Biomedical subjects

Melania Pintilie

Publications and source records attributed to Melania Pintilie.

At least 19 recordsLinked to original sources

PubMed2007

Analysing and interpreting competing risk data.

When competing risks are present, two types of analysis can be performed: modelling the cause specific hazard and modelling the hazard of the subdistribution. This paper contrasts these two methods and presents the benefits of each. The interpretation is specific to the analysis performed. When modelling the cause specific hazard, one performs the analysis under the assumption that the competing risks do not exist. This could be beneficial when, for example, the main interest is whether the treatment works in general. In modelling the hazard of the subdistribution, one incorporates the competing risks in the analysis. This analysis compares the observed incidence of the event of interest between groups. The latter analysis is specific to the structure of the observed data and it can be generalized only to another population with similar competing risks.

Causality↗

PubMed2007

Fertility among female hodgkin lymphoma survivors attempting pregnancy following ABVD chemotherapy.

Although ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy is infrequently associated with premature amenorrhea, little is known about the success rate of women attempting pregnancy following ABVD. In the present study females treated for HL with ABVD chemotherapy without pelvic radiation therapy (RT) and who were alive without relapse > or =3 years after treatment were identified from a clinical database and screened for inclusion. Using a standardized questionnaire, we determined the pregnancy rate (i.e. time-to-pregnancy, TTP) among survivors who had become pregnant, tried to become pregnant, or who had been sexually active for over 2 months without using contraception at any time following ABVD. The cumulative incidence of pregnancy was calculated using the Kaplan-Meier method. Cox proportional hazards models were constructed to compare the pregnancy rate among HL survivors to that reported by friend or sibling controls. Thirty-six female HL survivors, who had attempted pregnancy after ABVD treatment, and 29 controls, completed the survey. Eighteen patients (50%) received 2-4 cycles of ABVD, 16 (44%) received 4-6 cycles, and 2 (6%) received >6 cycles. The median TTP among both HL survivors and controls was 2.0 months. The 12-month pregnancy rates were 70% and 75%, respectively. The fertility ratio (FR) for HL survivors versus controls was 0.94 (95%CI = 0.53-1.66; p = 0.84) after adjusting for age and frequency of intercourse (where FR < 1 indicates subfertility). Age at treatment and the number of cycles of chemotherapy were not associated with pregnancy rate among HL survivors. Female HL patients who had survived without recurrence > or =3 years and who had attempted pregnancy after ABVD did not experience significant sub-fertility.

Adolescent↗

PubMed2006

A prospective phase I-II trial of the cyclooxygenase-2 inhibitor celecoxib in patients with carcinoma of the cervix with biomarker assessment of the tumor microenvironment.

PURPOSE: To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer. METHODS AND MATERIALS: Thirty-one patients were accrued to a phase I-II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP(5)) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1-4.4 years). RESULTS: The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, -4.6 mm Hg; p = 0.09; relative, -21%; p = 0.07), whereas HP(5) did not change significantly (absolute increase, 3.6%; p = 0.51; median relative increase, 11%; p = 0.27). No significant associations were seen between changes in HP(5) or IFP and response to treatment (p = 0.2, relative HP(5) change and p = 0.14, relative IFP change). CONCLUSIONS: Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response.

Adult↗

PubMed2006

Gene expression profiling in cervical cancer: an exploration of intratumor heterogeneity.

PURPOSE: To explore intratumor heterogeneity in gene expression profiles from patients with cervical cancer. EXPERIMENTAL DESIGN: A total of 33 biopsies were obtained from 11 patients, sampling between two and five different areas for each tumor. The extracted RNA was hybridized onto the Affymetrix U133 Plus 2.0 oligonucleotide chip. The variance of expression within a patient (W), between patients (B) and the total variance (T = W + B) were calculated for each ProbeSet, and the ratio W/T was used as a measure of intratumor heterogeneity. Gene Ontology functional analysis was done to assess the function of genes that had high W/T (top 10%) and low W/T (bottom 10%) values. RESULTS: In total, 448 ProbeSets (2.2% of the total) had W/T < 0.10, indicating low intratumor heterogeneity, and 537 ProbeSets (2.7% of the total) had W/T > 0.90, indicating high intratumor heterogeneity. In total 14,473 ProbeSets (72.4%) had higher intertumor than intratumor heterogeneity (W/T < 0.5). Genes with low intratumor heterogeneity were characterized by a statistically significant enrichment of immune-related functions (P < 0.0001). Genes with high intratumor heterogeneity were characterized by a significant tendency towards nuclear localization and nucleic acid binding (both P < 0.0001). For genes with W/T > 0.5, more than six biopsies would be required to minimize the intratumoral heterogeneity to <0.15; if W/T is 0.3 to 0.4, four biopsies are required; and for low W/T of 0.16 to 0.3, only two to three biopsies would be needed. CONCLUSION: Although the intratumor heterogeneity was low for the majority of the tested ProbeSets, for many genes, multiple biopsies are required to obtain a reliable estimate of gene expression.

