Biomedical subjects

Sunil Krishnan

Publications and source records attributed to Sunil Krishnan.

16 recordsLinked to original sources

PubMed2026

Exploiting DNA damage tolerance for precision oncology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

DDT↗

PubMed2006

Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation.

BACKGROUND: Although patients with locally advanced pancreatic cancer (LAPC) have an extremely poor prognosis, they are a heterogeneous group. Prognostic factors are inadequately defined for disease-free survival and overall survival in patients with LAPC who are receiving chemoradiation, so more definitive prognostic factors would be very useful for designing clinical trials. METHODS: Between December 1993 and July 2005, 247 patients with nonmetastatic LAPC were treated at M. D. Anderson Cancer Center (Houston, Tex) with concurrent chemoradiation (CRT). Median radiation dose was 30 Gy (range, 15-52.2 Gy). Radiosensitizers included 5-fluorouracil (54%), gemcitabine (33%), and capecitabine (13%). Actuarial univariate and multivariate statistical methods were used to determine significant prognostic factors for disease-free survival and overall survival. RESULTS: Median follow-up was 4.3 months (range, 1-63 months). Median disease-free survival and overall survival were 4.2 months and 8.5 months, respectively. On univariate analysis, prognostic factors for improved disease-free survival were a Karnofsky performance scale (KPS) status of >80 (P < .01) and a hemoglobin (Hgb)level at presentation of >/=12 (P = .03). On multivariate analysis, KPS was the only independent prognostic factor for disease-free survival. Median disease-free survival was 4.9 months among patients with a KPS score of >80 and was 3.9 months among those with a KPS score of </=80. On univariate analysis, prognostic factors for improved overall survival were an Hgb level of >/=12 (P = .02), KPS>80 (P < .001), and <5% weight loss (P = .03). On multivariate analysis, Hgb and KPS were independent prognostic factors for overall survival. CONCLUSIONS: In the current study, KPS score was an independent prognostic factor for disease-free and overall survival among patients treated with chemoradiation for LAPC. The pretreatment Hgb level was an additional independent prognostic factor for overall survival.

Adenocarcinoma↗

PubMed2006

Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer.

PURPOSE: The aim of this study was to determine the efficacy of capecitabine (Xeloda), an oral fluoropyrimidine, as a radiosensitizer in the neoadjuvant treatment of locally advanced rectal cancer (LARC). METHODS AND MATERIALS: We conducted a phase II study of capecitabine (825 mg/m2 orally, twice daily continuous) with radiotherapy (52.5 Gy/30 fractions to the primary tumor and perirectal nodes) in 54 patients with LARC (node-negative > or = T3 or any node-positive tumor) staged by endoscopic ultrasound (EUS). The primary endpoint was pathologic response rate; secondary endpoints included toxicity profiles and survival parameters. RESULTS: Of the 54 patients (median age, 56.7 years; range, 21.3-78.7 years; male:female ratio, 1.7; Eastern Cooperative Oncology Group performance status 0-1: 100%), 51 patients (94%) had T3N0 or T3N1 disease by EUS. Surgery was not performed in 3 patients; 2 of these patients had metastatic disease, and the third patient refused after a complete clinical response. Of the 51 patients evaluable for pathologic response, 9 patients (18%) achieved complete response, and 12 patients (24%) had microscopic residual disease (< 10% viable cells). In addition, 26 patients of all 54 patients (51%) achieved T-downstaging, and 15 patients of 29 patients (52%) achieved N-downstaging. Grade 3/4 toxicities were radiation dermatitis (9%) and diarrhea (2%). Sphincter preservation rate for tumor < or = 5 cm from the anal verge was 67% (18/27). CONCLUSION: This regimen of radiotherapy plus capecitabine is well tolerated and is more convenient than protracted venous infusion of 5-FU. The pathologic response rate is comparable to our previous experience using protracted venous infusion 5-FU for LARC.

Adult↗

PubMed2006

Concurrent capecitabine and upper abdominal radiation therapy is well tolerated.

