ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion: Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration: Clinicaltrials.gov ID: NCT05610163 ; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Effects of Chromophoric Dissolved Organic Matter on Anthracene Photolysis Kinetics in Aqueous Solution and Ice.

We measured photolysis kinetics of the PAH anthracene in aqueous solution, in bulk ice, and at ice surfaces in the presence and absence of chromophoric dissolved organic matter (CDOM). Self-association, which occurs readily at ice surfaces, may be responsible for the faster anthracene photolysis observed there. Photolysis rate constants in liquid water increased under conditions where anthracene self-association was observed. Concomitantly, kinetics changed from first-order to second-order, indicating that the photolysis mechanism at ice surfaces might be different than that in aqueous solution. Other factors that could lead to faster photolysis at ice surfaces were also investigated. Increased photon fluxes due to scattering in the ice samples can account for at most 20% of the observed rate increase, and other factors including singlet oxygen (1O2*) production and changes in pH and polarity were determined not to be responsible for the faster photolysis. CDOM (in the form of fulvic acid (FA)) did not affect anthracene photolysis kinetics in aqueous solution but suppressed photolysis in ice cubes and ice granules (by 30% and 56%, respectively). This was primarily due to competitive photon absorption (the inner filter effect). Freeze-concentration (or "salting out") appears to slightly increase the suppressing effects of FA on anthracene photolysis. This may be due to increased competitive photon absorption or to physical interactions between anthracene and FA.

Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial.

BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ). PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken. RESULTS: Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS. CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population. CLINICALTRIALSGOV IDENTIFIER: NCT01246960.

Nonchromophoric organic matter suppresses polycyclic aromatic hydrocarbon photolysis in ice and at ice surfaces.

We have investigated the effects of organic matter (OM) that does not absorb sunlight ("nonchromophoric") on the reactive environment presented by bulk ice and ice surfaces. Fluorescence spectroscopy showed that the presence of as little as 2.5 × 10(-4) M octanol or decanol reduces the extent to which naphthalene self-associates at ice surfaces, which indicates that naphthalene partitions between ice and organic phases present there. We also measured photolysis kinetics of the polycyclic aromatic hydrocarbons (PAHs) anthracene, pyrene, and phenanthrene in bulk ice and at ice surfaces containing 2.5 × 10(-5) M to 7.5 × 10(-3) M OM. In bulk ice, even the lowest concentrations of OM reduced photolysis kinetics to below our detection limits. Organic matter also reduced measured photolysis kinetics of PAHs at ice surfaces, but generally to a lesser extent than in bulk ice. Our results support previous reports that bulk ice and ice surfaces present distinct reaction environments, and show for the first time that OM can affect PAH photolysis kinetics by altering the physical environment within bulk ice and at ice surfaces.

MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer.

BACKGROUND: A major challenge to the development of biomarkers for pancreatic cancer (PC) is the small amount of tissue obtained at the time of diagnosis. Single-gene analyses may not reliably predict biology of PC because of its complex molecular makeup. MicroRNA (miRNA) profiling may provide a more informative molecular interrogation of tumours. The primary objective of this study was to determine the feasibility of performing miRNA arrays and quantitative real-time PCR (qRT-PCR) from archival formalin-fixed paraffin-embedded (FFPE) cell blocks obtained from fine-needle aspirates (FNAs) that is the commonest diagnostic procedure for suspected PC. METHODS: MicroRNA expression profiling was performed on FFPE from FNA of suspicious pancreatic masses. Subjects included those who had a pathological diagnosis of pancreatic adenocarcinoma and others with a non-malignant pancreatic histology. Exiqon assay was used to quantify miRNA levels and qRT-PCR was used to validate abnormal expression of selected miRNAs. RESULTS: A total of 29 and 15 subjects had pancreatic adenocarcinoma and no evidence of cancer, respectively. The RNA yields per patient varied from 25 to 100 ng. Profiling demonstrated deregulation of over 228 miRNAs in pancreatic adenocarcinoma of which the top 7 were further validated by qRT-PCR. The expression of let-7c, let-7f, and miR-200c were significantly reduced in most patients whereas the expression of miR-486-5p and miR-451 were significantly elevated in all pancreas cancer patients. MicroRNAs let-7d and miR-423-5p was either downregulated or upregulated with a significant inter-individual variation in their expression. CONCLUSION: This study demonstrated the feasibility of using archival FFPE cell blocks from FNAs to establish RNA-based molecular signatures unique to pancreatic adenocarcinoma with potential applications in clinical trials for risk stratification, patient selection, and target validation.

