history of blunt trauma to the lower chest having occurred 5 days earlier. Although missed initially, serial chest X-rays and a computed tomographic (CT) scan revealed an isolated traumatic right-sided diaphragmatic hernia without any injury to the viscera or the ribcage. Laparotomy with reduction of the herniated right lobe of the liver and the transverse colon was performed. Recovery was uneventful. The presentation, diagnosis and management of this relatively uncommon injury is discussed. The need for a high index of suspicion and critical evaluation of appropriate investigations to prevent diagnostic delay and optimize management in patients with traumatic diaphragmatic injury is emphasized.

Phase I/II trial of docetaxel and concurrent radiation therapy in localized high risk prostate cancer (AGUSG 03-10).

PURPOSE: A Phase I/II trial was conducted to assess the radiosensitizer docetaxel administered weekly (20 mg/m(2)) with concurrent intensity modulated radiation therapy (72 Gy at 1.8 Gy/fraction) in high risk prostate cancer. PATIENTS AND METHODS: Patients with high risk prostate cancer (clinical stage > or = T3; Gleason score 8, 9, or 10; Gleason score 7 and PSA > 10) received IMRT (Clinac 600 CD with 6 MV photons and sliding window technique) and concurrent weekly docetaxel (20 mg/m(2)) as a continuous 30 minute infusion for 8 weeks. Patients desirous of concurrent androgen suppression were not excluded. RESULTS: Twenty men (median age: 64 years; range, 50-78 years) were enrolled in the chemoradiation protocol. Three patients experienced treatment interruptions: dehydration requiring inpatient hydration (n = 2); NSAID induced GI bleed (n = 1). An additional patient required outpatient hydration (<24 hours) with no treatment interruption. Overall, the most frequently observed toxicities were grade 2 diarrhea (40%), grade 2 fatigue (40%), grade 2 urinary frequency (35%), taste aversion (20%), grade 2 constipation (20%), and rectal bleeding (15%). No significant hematologic toxicity (grades 2-4) was encountered among the 20 patients. Although the follow-up interval was relatively short, no significant subacute gastrointestinal toxicities have been observed. At a median follow-up duration of 11.7 months, 17 patients were free of biochemical disease recurrence, and all patients are alive. CONCLUSION: The radiosensitizer docetaxel administered weekly (20 mg/m(2)) with concurrent IMRT is well tolerated with acceptable toxicity. Early oncologic outcomes in this challenging patient cohort are encouraging.

Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935.

BACKGROUND AND OBJECTIVES: CALGB 8935 was a phase II protocol for mediastinoscopically staged IIIA (N2) non-small cell lung cancer. Induction cisplatin/vinblastine chemotherapy was followed by surgical resection, adjuvant cisplatin/vinblastine, and radiotherapy. We now evaluate the prognosis of pathologic nodes. METHODS: Failure-free survival was calculated from a landmark 3 months after resection to account for heterogeneity in adjuvant therapy. RESULTS: Nine of 42 (21%) resected patients had no residual N2 disease. This subset of 9 had a median failure-free interval of 47.8 months from landmark, whereas the 33 patients (79%) with persistent N2 disease had a median failure-free survival of 8.2 months from landmark (P=0.01). Although 21/42 (50%) had an incomplete resection (positive highest resected node and/or margin), completeness of resection did not influence failure-free survival. There were 3 distant and no local recurrences among the N2 negative group, and 12 local recurrences among patients with residual N2 disease (P=0.041). CONCLUSIONS: These data suggest: (1) persistent N2 disease following induction chemotherapy is unfavorable; (2) patients downstaged to N2 negative may benefit from surgical resection; however, (3) 33% of N2 negative patients suffered disease relapse.

Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615.

PURPOSE: To determine the feasibility of high-dose intra-arterial (IA) cisplatin and concurrent radiation therapy (RT) for head and neck squamous cell carcinoma in the multi-institutional setting (Multi-RADPLAT). PATIENTS AND METHODS: Eligibility included T4 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received cisplatin (150 mg/m(2) IA with sodium thiosulfate 9 g/m(2) intravenous [IV], followed by 12 g/m(2) IV over 6 hours, weekly for 4 weeks) and concurrent RT (70 Gy, 2.0 Gy/fraction, daily for 5 days over 7 weeks). Between May 1997 and December 1999, 67 patients from three experienced and eight inexperienced centers were enrolled, of whom 61 were eligible for analysis. RESULTS: Multi-RADPLAT was feasible (ie, three or four infusions of IA cisplatin and full dose of RT) in 53 patients (87%). The complete response (CR) rate was 85% at the primary site and 88% at nodal regions, and the overall CR rate was 80%. At a median follow-up of 3.9 years for alive patients (range, 0.9 to 6.1 years), the estimated 1-year and 2-year locoregional tumor control rates are 66% and 57%, respectively. The estimated 1-year and 2-year survival rates are 72% and 63%, respectively. The estimated 1-year and 2-year disease-free survival rates are 62% and 46%, respectively. The rates of grade 4 and 5 toxicities at the experienced and the inexperienced institutions were 14% and 0% v 47% and 4%, respectively. CONCLUSION: This intensive treatment regimen for head and neck cancer is feasible and effective in a multi-institutional setting.

