Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice.

BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and ß-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older.

Randomized trials of chemoradiation for esophageal cancer have included very few patients age > or = 75. In this retrospective study, we describe the outcomes and toxicity of full-dose chemoradiation in elderly patients with esophageal cancer. Patients, age > or = 75, treated with full-dose chemoradiation for esophageal carcinoma from 2002 to 2008 were retrospectively reviewed. Thirty-four patients were identified with a median age of 79.5 (range 75-89). The median Eastern Cooperative Oncology Group performance status was 1 (range 0-3) and the median Adult Comorbidity Evaluation-27 score was 1 (range 0-3). Twenty-eight patients received definitive and six received neoadjuvant chemoradiation. The median radiation dose delivered was 50.4 Gray (range 3.6-68.4 Gray). Platinum-based chemotherapy was used in 79.4% of patients. Fifty percent of the patients completed all planned radiation therapy (RT) and chemotherapy; 85.3% completed RT. Acute toxicity > or = grade 4 occurred in 38.2% of patients, and 70.6% of the patients required hospitalization, emergency department visit, and/or RT break. Median follow-up was 14.5 months among 7 survivors, and median survival was 12.0 months (95% confidence interval [CI]: 9.7 to 24.1 months). The actuarial overall survival at 2 years was 29.7% (95% CI: 16.6 to 52.6%). There were four treatment-related deaths. The median time to any recurrence was 10.4 months. Nineteen patients had a local and/or distant recurrence. In conclusion, elderly patients experienced substantial morbidity from chemoradiation, and long-term survival was low. Future efforts to improve treatment tolerability in the elderly are needed.

Two-dimensional modelling of benzene transport and biodegradation in a laboratory-scale aquifer.

In this study biodegradation of aqueous benzene during transport in a laboratory-scale aquifer model was investigated by conducting a 2-D plume test and numerical modelling. Benzene biodegradation and transport was simulated with the 2-D numerical model developed for solute transport coupled with a Haldane-Andrews type function for inclusion of an inhibition constant which is effective for high concentrations. Experimental data revealed that in the early stages the benzene plume showed a rather clear shape but lost its shape with increased travel time. The mass recoveries of benzene at 9, 16, and 22 h were 37, 13 and 8%, respectively, showing that a significant mass reduction of aqueous benzene occurred in the model aquifer. The major processes responsible for the mass reduction were biodegradation and irreversible sorption. The modelling results also indicated that the simulation based on the microbial parameters from the batch experiments slightly overestimated the mass reduction of benzene during transport. The sensitivity analysis demonstrated that the benzene plume was sensitive to the maximum specific growth rate and slightly sensitive to the half-saturation constant of benzene but almost insensitive to the Haldane inhibition constant. The insensitivity to the Haldane inhibition constant was due to the rapid decline of the benzene peak concentration by natural attenuation such as hydrodynamic dispersion and irreversible sorption. An analysis of the model simulation also indicated that the maximum specific growth rate was the key parameter controlling the plume behaviour, but its impact on the plume was affected by competing parameter such as the irreversible sorption rate coefficient.

Modeling of growth kinetics for Pseudomonas putida during toluene degradation.

Glucose has been often used as a secondary substrate to enhance the degradation of primary substrate as well as the increase of biomass, especially for the inhibitory range of substrate concentration. In this study, we investigated the effect of glucose concentration on growth kinetics of Pseudomonas putida during toluene degradation for a wide concentration range (60-250 mg/l). Batch microcosm studies were conducted in order to monitor bacterial growth for three different initial concentrations (2, 5, 10 mg/ml) of glucose for a given toluene concentration. Modeling of growth kinetics was also performed for each growth curve of glucose dose using both Monod and Haldane kinetics. Batch studies revealed that bacterial growth showed a distinct inhibitory phase above some limit (approximately 170 mg/l) for the lowest (2 mg/ml) glucose dose, but the degree of inhibition decreased as the glucose dose increased, leading to three different growth patterns. The bacterial growth followed each of the modified Wayman and Tseng, Wayman and Tseng, and Luong model as the glucose dose increased from 2 to 10 mg/ml. This indicates that glucose has a prominent influence on bacterial growth during toluene degradation and that different kinetics should be adopted for each broth condition.