Prevalence and outcome of subclinical rheumatic heart disease in India: the RHEUMATIC (Rheumatic Heart Echo Utilisation and Monitoring Actuarial Trends in Indian Children) study.

OBJECTIVE: To study the prevalence and medium term outcome of subclinical rheumatic heart disease (RHD) in India. DESIGN: Cross sectional echocardiographic screening study. SETTING: School children aged 5-15 years living in rural areas of north India. PATIENTS: A cross sectional echocardiographic screening study was carried out among 6270 randomly selected school children aged 5-15 years (10.8 ± 2.6 years; 52.7% male). Of all the abnormal cases, 100 children (78%) were restudied at a mean follow-up of 15.4 ± 6.6 months. INTERVENTION: Echocardiographic screening. MAIN OUTCOME MEASURE: Echocardiography-Doppler criteria based prevalence of RHD. RESULTS: Clinical examination detected mitral regurgitation in five patients and the estimated prevalence of clinical RHD was 0.8/1000 school children. Echocardiography-Doppler diagnosed RHD in 128 cases, giving a prevalence of 20.4/1000 school children (95% CI 16.9 to 23.9/1000 children). On multivariate analysis, older age (OR 1.93, 95% CI 1.29 to 2.88; p = 0.001), female sex (OR 1.84, 95% CI 1.25 to 2.72; p = 0.002) and government funded school student, which is a surrogate measure of lower socioeconomic status (OR 1.55, 95% CI 1.02 to 2.34; p = 0.039) were found to be independent predictors of RHD. On follow up, the severity of subclinical RHD was non-progressive in 68 children (68%) while it worsened in four (4%) and regressed in 28 children (28%). CONCLUSIONS: The prevalence of RHD is several fold higher using echocardiographic screening compared with clinical examination. The prevalence is higher among girls and children of lower socioeconomic status. In the majority of cases, subclinical RHD appears to be non-progressive on medium term follow up. Routine echocardiographic screening may be indicated in populations at high risk of RHD.

Expression of microRNAs: potential molecular link between obesity, diabetes and cancer.

Clinicians are routinely challenged in their management of cancer patients because of the complexities of obesity and diabetes that are often found as comorbid conditions. Although attention has been given to optimizing treatment planning for these patients, less attention has been given to manage their obesity and diabetes. This suggests that newer, comprehensive approaches must be developed for the treatment of cancer patients as a 'whole' rather than as a single disease. While the specific pathologies of each are unique, years of research have indicated intimate molecular links between these chronic diseases. The contribution of sedentary lifestyles and poor dietary habits is recognized; however, the precise molecular links are still not well-explored. In addition, emerging evidence suggests the important role of microRNAs (miRNAs) in the development and progression of several diseases, yet their roles in linking obesity, diabetes and cancer are only now beginning to be recognized. It is hoped that miRNAs will serve as novel biomarkers and molecular targets for cancer therapy in patients with comorbid conditions. In this review, we discuss the current understanding of the pathobiology of obesity, diabetes and cancer, and document molecular roles of miRNAs linking cancer with obesity and diabetes.

Predictors of clinical outcomes in elderly patients with heart failure.

AIMS: Heart failure (HF) in the elderly carries a poor prognosis. We used the SENIORS dataset of elderly HF patients aged ≥70 years in order to develop a risk model for this population. METHODS AND RESULTS: The SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients ≥70 years with HF (ejection fraction ≤35%, or recent HF admission). We randomly selected 1400 patients from the full dataset to produce a derivation cohort and the remaining 728 patients were used as a validation cohort. Baseline variables were entered into a bootstrap model with 200 iterations to determine their association with two outcomes, the composite of all-cause mortality or cardiovascular hospitalization, or all-cause mortality alone. Variables retaining a significant association with these outcomes in a multivariate model were used to develop a risk prediction score tested in the validation cohort. Five factors were associated with increased risk of both outcomes in the multivariate model: higher New York Heart Association class, higher uric acid level, lower body mass index, prior myocardial infarction, and larger left atrial (LA) dimension. For the composite outcome, peripheral arterial disease, years with heart failure, right bundle branch block, diabetes mellitus, and orthopnoea were also retained. For all-cause mortality, creatinine, 6 min walk test distance, coronary artery disease, and age were retained. CONCLUSION: In addition to conventional prognostic markers, uric acid and LA dimension appear to be important novel risk prediction markers in elderly patients with heart failure, and could be useful in guiding management.

MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy.

Zinc has a crucial role in the biology of p53 in that p53 binds to DNA through a structurally complex domain stabilized by zinc atom. The p53 negative regulator MDM2 protein also carries a C-terminal RING domain that coordinates two zinc atoms, which are responsible for p53 nuclear export and proteasomal degradation. In this clinically translatable study, we explored the critical role of zinc on p53 reactivation by MDM2 inhibitor, MI-219, in colon and breast cancer cells. ZnCl(2) enhanced MI-219 activity (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), apoptosis and colony formation), and chelation of zinc not only blocked the activity of MI-219, but also suppressed reactivation of the p53 and its downstream effector molecules p21(WAF1) and Bax. N,N,N'N'-tetrakis(-)[2-pyridylmethyl]-ethylenediamine (TPEN), a specific zinc chelator, but not 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (Bapta-AM), a calcium chelator, blocked MI-219-induced apoptosis. Nuclear localization is a prerequisite for proper functioning of p53 and our results confirm that TPEN, and not Bapta-AM, could abrogate p53 nuclear localization and it interfered with p53 transcriptional activation. Addition of zinc suppressed the known p53 feedback MDM2 activation, which could be restored by TPEN. Co-immunoprecipitation studies verified that MI-219-mediated MDM2-p53 disruption could be suppressed by TPEN and restored by zinc. As such, single-agent therapies that target MDM2 inhibition, without supplemental zinc, may not be optimal in certain patients owing to the less recognized mild zinc deficiency among the 'at-risk population' as in the elderly who are more prone to cancers. Therefore, use of supplemental zinc with MI-219 will benefit the overall efficacy of MIs and this potent combination warrants further investigation.

A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers.

BACKGROUND: Bevacizumab has demonstrated antitumor activity in multiple diseases. This phase II study was undertaken to determine the effects of adding bevacizumab to a regimen of docetaxel and oxaliplatin in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. PATIENTS AND METHODS: Previously untreated patients with locally advanced or metastatic disease and a performance status (PS) of 0-1 were eligible for this study. Patients received bevacizumab at 7.5 mg/kg, docetaxel at 70 mg/m(2), and oxaliplatin at 75 mg/m(2) administered on day 1 of a 21-day cycle. The primary end point of the study was progression-free survival (PFS). RESULTS: A total of 38 eligible patients (median age 57 years, 45% gastric, 55% PS 0) were enrolled on to the study. Median PFS was 6.6 months [95% confidence interval (CI) 4.4-10.5] and median survival 11.1 months (95% CI 8.2-15.3). Complete responses were documented in 2 (5%) patients, partial responses in 14 (37%), and stable disease in 14 (37%). No treatment-related deaths were observed. The most commonly reported grade 3-4 toxicity was neutropenia (34%), and gastrointestinal perforation occurred in three patients (8%). CONCLUSION: The combination of bevacizumab, docetaxel, and oxaliplatin has promising activity for further evaluation in randomized trials.

A randomised phase II study of OSI-7904L versus 5-fluorouracil (FU)/leucovorin (LV) as first-line treatment in patients with advanced biliary cancers.

The prognosis of advanced biliary tract carcinoma is poor with chemotherapy limited to a palliative role. This randomised study was designed to evaluate the effectiveness of a new liposomal thymidylate synthase inhibitor (TSI), OSI-7904L, in parallel with a modified de Gramont regimen of 5-FU/LV in patients with advanced biliary cancer. Patients with previously untreated advanced or metastatic carcinoma of the biliary tract were randomised to receive either OSI-7904L 12 mg/m2 intravenously every 21 days or a modified de Gramont schedule of 5-FU/LV (intravenous l-LV 200 mg/m2, bolus 5-FU 400 mg/m2 and a 46-h infusion of 5-FU 2,400 mg/m2) every 14 days. Twenty-two patients were randomised, 11 to each group. No patients responded in the OSI-7904L arm, while one patient achieved a partial response in the 5-FU/LV arm. The rates of disease stabilisation were 4/11 (OSI-7904L) and 10/11 (5-FU/LV). Both treatment arms were generally well tolerated. These results show that the activity of OSI-7904L is below a level of clinical relevance in advanced biliary tract cancer, providing only a small degree of disease stabilisation. A simplified de Gramont schedule appears to have marginally more activity. Both treatments were well tolerated.

Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6.

The aim was to identify the hepatic cytochromes P450 (CYPs) responsible for the enantioselective metabolism of ifosfamide (IFA). The 4-hydroxylation, N2- and N3-dechloroethylation of IFA enantiomers were monitored simultaneously in the same metabolic systems using GC/MS and pseudoracemate techniques. In human and rat liver microsomes, (R)-IFA was preferentially metabolized via 4-hydroxylation, whereas its antipode was biotransformed in favour of N-dechloroethylation. CYP3A4 was the major enzyme responsible for metabolism of IFA enantiomers in human liver. The study also revealed that CYP3A (human CYP3A4/5 and rat CYP3A1/2) and CYP2B (human CYP2B6 and rat CYP2B1/2) enantioselectively mediated the 4-hydroxylation, N2- and N3-dechloroethylation of IFA. CYP3A preferentially supported the formation of (R)-4-hydroxyIFA (HOIF), (R)-N2-dechloroethylIFA (N2D) and (R)-N3-dechloroethylIFA (N3D), whereas CYP2B preferentially mediated the generation of (S)-HOIF, (S)-N2D and (S)-N3D. The enantioselective metabolism of IFA by CYP3A4 and CYP2B1 was confirmed in cDNA transfected V79 cells.

Secondary cancers after a lung carcinoid primary: a population-based analysis.

Carcinoid tumors of the lung were first described in 1937, yet little is known about their etiology. The aim of the present investigation was to determine if there was excess risk of secondary cancers in a population-based sample after a lung carcinoid tumor diagnosis which may provide insight to the etiology. Subjects were 1882 cases diagnosed with carcinoid tumors of the lung between 1988 and 2000 whose information was obtained from the Surveillance, Epidemiology and End Results (SEER) Program database. Standardized incidence ratios were calculated by dividing the observed number of second primary cancers by the expected number of cancers. Excess risk of breast cancer was seen following diagnosis of a carcinoid tumor (SIR=1.80 95% CI 1.22-2.55). When stratified by time after diagnosis, excess risk of breast cancers in women was seen in the first 5 years after carcinoid diagnosis (SIR=1.68 95% CI 1.08-2.50) but fewer than expected breast cancers were diagnosed greater than 5 years after carcinoid diagnosis (SIR=0.29 95% CI 0.09-0.68). Prostate cancers also occurred 2.8 times more often than expected (95% CI 1.66-4.43), with risk being elevated only in the first 5 years post-carcinoid diagnosis. Development of lung carcinoids may be the result of genetic predisposition or environmental exposures, particularly those that are hormonally related. The role of genetics and sex hormones in lung carcinoid development, as well as the identification of other risk factors, should be explored.

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.

Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer.

PURPOSE: This phase II study was undertaken to determine the efficacy of adding infusional fluorouracil (FU) to the chemotherapy doublet of gemcitabine and cisplatin in patients with advanced pancreatic cancer. PATIENTS AND METHODS: The eligibility criteria included histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m2 intravenously (IV) on days 1, 8, and 15; cisplatin 50 mg/m2 IV on days 1 and 15; and FU 175 mg/m2/d from days 1 to 15 by continuous IV infusion. Cycles were repeated every 28 days. Objective tumor response and toxicity were evaluated according to the World Health Organization criteria. RESULTS: A total of 47 patients (median age, 57 years; males, 59%) were enrolled. Sixteen patients had locally advanced (LA) disease, and 31 patients had metastatic disease. A total of 183 cycles of chemotherapy were administered. In patients with metastatic disease (n = 31), the probability of survival at 6 and 12 months was 66% and 34%, respectively. Objective partial response or stable disease was observed in 26% (90% confidence interval [CI], 0.14 to 0.41) and 61% (90% CI, 0.45 to 0.74) of patients, respectively. In patients with LA disease (n = 16), there were three partial responses (19%; 90 CI, 0.07 to 0.39). One patient in this group was successfully resected after FU-based radiotherapy. The most common grade 3 to 4 toxicities were neutropenia (60%), thrombocytopenia (42%), and anemia (26%). Thirteen patients were hospitalized for treatment-related complications. CONCLUSION: The combination of gemcitabine, cisplatin, and infusional FU has significant activity in patients with advanced pancreatic cancer.