We retrospectively evaluated acute toxicity in 88 patients that were treated with capecitabine and concurrent radiotherapy to the upper abdomen. These patients included 28 (32%) with pancreatic adenocarcinoma, 18 (20%) with cholangiocarcinoma, 11 (13%) with ampullary carcinoma, 11 (13%) with other primary tumors, 14 (16%) with liver metastases, and 6 (7%) with metastases at other sites. The median dose of radiotherapy was 45 Gy (range 30-72 Gy). The median dose of capecitabine was 850 mg/m(2) twice daily, with 77% receiving 800-900 mg/m(2) twice daily. The highest grade of acute toxicity was Common Terminology Criteria (CTC) grade 0 in 5 (6%), grade 1 in 60 (68%), grade 2 in 18 (20%), and grade 3 in 5 (6%) patients. No patient had CTC grade 4 toxicity. The most common grade 2 toxicities were nausea, hand-foot syndrome, fatigue, anorexia and diarrhea. The grade 3 toxicities included nausea, vomiting and fatigue. Three patients (3%) required hospitalization due to grade 3 acute toxicity. Capecitabine was interrupted, discontinued or given at an adjusted dose in 13 (15%) patients because of acute toxicity. Therefore, capecitabine and concurrent radiotherapy to the upper abdomen appears to be well tolerated. Capecitabine may serve as an alternative to bolus or infusional 5-FU during chemoradiation for upper gastrointestinal malignancies.

Antimetabolites, Antineoplastic↗

PubMed2006

Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis.

PURPOSE: To retrospectively compare the acute toxicity, pathologic response, relapse rates, and survival in rectal cancer patients treated with preoperative radiotherapy (RT) and either concurrent capecitabine or concurrent protracted infusion 5-fluorouracil (5-FU). METHODS: Between June 2001 and February 2004, 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT and concurrent capecitabine, followed by mesorectal excision. These patients were individually matched by clinical T and N stage (as determined by endoscopic ultrasound and CT scans) with 89 control patients treated with preoperative RT and concurrent protracted infusion 5-FU between September 1997 and August 2002. RESULTS: In each group, 5 patients (6%) had Grade 3-4 toxicity during chemoradiotherapy. The pathologic complete response rate was 21% with capecitabine and 12% with protracted infusion 5-FU (p = 0.19). Of the 89 patients in the capecitabine group and 89 in the 5-FU group, 46 (52%) and 55 (62%), respectively, had downstaging of the T stage after chemoradiotherapy (p = 0.20). The estimated 3-year local control (p = 0.15), distant control (p = 0.86), and overall survival (p = 0.12) rate was 94.4%, 86.3%, and 89.8% for patients treated with capecitabine and 98.6%, 86.6%, and 96.4% for patients treated with protracted infusion 5-FU, respectively. CONCLUSION: Preoperative concurrent capecitabine and concurrent protracted infusion 5-FU were both well tolerated, with similar, low rates of Grade 3-4 acute toxicity. No significant differences were seen in the pathologic response, local and distant recurrence, or overall survival among patients treated with preoperative RT and concurrent capecitabine compared with those treated with RT and concurrent protracted infusion 5-FU.

Adult↗

PubMed2006

Adjuvant therapy for ampullary carcinomas: the Mayo Clinic experience.

PURPOSE: To determine the effects of adjuvant radiotherapy and chemotherapy for carcinoma of the ampulla of Vater. METHODS AND MATERIALS: We retrospectively reviewed the records of 125 patients who underwent definitive surgery for carcinomas involving the ampulla of Vater between April 1977 and February 2005 and who survived more than 50 days after surgery. Twenty-nine of the patients also received adjuvant radiotherapy (median dose, 50.4 Gy in 28 fractions) with concurrent 5-fluorouracil chemotherapy. Adverse prognostic factors were investigated, and overall survival (OS) and local and distant failure were estimated. RESULTS: Adverse prognostic factors for decreased OS by univariate analysis included lymph node (LN) involvement, locally advanced tumors (T3/T4), and poor histologic grade. By multivariate analysis, positive LN status (p=0.02) alone was associated with decreased OS. The addition of adjuvant radiotherapy and chemotherapy improved OS for patients with positive LN (p=0.01). Median survival for positive LN patients receiving adjuvant therapy was 3.4 years, vs. 1.6 years for those with surgery alone. CONCLUSIONS: The addition of adjuvant radiotherapy and 5-fluorouracil chemotherapy may improve OS in patients with LN involvement. The effect of adjuvant therapy on outcomes for patients with poor histologic grade or T3/T4 tumors without LN involvement could not be assessed.

Adult↗

PubMed2006

Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: results of North Central Cancer Treatment Group protocol N0177.