Effect of dissolved oxygen regime on growth dynamics of Pseudomonas spp during benzene degradation.

We investigated the effect of different oxygen regimes on growth patterns of Pseudomonas spp. during benzene degradation in microcosm batch studies. Benzene degradation was induced by limiting oxygen available for microbial activity, which consists of three initial-dissolved oxygen (DO) levels of oxic, hypoxic, and anoxic conditions. Batch experiments were performed for cell growth and benzene degradation by inoculating three strains of Pseudomonas spp. (Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida) in mineral salt medium containing aqueous benzene. Results showed that all strains were capable to grow and degrade benzene under all oxygen regimes but in a different manner. The highest cell growth of P. aeruginosa and P. fluorescens was achieved under oxic and anoxic condition, respectively, but there was no substantial difference on benzene degradation between the oxygen treatments with about 25% reduction for both strains. P. putida showed a facultative process for both cell growth and benzene degradation. This reveals that care should be taken in selection of microorganisms with regard to environmental studies since they exhibit different responses for given environmental conditions such as DO levels.

Modeling of growth kinetics for Pseudomonas spp. during benzene degradation.

A modeling study was conducted on growth kinetics of three different strains of Pseudomonas spp. (Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida) during benzene degradation to determine optimum substrate concentrations for most efficient biodegradation. Batch tests were performed for eight different initial substrate concentrations to observe cell growth and associated substrate degradation using benzene-adapted cells. Kinetic parameters of both inhibitory (Haldane-Andrews, Aiba-Edwards) and noninhibitory (Monod) models were fitted to the relationship between specific growth rate and substrate concentration obtained from the growth curves. Results showed that half-saturation constant of P. fluorescens was the highest among the three strains, indicating that this strain could grow well at high concentration, while P. putida could grow best at low concentration. The inhibition constant of P. aeruginosa was the highest, implying that it could tolerate high benzene concentration and therefore could grow at a wider concentration range. Estimated specific growth rate of P. putida was lower, but half-saturation constant was higher than those from literature study due to high substrate concentration range used in this study. These two kinetic parameters resulted in substantial difference between Monod- and Haldane-type models, indicating that distinction should be made in applying those models.

Reliability of perfusion MR imaging in symptomatic carotid occlusive disease. Cerebral blood volume, mean transit time and time-to-peak.

PURPOSE: Perfusion MR imaging offers an easy quantitative evaluation of relative regional cerebral blood volume (rrCBV), relative mean transit time (rMTT) and time-to-peak (TTP). The purpose of this study was to investigate the reliability of these parameters in assessing the hemodynamic disturbance of carotid occlusive disease in comparison with normative data. MATERIAL AND METHODS: Dynamic contrast-enhanced T2*-weighted perfusion MR imaging was performed in 19 patients with symptomatic unilateral internal carotid artery occlusion and 20 control subjects. The three parameters were calculated from the concentration-time curve fitted by gamma-variate function. Lesion-to-contralateral ratios of each parameter were compared between patients and control subjects. RESULTS: Mean +/- SD of rrCBV, rMTT and TTP ratios of patients were 1.089 +/- 0.118, 1.054 +/- 0.031 and 1.062 +/- 0.039, respectively, and those of control subjects were 1.002 +/- 0.045, 1.000 +/- 0.006, 1.001 +/- 0.006, respectively. The rMTT and TTP ratios of all patients were greater than 2 SDs of control data, whereas in only 6 patients (32%), rrCBV ratios were greater than 2 SDs of control data. The three parameter ratios of the patients were significantly high compared with those of control subjects, respectively (p < 0.01 for rrCBV ratios, p < 0.0001 for rMTT ratios, and p < 0.0001 for TTP ratios). CONCLUSION: Our results indicate that rMTT and TTP of patients, in contrast to rrCBV, are distributed in narrow ranges minimally overlapped with control data. The rMTT and TTP could be more reliable parameters than rrCBV in assessing the hemodynamic disturbance in carotid occlusive disease.

Comparative evaluation of cerebral blood volume and cerebral blood flow in acute ischemic stroke by using perfusion-weighted MR imaging and SPECT.