Developments in the systemic therapy of pancreatic cancer.

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the United States of America. Progress in the treatment of this disease in the past several decades has been very modest. Several new agents with activity against pancreatic cancer have been identified. Of these, gemcitabine is the most promising agent when used in combination with other drugs. Pilot phase II studies combining gemcitabine with 5-flourouracil, irinotecan, docetaxel, or cisplatin show improved outcomes in objective response rates and survival that need to be confirmed in larger randomized studies. Advancement in the understanding of the molecular biology of neoplasia in recent years has helped identify several molecular targets for future new drug development in pancreatic cancer. Assessment of response to therapy of pancreatic cancer has been a difficult challenge. Functional imaging with techniques such as positron emission tomography (PET) may yield a more precise and timely objective evaluation of response to treatment.

A single-institution experience with concurrent capecitabine and radiation therapy in gastrointestinal malignancies.

PURPOSE: We report our clinical experience with 32 patients receiving concurrent irradiation and capecitabine. METHODS AND MATERIALS: Medical records of patients with gastrointestinal malignancies treated with radiation and capecitabine therapy were reviewed. RESULTS: The population consisted of 20 males and 12 females, with a median age of 67.5 years (45-84 years) and adequate hepatic and bone marrow function. Histology was adenocarcinoma in all patients, except two with esophageal squamous carcinoma. Twenty-one patients received the regimen as adjuvant therapy, three received preoperative therapy, and 8 patients received therapy for palliation. The median dose of capecitabine was 1600 mg/m(2)/day (1200-2500 mg/m(2)/day) orally for 5 days per week for the duration of radiation therapy. Thirty patients received a total dose ranging from 45 Gy to 64 Gy over 4-6 weeks. Two previously radiated patients received total doses of 29.9 Gy and 46 Gy. Grade 3/4 toxicities observed were neutropenia in 3 patients and diarrhea, thrombocytopenia, fatigue, and myocardial infarction in 1 patient each. No treatment-related mortality was observed. Twenty of 21 patients (95.2%) who received adjuvant therapy continue to be in complete remission. Four of 11 (36%) evaluable patients demonstrated a response. CONCLUSION: Concurrent capecitabine and radiation were very well tolerated and warrant further investigation in prospective trials.

Bryostatin 1 induces differentiation and potentiates the antitumor effect of Auristatin PE in a human pancreatic tumor (PANC-1) xenograft model.

Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Hence, there is a tremendous need for development of new and effective therapy for this tumor. In an earlier study we reported a potent antitumor activity of Auristatin PE (AuriPE) against pancreatic tumor. In addition, we have also reported that bryostatin 1 (bryo1) induces differentiation of leukemia cells, but the effect of bryo1 has not been investigated in pancreatic tumors. This is the first report where we demonstrate that bryo1 induces differentiation and potentiates the antitumor effect of AuriPE in a human pancreatic tumor (PANC-1) xenograft model. A xenograft model was established by injecting the PANC-1 cells s.c. in severe combined immune deficient (SCID) mice. After development of the s.c. tumors, tumors were dissected and small fragments were transplanted in vivo to new SCID mice, with a success rate of 100% and a doubling time of 4.8 days. The SCID mouse xenograft model was used to test the in vivo differentiation effect of bryo1 and its efficacy when given alone or in combination with AuriPE. Sections from paraffin-embedded tumors excised from untreated (control) SCID mice revealed typical poorly differentiated adenocarcinoma of the pancreas. Interestingly, sections of s.c. tumors taken from bryo1-treated mice revealed carcinomas that were much lower grade and less aggressive, and displayed prominent squamous and glandular differentiation. In this study, the tumor growth inhibition (T/C), activity score and cure rate for bryo1, AuriPE and bryo1+AuriPE were 80%, (+) and 0/4; 0.0%, (++++) and 3/5; and 0.0%, (++++) and 3/4, respectively. Mice treated with either AuriPE or bryo1+AuriPE were free of tumors for more than 150 days and were considered cured. The use of bryo1 as a novel differentiating agent and its combination with AuriPE should be further explored for the treatment of adenocarcinoma of the pancreas.