PURPOSE: To evaluate the toxicity and maximum tolerated dose (MTD) of erlotinib plus radiation therapy (RT) in patients with glioblastoma multiforme (GBM) in a multicenter phase I trial. METHODS AND MATERIALS: Patients were stratified on the basis of the use of enzyme-inducing anticonvulsants (EIACs). After resection or biopsy, patients were treated with erlotinib for 1 week before concurrent erlotinib and 6 weeks (60 Gy) of RT and maintained on erlotinib until progression. The erlotinib dose was escalated in cohorts of 3 starting at 100 mg/day. RESULTS: Twenty patients were enrolled and 19 were evaluable for the MTD and efficacy endpoints. Of these patients, 14 were males and 5 were females, with a median age of 54 years. Seven had undergone biopsy only, 5 had subtotal resections, and 7 had gross total resections. The highest dose level was 150 mg/day erlotinib for patients not on EIACs (Group 1) and 200 mg/day for patients on EIACs (Group 2). MTD was not reached in either group. In Group 1 at 100 mg (n=6) and at 150 mg (n=4), only 1 dose-limiting toxicity (DLT) occurred (stomatitis at 100 mg). No DLTs have occurred in Group 2 at 100 mg (n=3), 150 mg (n=3), and 200 mg (n=3). With a median follow-up of 52 weeks, progression was documented in 16 patients and 13 deaths occurred. Median time to progression was 26 weeks, and median survival was 55 weeks. CONCLUSION: Toxicity is acceptable at the current doses of erlotinib plus RT. The study was modified to include concurrent and adjuvant temozolomide, and accrual is in progress.

Adult↗

PubMed2006

The optimization of dose delivery for intraoperative high-dose-rate radiation therapy using curved HAM applicators.

BACKGROUND AND PURPOSE: To determine the effect of the curvature of Harrison-Anderson-Mick applicators on the dose distribution in high-dose-rate intraoperative radiation therapy (HDR-IORT). MATERIAL AND METHODS: Treatment planning was performed with flat applicators using (192)Ir as the radioactive source, and dwell times were optimized using dose-point optimization techniques. These optimized dwell times were then used for the curved applicators, and the dose distributions that would actually be delivered to patients were determined. RESULTS: The dose directly below the central catheter was strongly dependent on the curvature of the applicator. Steep parabolic curves caused underdoses of as much as 19% at a point 1cm from the convex side of the applicator. The rate of dose reduction with increasing distance from the applicator surface was also a function of the curvature of the applicator. CONCLUSIONS: The curvature of the applicator profoundly affects dosimetry and can be exploited to optimize coverage of the target during HDR-IORT procedures. To ensure accurate dose delivery, these dose perturbations must be accounted for in the planning process. We recommend maintaining a dosimetry atlas of various applicator sizes and curvatures in addition to one for flat applicators.

Brachytherapy↗

PubMed2006

Clinical and pathologic predictors of locoregional recurrence, distant metastasis, and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer.

OBJECTIVES: To identify predictive factors for locoregional recurrence (LR), distant metastasis (DM), and overall survival (OS) in patients treated with chemoradiation and surgery for rectal cancer. METHODS: Between 1989 and 2001, 470 patients with rectal cancer were treated with preoperative (89%) or postoperative (11%) chemoradiation and mesorectal excision. Median radiation dose was 45 Gy; 97% received concurrent infusional 5-fluorouracil, and 65% received adjuvant chemotherapy. Median follow-up interval was 5.7 years. RESULTS: The 5-year rates of freedom from LR, freedom from DM, and OS were 90%, 79%, and 80%, respectively. On univariate analysis, significant predictors of LR were female sex, clinical T stage, pathologic T and N stages, and positive radial margin. Significant univariate predictors of DM were circumferential extent of tumor, tumor immobility, lymphovascular invasion, perineural involvement, and pathologic T and N stages. Significant univariate predictors of lower OS were age, circumferential extent of tumor, shorter distance from anal verge, tumor size, tumor immobility, anal canal involvement, lymphovascular invasion, perineural involvement, positive radial margin, and pathologic T and N stages. On Cox multivariate analysis, female sex and pathologic T and N stages independently predicted for LR; pathologic T and N stages independently predicted for DM; and age, circumferential extent of tumor, positive radial margin, and pathologic T and N stages independently predicted for lower OS. CONCLUSIONS: Pathologic T and N stages significantly predicted for all 3 end points (LR, DM and OS) on multivariate analysis. Investigations of more aggressive adjuvant chemotherapy appear warranted for pathologic stage T3/T4 or N1/2 rectal cancer.

Adult↗

PubMed2006

Conformal radiotherapy of the dominant liver metastasis: a viable strategy for treatment of unresectable chemotherapy refractory colorectal cancer liver metastases.