Phase I trial of weekly docetaxel with concurrent three-dimensional conformal radiation therapy in the treatment of unfavorable localized adenocarcinoma of the prostate.

PURPOSE: A phase I trial was conducted to determine the maximally tolerated dose (MTD) of concurrent weekly docetaxel and three-dimensional conformal radiation therapy (3-D CRT) in unfavorable localized adenocarcinoma of the prostate. PATIENTS AND METHODS: Patients with unfavorable localized adenocarcinoma of the prostate underwent daily 3-D CRT to a total dose of 70.2 Gy at 1.8 Gy/fraction and concurrent docetaxel given once a week for 8 to 9 weeks. The initial weekly docetaxel dose level was 5 mg/m(2) and the docetaxel doses were escalated as follows: 8, 12, 16, 20, and 25 mg/m(2). RESULTS: Between January 2000 and August 2002, 22 men completed the chemoradiation therapy protocol. The dose-limiting toxicity was grade 3 diarrhea, which occurred in the first two patients treated at the 25 mg/m(2) docetaxel dose level. The MTD of weekly docetaxel was determined to be 20 mg/m(2). The overall incidence of grade 2 diarrhea and grade 2 dysuria was 36% and 23%, respectively. Seven (32%) and 15 (68%) patients did not experience any diarrhea or dysuria, respectively. No neutropenia or thrombocytopenia was observed. One patient required intermittent urinary catheterization 10 months postcompletion of therapy, which resolved without any surgical intervention. Seventeen patients remain in prostate-specific antigen remission. At a median follow-up interval of 8 months (range, 2 to 27 months), all patients are alive. CONCLUSION: Concurrent weekly docetaxel in conjunction with 3-D CRT is well tolerated with acceptable toxicity. The MTD of weekly docetaxel was determined to be 20 mg/m(2) with concurrent 3-D CRT.

Factors predictive of local disease control after intra-arterial concomitant chemoradiation (RADPLAT).

OBJECTIVES: To determine the relative risk of prognostic factors for local disease control following RADPLAT. STUDY DESIGN: Prospective study, academic medical center. METHODS: Analyses of nine categories of risk factors among 240 patients with Stage II-IV carcinoma consecutively treated with RADPLAT (cisplatin 150 mg/m IA and sodium thiosulfate 9 g/m IV, weekly x4; radiotherapy 2 Gy/fraction/d, 5x weekly, 68-74 Gy over 6 to 7 weeks). Median follow-up: 58 months (range, 12-96 mo). RESULTS: The percentage of patients who had local disease control was 87.5%. Univariant analysis showed T classification (P =.01), laterality of neck disease (P =.026), number of neck levels involved (P =.008), total dose of radiation greater versus less than 60 Gy (P =.027), and presence of pathologically positive lymph nodes following chemoradiation (P =.01) to be significant. Logistic regression analysis showed total dose of radiation (P =.03) and the presence of pathologically positive lymph nodes following chemoradiation (P =.05) to be significant. For Kaplan-Meier estimates of local disease control at 5 years, T classification (P =.038), number of levels with nodal disease (P =.006), and total dose of radiation therapy (P =.0001) were significant. The log-rank test identified as significant the total dose of radiation therapy (P <.0001), the presence of pathologically positive lymph nodes following chemoradiation (P =.005), and the number of neck levels with positive nodes (P =.006). The Cox regression model showed significance for the total dose of radiation (P =.001), the presence of pathologically positive lymph nodes following chemoradiation (P =.007), and the T classification (P =.029). CONCLUSION: Risk factors significantly associated with local disease control after RADPLAT appears to differ from more traditional therapy and is suggestive of a paradigm shift.

Presurgical cytoreduction of oral cancer using intra-arterial cisplatin and limited concomitant radiation therapy (Neo-RADPLAT).