PURPOSE: To investigate the relationship between relative cerebral blood volume (CBV) measured with perfusion-weighted (PW) MR imaging and relative cerebral blood flow (CBF) measured with SPECT in acute ischemic stroke. MATERIAL AND METHODS: Fifteen patients who had acute unilateral middle cerebral artery occlusion underwent both PW MR imaging and 99mTc-HMPAO SPECT with an interval less than 20 min between the two examinations within 6 h after stroke onset. Lesion-to-contralateral relative CBV and CBF ratios measured in multiple regions of interest were compared to evaluate the relationship of the two parameters. RESULTS: An overall linear relationship was found between relative CBV and relative CBF ratios (R2 = 0.54, p < 0.0001). The two parameters correlated linearly to each other in regions with evolving infarction (R2 = 0.43, p<0.0001), but not in regions without evolving infarction (R2 = 0.001, p>0.05). Regions with evolving infarction had more severe hypoperfusion (mean relative CBF ratio, 0.38 +/- 0.22) than regions without (mean relative CBF ratio, 0.70+/-0.13) (p<0.0001). CONCLUSION: A significant linear relationship existed between relative CBV and relative CBF in acute ischemic stroke, although relative CBV did not change linearly to relative CBF in mild hypoperfusion. Relative CBV can be used as an alternative to relative CBF within 6 h after stroke onset, particularly in regions with severe hypoperfusion proceeding to infarction.

Correlative assessment of hemodynamic parameters obtained with T2*-weighted perfusion MR imaging and SPECT in symptomatic carotid artery occlusion.

BACKGROUND AND PURPOSE: Perfusion MR imaging and single-photon emission CT (SPECT) are commonly used to evaluate hemodynamic status in patients with symptomatic occlusive cerebrovascular disease. These techniques rely on different underlying physiological mechanisms, and the data may not correspond. We studied the relationship between hemodynamic parameters obtained with these two methods. METHODS: We performed perfusion MR imaging and SPECT in 10 patients with symptomatic unilateral internal carotid artery occlusion. Relative cerebral blood volume (rCBV) and uncorrected mean transit time (uMTT) were obtained with dynamic contrast-enhanced T2*-weighted MR imaging. Relative cerebral blood flow (rCBF) and vascular reserve capacity were measured with 99mTc-HMPAO SPECT; vascular reserve capacity was calculated by the difference in CBF before and after acetazolamide challenge. Ratios of these hemodynamic parameters between the affected and contralateral vascular territories were calculated and compared. RESULTS: Normal-to-increased CBV, prolonged uMTT, decreased CBF, and normal-to-diminished vascular reserve capacity were observed in the affected vascular territories. Reduction of vascular reserve capacity corresponded well with uMTT but not with CBF and CBV. CBF, CBV, and uMTT did not correspond to one another. CONCLUSION: uMTT is more sensitive than the other parameters in estimating vascular reserve capacity. The relationship between parameters obtained with perfusion MR imaging and SPECT should be considered in assessing the hemodynamic status of patients with symptomatic occlusive cerebrovascular disease.

Triphasic perfusion computed tomography in acute middle cerebral artery stroke: a correlation with angiographic findings.