OBJECTIVES: To evaluate the safety and efficacy of conformal radiotherapy (RT) of the dominant liver metastasis as palliative treatment of patients with unresectable colorectal cancer liver metastases. METHODS: We retrospectively reviewed the hospital and RT records of 17 patients with unresectable colorectal liver metastases who had been treated with palliative RT to the dominant liver metastasis at our institution. RESULTS: The median size of the dominant liver metastasis was 10 cm (range, 3-19 cm). Twelve patients (71%) had evidence of extrahepatic disease. A median of 2 (range, 0-4) prior chemotherapy regimens had been administered. Median radiation dose was 42 Gy (range, 7.5-72 Gy). Concurrent chemotherapy included celecoxib in 1 (6%), capecitabine in 6 (35%), and both agents in 9 (53%) patients. Frequencies of acute diarrhea, nausea, vomiting, fatigue, hand-foot syndrome, and neutropenia were 29%, 47%, 6%, 29%, 7%, and 0%, respectively (all grade 2 or lower; no grade 3 toxicities). No late toxicities were noted. With a median follow-up time of 9.2 months, the median actuarial overall survival time from RT was 12.6 months (95% confidence interval [CI]: 3.3-40.9 months). The actuarial in-field local control rate was 62% at 6 months. The median actuarial time to in-field, out-of-field hepatic and distant progression were 6.8, 3.9, and 4.1 month, respectively (95% CIs, 3.9-15.8, 1.8-6.3, and 1.8-11.5 months, respectively). CONCLUSIONS: Conformal RT to the dominant liver metastasis as palliative therapy for unresectable colorectal cancer liver metastases has an acceptable toxicity profile and may improve survival. This approach merits further exploration.

Adult↗

PubMed2005

Intraoperative radiotherapy using a mobile electron LINAC: a retroperitoneal sarcoma case.

The advent of mobile LINACs for use in intraoperative radiation therapy (IORT) promises to make IORT more accessible than before and easier to deliver to patients undergoing surgery. Although mobile IORT systems have been available since 1999, few treatment centers currently use them. Here, we present the case of a typical patient undergoing IORT for retroperitoneal sarcoma to show how easy these mobile systems are to use and how adaptable they are within the operating room (OR) environment. We also discuss the roles and coordination of multidisciplinary team members during IORT and the feasibility of using mobile LINACs for IORT.

Electrons↗

PubMed2005

Phase II trial of carmustine, cisplatin, and oral etoposide chemotherapy before radiotherapy for grade 3 astrocytoma (anaplastic astrocytoma): results of North Central Cancer Treatment Group trial 98-72-51.

PURPOSE: To evaluate the efficacy of preradiotherapy (RT) chemotherapy with carmustine, cisplatin, and oral etoposide combined with RT in the treatment of newly diagnosed anaplastic astrocytoma. METHODS AND MATERIALS: Therapy consisted of carmustine (40 mg/m(2)/d) on Days 1-3, oral etoposide (50 mg/d) on Days 1-21 and 29-49, and cisplatin (20 mg/m(2)/d i.v.) on Days 1-3 and 29-31. The regimen was repeated every 8 weeks for three cycles, with conventionally fractionated RT (5000 cGy with a 1000-cGy boost) delivered concurrently with the third cycle. RESULTS: A total of 29 patients were enrolled between December 1999 and March 2001. For varying reasons (e.g., progression, refusal, death, or toxicity), only 48% completed the chemotherapy regimen and 76% completed RT. Grade 3-4 toxicities were observed in 14 patients (48%). The primary study endpoint was the 23-month (700-day) survival, the median survival of patients with anaplastic astrocytoma in a previous North Central Cancer Treatment Group trial. To be considered an active treatment, a maximum of 9 patient deaths (of the first 25) were allowed before 700 days. However, 14 patients had died by 700 days after therapy. CONCLUSION: Our results have demonstrated that pre-RT chemotherapy with this regimen is insufficiently active in patients with anaplastic astrocytoma.

Administration, Oral↗

PubMed2005

Radiosurgery for cranial base chordomas and chondrosarcomas.