OBJECTIVE: To determine the effectiveness of a cytoreduction strategy for oral cancer using a novel trimodal therapy. METHODS: Prospective analysis of 25 patients treated between October 1995 and June 2000 with a protocol named neo-RADPLAT consisting of 4 weekly intra-arterial infusions of cisplatin (150 mg/m2) and intravenous infusions of sodium thiosulfate (9 g/m2), and concurrent radiation therapy (2 daily doses of 50 Gy) followed by tumor nidusectomy (a conventional surgery) at 8 weeks. Five patients had T2 lesions and 20 patients had T3 lesions; the clinical neck cancer stages were N0 in 12 patients, N1 in 9, and N2 in 4 (2 N2a, 1 N2b, and 1 Nc); and there were 17 tumors of the oral cavity (11 of the oral tongue, 5 of the retromolar trigone, and 1 of the floor of mouth) and 8 of the oropharynx (4 of the tonsillar fossa, 3 of the base of tongue, and 1 of the soft palate). RESULTS: Twenty patients (80%) had a complete response to chemoradiation in the primary site and 11 (79%) had a complete response in the neck. Among the 19 patients who had a tumor nidusectomy after chemoradiation, 5 had residual cancer and required a conventional resection. With regard to major toxicity, there were 6 cases of grade 3 and 1 case of grade 4 hematologic effects, 1 case of grade 3 neurologic effect, 1 case of grade 3 gastrointestinal effect, 1 case of grade 5 cardiac effect, as well as 16 cases of grade 3 mucositis. With a median follow-up of 56 months (range, 28-84 months), the 5-year estimates for overall survival, disease-specific survival, and locoregional control were 54%, 64%, and 74%, respectively. Fourteen patients remain without disease, 6 have died of the disease, and 5 have died of other causes. CONCLUSIONS: Preoperative intra-arterial chemoradiation cytoreduction followed by limited surgery is effective for controlling oral cancer. This tissue-sparing and reduced-radiation strategy may also preserve oral function.

A new paradigm for the treatment of high-risk prostate cancer: radiosensitization with docetaxel.

Survival and biochemical outcome of patients with localized, high-risk prostate cancer treated with definitive three-dimensional conformal radiation therapy (3-D CRT) with or without hormonal therapy are poor. Other therapeutic strategies are needed to improve outcome in these poor-prognostic-group patients. One such strategy involves the use of chemotherapeutic agents to radiosensitize the effects of local 3-D CRT. Very few investigators have tested this novel concept of chemotherapeutic radiosensitization. Two studies evaluated the combination of estramustine phosphate and vinblastine (EV) with radiation therapy (RT). In both studies, the combination of EV and RT resulted in moderate to severe acute and late toxicity. A recently completed, phase I trial evaluated the maximally tolerated dose (MTD) of weekly docetaxel that could be concurrently delivered with 3-D CRT (70.2 Gy) in men with high-risk prostate cancer. The MTD of concurrent weekly docetaxel with 3-D CRT was determined to be 20 mg/m(2), and this combination was shown to be safe and well tolerated. This was the first trial to evaluate taxane radiosensitization in prostate cancer. Other phase I/II studies are needed to further assess chemotherapeutic radiosensitization in localized, high-risk prostate cancer.

Radiotherapy versus chemotherapy plus radiotherapy in surgically treated IIIA N2 non-small-cell lung cancer.

Preoperative chemotherapy in patients with stage III non-small-cell lung cancer (NSCLC) remains controversial. Phase II trials utilizing preoperative chemotherapy in selected patients have achieved complete resection rates of 50%-70% with 3-5 year failure-free survival rates of 15%-33%. Between October 1992 and November 1994, 57 adults (50 of whom were evaluable) with surgically staged IIIA NSCLC and pathologically documented ipsilateral mediastinal nodal involvement (N2) were enrolled in a Cancer and Leukemia Group B randomized trial. Preoperative therapy was thought to be critical to facilitating surgical resectability. For patients randomized to the radiotherapy/surgery/radiotherapy (RSR) arm (n = 24), treatment consisted of preoperative radiation therapy (RT) at 40 Gy, surgery, and then additional RT at 14-20 Gy. For patients randomized to the chemotherapy/surgery/chemotherapy/radiotherapy (CSCR) arm (n = 26), treatment consisted of 2 cycles of cisplatin/etoposide with filgrastim support (PE) followed by surgery, 2 more cycles of PE, then RT 54-60 Gy. The total dose of RT on either arm was 54 Gy if completely resected or 60 Gy if incompletely resected or unresected. Clinical characteristics were well balanced between the two arms. Thoracotomy was performed in 42 patients (84%), 28 (67%) of whom had complete resection. The median failure-free and overall survival rates were 12 months (95% confidence interval [CI], 9-23 months) and 23 months (95% CI, 19 months-infinity) for the RSR arm and 11 months (95% CI, 5-20 months) and 18 months (95% CI, 12-32 months) for the CSCR arm. The rates of overall and complete surgical resection, downstaging of nodal involvement, and failure-free (P = 0.92) and overall survival (P = 0.41) did not differ between the two treatment arms. Moreover, in this trial, the chemotherapy regimen was sufficiently toxic to have had a lower completion rate of prescribed therapy in the CSCR arm than in the RSR arm.