OBJECTIVE: To evaluate the usefulness of triphasic perfusion computed tomography (TPCT) in diagnosing middle cerebral artery (MCA) occlusion and in assessing the perfusion deficit and collateral circulation in patients with acute ischemic stroke. BACKGROUND: Conventional angiography is the criterion standard for the diagnosis of MCA occlusion and for the assessment of perfusion deficit and collateral blood supply. The risk of hemorrhagic transformation after recanalization of occluded arteries by thrombolytic therapy is considered high when pretherapeutic residual flow is markedly reduced. PATIENTS AND METHODS: In 8 patients within 3 hours of onset of acute MCA stroke, precontrast computed tomographic scans were taken, and then TPCT was performed after power-injector controlled intravenous administration of contrast media. Sequential images of early, middle, and late phases were obtained. The whole procedure took 5 minutes. Perfusion deficit on TPCT was graded as "severe" or "moderate," depending on the state of collateral flow. Digital subtraction angiography (DSA) was performed in all patients within 6 hours of acute stroke. Direct intra-arterial urokinase infusion was begun immediately after the angiographic superselection of the MCA occlusion site in 6 of the 8 patients within 7 hours of onset (range, 4.3-6.2 hours). RESULTS: The DSA findings showed occlusion of the MCA stem (n = 1) and at the bifurcation (n = 4). The sites of proximal MCA occlusion could be identified on the early and middle images of TPCT in all 5 patients. On DSA findings, all 8 patients had a zone of perfusion deficit with markedly slow leptomeningeal collaterals and a zone of perfusion deficit with no collaterals. The zone of severe perfusion deficit on TPCT corresponded to the zone of perfusion deficit with no or few collaterals on angiography, and the zone of moderate perfusion deficit on TPCT corresponded to that of perfusion deficit with markedly slow leptomeningeal collaterals. Early parenchymal hypoattenuation on precontrast computed tomography was confined to the zone of severe perfusion deficit on TPCT. The initial National Institutes of Health Stroke Scale score correlated better with the total extent of severe perfusion deficit and moderate perfusion deficit on TPCT than that of severe perfusion deficit alone. After direct intra-arterial thrombolysis within 7 hours of onset, symptomatic hemorrhagic transformation did not develop in 4 patients with small severe perfusion deficit (33% or less of the presumed MCA territory). However, the remaining 2 patients with large severe perfusion deficit (more than 50% of the presumed MCA territory) deteriorated to death with hemorrhagic transformation. CONCLUSIONS: Triphasic perfusion computed tomography is useful for diagnosing proximal MCA occlusion and assessing perfusion deficit and collateral circulation as reliably as DSA. The zone of severe perfusion deficit on TPCT may be presumed to be the ischemic core, and that of moderate perfusion deficit, the penumbra zone. Triphasic perfusion computed tomography may be used as a rapid and noninvasive tool to make thrombolysis safer.

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

Various patterns of perfusion-weighted MR imaging and MR angiographic findings in hyperacute ischemic stroke.

BACKGROUND AND PURPOSE: Various clinical subtypes of patients presenting with sudden-onset ischemic stroke have been recognized, but classification of those types is not simple. We identified various patterns of perfusion-weighted MR imaging and MR angiographic findings in hyperacute ischemic stroke with relation to clinical outcomes. METHODS: Twelve patients with symptoms of acute ischemic stroke due to middle cerebral artery occlusion underwent perfusion-weighted MR imaging and MR angiography within 6 hours after the onset of symptoms. Perfusion-weighted imaging was performed with a conventional dynamic contrast-enhanced T2*-weighted sequence, and cerebral blood volume (CBV) maps were then created. CBV maps and MR angiographic findings were compared with 99mTc-HMPAO brain SPECT scans, short-term outcomes, and follow-up imaging findings. RESULTS: The combined CBV and MR angiographic findings were classified into three patterns: arterial occlusion and decreased CBV (n = 8), arterial occlusion and increased CBV (n = 2), and no arterial occlusion and normal CBV (n = 2). These three patterns were strongly related to SPECT findings, short-term outcomes, and follow-up imaging findings. Perfusion on SPECT decreased markedly in the affected regions in all patients with the first pattern, decreased slightly in the second pattern, and was normal in the third pattern. Symptoms were not significantly changed at 24 hours after onset in any of the patients with the first pattern, but resolved completely in all patients with the latter two patterns. Follow-up imaging showed large infarctions in all patients with the first pattern. Initially, no infarction was seen in the second pattern, but watershed infarction developed later in one of these patients. CONCLUSION: Hyperacute ischemic stroke may be differentiated into three imaging patterns with different clinical outcomes. The combined use of perfusion-weighted MR imaging and MR angiography may play a substantial role in guiding the choice of treatment of this disease.

Superior sulcus lung tumors: impact of local control on survival.