OBJECTIVE: To evaluate the efficacy and toxicity of radiosurgery in the treatment of cranial base chordoma and chondrosarcoma. METHODS: We reviewed 29 patients with cranial base chordoma (n = 25) or chondrosarcoma (n = 4) who underwent stereotactic radiosurgery between September 1990 and December 2002. The median patient age was 45 years (range, 10-81 yr). Nineteen patients also had radiation therapy before or in conjunction with radiosurgery (median dose, 50.4 Gy). The median tumor volume was 14.4 cm3 (range, 0.6-65.1 cm3). The median tumor margin dose was 15 Gy (range, 10-20 Gy); the median maximum radiation dose was 30 Gy (range, 20-40 Gy). Median clinical and imaging follow-up periods were 4.8 and 4.5 years, respectively. RESULTS: Seven chordoma patients (28%) had tumor progression (in-field, n = 3; out-of-field, n = 4), whereas 18 had stable disease or tumor shrinkage. No patient with a chondroid chordoma had tumor enlargement. The actuarial tumor control rates were 89 and 32% at 2 and 5 years, respectively. All 4 patients with chondrosarcoma had tumor control. Clinically, 7 patients (24%) had improvement of pretreatment symptoms, 16 (55%) remained stable, and 6 (21%) worsened. Three patients with tumor progression died. Ten patients (34%) had radiation-related complications. Complications included cranial nerve deficits (n = 6), radiation necrosis (n = 5), and pituitary dysfunction (n = 3). Patients having radiosurgery alone had no toxicity. CONCLUSION: Cranial base chordomas and chondrosarcomas remain a formidable management challenge. Radiosurgery as an adjunct to surgical resection provides in-field tumor control for some patients, but radiation-related complications are relatively high, especially when radiosurgery is combined with fractionated radiation therapy.

Chondrosarcoma↗

PubMed2004

Choroid plexus papillomas: a single institutional experience.

OBJECTIVE: To determine the long-term outcome of resected choroid plexus papillomas (CPPs). METHODS: Medical records and histologic specimens were reviewed for 41 patients (19 male, 22 female; median age, 36 years; range, 6 months to 74 years) with CPP seen between 1974 and 2000. Tumor locations were as follows: 76%, fourth ventricle; 17%, lateral ventricle, and 7%, third ventricle. Fifty-six percent had a gross total resection (GTR) and 44% had a subtotal resection (STR). Median follow-up was 6.5 years. RESULTS: Five-year local control, distant brain control, and overall survival were 84%, 92%, and 97%, respectively. Comparison of GTR and STR at 5 years showed a significant increase in local control (100% vs. 68%; P = 0.04) but not in overall survival (100% vs. 94%). Even after STR, only 50% of patients required a subsequent resection for recurrence. Addition of radiation therapy to initial STR did not seem to influence outcomes. At first relapse, GTR was accomplished in 1 patient, and only STR was accomplished in the others. Addition of radiation therapy to STR in our study led to disease control in half the patients treated, and STR alone led to disease control in only a quarter of the patients. Second relapses were treated palliatively with radiation therapy. CONCLUSIONS: Surgical resection is the treatment of choice for CPPs. After initial STR, reoperations for recurrence are required only half the time. Therefore, there seems to be no role for radiation therapy after initial STR. For STRs at first relapse, local control outcome is poor.

Adolescent↗

PubMed2003

Genetic and signaling pathway alterations in glioblastoma: relevance to novel targeted therapies.

Glioblastomas multiforme (GBM) is the most common malignant primary brain tumor in adults. GBM patients have a dismal prognosis, with a median survival of less than 1 year. During the past decade, significant advances have been made in our understanding of the molecular pathogenesis of these tumors. Specific genetic defects have been identified that appear to be important for the development, as well as maintenance of the malignant characteristics that are associated with GBM. Some of these genetic aberrations appear to have prognostic significance. However, even more exciting in this era of molecularly targeted therapy are the clues these gene alterations provide for identifying signaling mechanisms responsible for carcinogenesis, and for identifying potential therapeutic targets. Cancer drug therapy is currently undergoing a major transition with an attempt to move from the use of cytotoxic drugs towards the use of tumor mechanism-based drugs. Advances such as the decoding of the human genome, combinatorial chemistry, and gene expression profiling have led to an increase in the rate at which new drugs are being developed. In this review, we will describe the most common genetic and signaling pathway alterations that have relevance to new drug development for the treatment of GBM.

Animals↗

PubMed2003

Combination of epidermal growth factor receptor targeted therapy with radiation therapy for malignant gliomas.

Glioblastoma multiforme (GBM) are extremely aggressive brain tumors characterized by resistance to standard treatment modalities including surgery, radiation therapy and chemotherapy. While radiation therapy is the standard treatment after surgical resection, these tumors invariably recur and are associated with a uniformly dismal prognosis. Cytotoxic chemotherapy has failed to improve on the modest gains conferred by radiation therapy. Our understanding of the molecular events driving gliomagenesis has led to the recognition of frequent alterations in the epidermal growth factor receptor (EGFR) pathway, leading to increased aggressiveness and a poorer prognosis. Based on the importance of EGFR in the development of malignancy in multiple tumor types, several classes of novel therapeutic agents have been developed that specifically target EGFR. This review outlines the relevance of normal and aberrant EGFR signaling in the biology of gliomas, the strategies for inhibiting EGFR activity and the rationale for combining EGFR inhibitors with radiation therapy in the treatment of GBM.

Animals↗