OBJECTIVES: Our goal was to assess patient survival and response to treatment for superior sulcus tumors treated with combined radiation therapy and surgery when possible, or with radiation alone when surgery was not possible. METHODS: Seventy-three patients were treated for primary non-small cell carcinoma of the superior pulmonary sulcus. Thirty-four patients received combined resection and irradiation. Thirty-nine patients who had extensive primary disease, distant metastases, or who were medically unfit for surgery were treated with radiation alone. Thirty-one patients (91%) assigned to the resection/irradiation group completed treatment. Combined therapy patients routinely received 40 Gy before the operation, with additional postoperative irradiation based on the surgical findings. RESULTS: Overall survival at 5 years was 19% and disease-specific survival was 20% for all patients. Overall survival and disease-specific survival at 5 years for the resection/irradiation group were 33% and 38%, respectively. Significant indicators of poor prognosis included unresected primary disease, low performance score, T4 stage, or positive node status. Eighty-two percent of the patients who received irradiation alone were treated with palliative intent. Freedom from local-regional progression, achieved initially in 66% of these patients, was associated with a median survival of 8 months. Median survival for 7 patients considered for definitive irradiation was 25 months. During the first 18 months, distant failures occurred in approximately 35% of patients in each treatment group. CONCLUSIONS: Selection of medically fit patients with resectable disease for combined surgery and aggressive radiation therapy resulted in a high likelihood of local control. Overall survival for the resection/irradiation group was significantly poorer for patients with T4 stage, nodal disease, or Horner's syndrome. Distant metastases eventually developed in 56% of patients undergoing resection. Median survival in the resection/irradiation group was significantly prolonged for those patients who could tolerate high-dose radiation treatment.

Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer.

PURPOSE: An improvement in radiation dose schedule is necessary to increase local tumor control and survival in limited-stage small-cell lung cancer. The goal of this study was to determine the maximum-tolerated dose (MTD) of radiation (RT) in both standard daily and hyperfractionated-accelerated (HA) twice-daily RT schedules in concurrent chemoradiation. METHODS: The study design consisted of a sequential dose escalation in both daily and HA twice-daily RT regimens. RT dose to the initial volume was kept at 40 to 40.5 Gy, while it was gradually increased to the boost volume by adding a 7% to 11 % increment of total dose to subsequent cohorts. The MTD was defined as the radiation dose level at one cohort below that which resulted in more than 33% of patients experiencing grade > or = 4 acute esophagitis and/or grade > or = 3 pulmonary toxicity. The study plan included nine cohorts, five on HA twice-daily and four on daily regimens for the dose escalation. Chemotherapy consisted of three cycles of cisplatin 33 mg/m2/d on days 1 to 3 over 30 minutes, cyclophosphamide 500 mg/m2 on day 1 intravenously (IV) over 1 hour, and etoposide 80 mg/m2/d on days 1 to 3 over 1 hour every 3 weeks (PCE) and two cycles of PE. RT was started at the initiation of the fourth cycle of chemotherapy. RESULTS: Fifty patients were enrolled onto the study. The median age was 60 years (range, 38-79), sex ratio 2.3:1 for male to female, weight loss less than 5% in 73%, and performance score 0 to 1 in 94% and 2 in 6% of patients. In HA twice-daily RT, grade > or = 4 acute esophagitis was noted in two of five (40%), two of seven (29%), four of six (67%), and five of six patients (86%) at 50 (1.25 Gy twice daily), 45, 50, and 55.5 Gy in 1.5 Gy twice daily, 5 d/wk, respectively. Grade > or = 3 pulmonary toxicity was not seen in any of these 24 patients. Therefore, the MTD for HA twice-daily RT was judged to be 45 Gy in 30 fractions over 3 weeks. In daily RT, grade > or = 4 acute esophagitis was noted in zero of four, zero of four, one of five (20%), and two of six patients (33%) at 56, 60, 66, and 70 Gy on a schedule of 2 Gy per fraction per day, five fractions per week. Grade > or = 3 pneumonitis was not observed in any of the 19 patients. Thus, the MTD for daily RT was judged to be at least 70 Gy in 35 fractions over 7 weeks. Grade 4 granulocytopenia and thrombocytopenia were observed in 53% and 6% of patients, respectively, during the first three cycles of PCE. During chemotherapy cycles 4 to 5, grade 4 granulocytopenia and thrombocytopenia were noted in 43% and 29% of patients at 45 Gy in 30 fractions over 3 weeks (MTD) by HA twice-daily RT and 50% and 17% at 70 Gy in 35 fractions over 7 weeks (MTD) by daily RT, respectively. The overall tumor response consisted of complete remission (CR) in 51% (24 of 47), partial remission (PR) in 38% (1 8 of 47), and stable disease in 2% (one of 47). The median survival time of all patients was 24.4 months and 2- and 3-year survival rates were 53% and 28%, respectively. With regard to the different radiation schedules, 2- and 3-year survival rates were 52% and 25% for the HA twice-daily and 54% and 35% for the daily RT cohorts. CONCLUSION: The MTD of HA twice-daily RT was determined to be 45 Gy in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 weeks for daily RT. A phase III randomized trial to compare standard daily RT with HA twice-daily RT at their MTD for local tumor control and survival would be a sensible research in searching for a more effective RT dose-schedule than those that are being used currently.

Temporal pattern of blood volume change in cerebral infarction: evaluation with dynamic contrast-enhanced T2*-weighted MR imaging.

OBJECTIVE: The purposes of this study were to evaluate the temporal pattern of blood volume change in cerebral infarction and to provide a guideline in the interpretation of blood volume data, which are known to vary according to the stage of infarction. SUBJECTS AND METHODS: Thirty-three patients with large middle cerebral infarctions were examined one to three times (one time in 20 patients, two times in eight patients, and three times in five patients) after the onset of stroke by dynamic contrast-enhanced T2*-weighted MR imaging and MR angiography. A total of 54 infarctions (29 in an acute stage [up to 7 days], 15 in a subacute stage [8-21 days], and 10 in a chronic stage [22-35 days]) were included. After blood volume maps were created, blood volume ratios (blood volume of the infarcted region divided by blood volume of corresponding contralateral region) were compared at different stages. Likewise, findings on MR angiography were compared at different stages. RESULTS: Mean blood volume ratios in each stage of infarction were 0.46 in the acute stage, 1.48 in the subacute stage, and 0.73 in the chronic stage (p < .001). Recanalization of occluded arteries occurred in 21% of infarctions in the acute stage and 80% in the subacute stage. Infarctions with recanalization had higher blood volume ratios than did those without recanalization (p < .001). A biphasic pattern of blood volume ratios was found in 13 patients who underwent at least two MR examinations: increased blood volume in the subacute stage and decreased blood volume in the chronic stage, regardless of recanalization (p < .01). CONCLUSION: Blood volume that initially decreases in cerebral infarction increases in the subacute stage, reflecting reperfusion hyperemia. Blood volume decreases again in the chronic stage. The time interval between onset of stroke and MR examination must be considered for correct interpretation of blood volume data in cerebral infarction at various stages.

Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapy: a phase I and II study.

OBJECTIVE: Induction chemoradiotherapy followed by surgery may improve survival rates among patients with esophageal carcinoma. We designed a novel intense induction regimen with paclitaxel and high-dose hyperfractionated radiotherapy to maximize complete response rates. METHODS: Forty patients with esophageal cancer were treated in a phase I and II trial of induction chemotherapy (cisplatin, 5-fluorouracil, and paclitaxel) at three dosage levels (75, 125, and 100 mg/m2) and concurrent hyperfractionated radiotherapy (45 Gy to the mediastinum, 58.5 Gy to the tumor). The mean age was 62 years, and 32 patients (80%) had adenocarcinoma. Twenty-eight of 40 (70%) patients had locally advanced tumors (T3, or stage IIB or greater). RESULTS: The average hospitalization for induction treatment was 17 days. Toxicity was substantial, with esophagitis necessitating nutritional support the most common complication. The maximum tolerated dose of paclitaxel was 100 mg/m2. Two patients died during induction treatment. Thirty-six patients (90%) underwent resection. The median length of stay was 10 days, and two patients died after the operation. Fourteen of 36 patients (39%) had a pathologic complete response. Patients who received all prescribed chemotherapy had a higher pathologic complete response rate (50%) than did patients who required dose reduction (17%; p = 0.076). The 2-year survival rate was 61% (95% CI 35% to 86%) with a median follow-up of 11.9 months. CONCLUSIONS: Paclitaxel at a dose of 100 mg/m2 appears to have acceptable toxicity. The high pathologic complete response rate in this regimen is encouraging, but it is associated with substantial toxicity. The toxicity of this regimen is not acceptable and will require substantial reduction in the radiation component. Survival data are too short-term to confirm enhanced survival.