Adenocarcinoma↗

PubMed2006

Prognostic significance of the Epstein-Barr virus, p53, Bcl-2, and survivin in nasopharyngeal cancer.

PURPOSE: Nasopharyngeal cancer (NPC) is a malignant epithelial carcinoma which is intimately associated with EBV. The latent presence of EBV affects the function of p53, Bcl-2, and survivin. We thus investigated the relationship between EBV status, p53, Bcl-2, and survivin in biopsy specimens from patients with primary NPC. EXPERIMENTAL DESIGN: Archival formalin-fixed, paraffin-embedded NPC biopsies were evaluated in 80 patients treated with curative radiation from a single institution. The presence of EBV was determined using EBER in situ hybridization, whereas p53, Bcl-2, and survivin were assessed using immunohistochemistry. RESULTS: The majority of NPC specimens in this patient cohort were EBER-positive (64 of 78, or 82%), which in turn, was significantly associated with ethnicity (P = 0.0007), and WHO subtype 2A/2B (P = 0.04). EBER-positive tumors were also associated with p53 (P = 0.002), Bcl-2 (P = 0.04), and nuclear survivin (P = 0.03) expression. Patients with EBER-positive NPC fared better, with a 10-year overall survival of 68% versus 48% for EBER-negative patients (P = 0.03). For nuclear survivin, patients with either low or high nuclear survivin fared worse than patients with intermediate survivin expression (P = 0.05), suggesting that there is an optimal proportion of survivin-expressing cells for best function and clinical outcome. CONCLUSIONS: With an extended median follow-up time of 11.4 years, EBV status remains a strong predictor for overall survival in NPC. EBV-positive NPC has strong molecular associations with p53, Bcl-2, and survivin expression. Furthermore, we provide clinical data revealing the potentially dual nature of survivin in predicting clinical outcome.

Carcinoma, Squamous Cell↗

PubMed2006

Clinical dose-volume histogram analysis in predicting radiation pneumonitis in Hodgkin's lymphoma.

PURPOSE: To quantify the incidence of radiation pneumonitis (RP) in a modern Hodgkin's lymphoma (HL) cohort, and to identify any clinically relevant parameters that may influence the risk of RP. METHODS AND MATERIALS: Between January 2003 and February 2005, 64 consecutive HL patients aged 18 years or older receiving radical mediastinal radiation therapy (RT) were retrospectively reviewed. Symptomatic cases of radiation pneumonitis were identified. Dose-volume histogram parameters, including V(13), V(20), V(30), and mean lung dose (MLD), were quantified. RESULTS: At a median follow-up of 2.1 years, the actuarial survival for all patients was 91% at 3 years. There were 2 (2/64) cases of Radiation Therapy Oncology Group (RTOG) Grade 2 RP (incidence 3.1%). Both index cases with corresponding V(20) values of 47.0% and 40.7% were located in the upper quartile (2/16 cases), defined by a V(20) value of > or =36%, an incidence of 12.5% (p = 0.03). Similarly for total MLD, both index cases with values of 17.6 Gy and 16.4 Gy, respectively, were located in the upper quartile defined by MLD > or =14.2 Gy, an incidence of 11.8% (2/17 cases, p = 0.02). CONCLUSIONS: Despite relatively high V(20) values in this study of HL patients, the incidence of RP was only 3%, lower compared with the lung cancer literature. We suggest the following clinically relevant parameters be considered in treatment plan assessment: a V(20) greater than 36% and an MLD greater than 14 Gy, over and above which the risk of RTOG Grade 2 or greater RP would be considered clinically significant.

Adolescent↗

PubMed2006

Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer.

OBJECTIVES: Hypoxia and high interstitial fluid pressure (IFP) have been shown to independently predict for nodal and distant metastases, as well as survival, in patients with cervix cancer. Using data from our prospective trial, we updated a cohort of patients treated with definitive radiation alone without chemotherapy, to assess the long-term prognostic impact of these microenvironmental features. METHODS: Between April 1994 and January 1999, 107 eligible patients with cervix cancer were entered into a prospective study of tumor oxygenation and IFP prior to primary radiation therapy. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of pO(2) readings <5 mm Hg (abbreviated as HP(5)). Patients with HP(5) values >50% were considered to have hypoxic tumors. IFP is presented in mmHg, divided into high and low IFP groups by the median value. Patients ranged in age from 23 to 78 years with a mean of 53 years. The maximum tumor size ranged from 2 to 10 cm, with a median diameter of 5 cm. FIGO stage was IB in 28 patients, IIA in 4, IIB in 42 and IIIB in 33 patients. Twenty-two patients (21%) had evidence of pelvic lymph node involvement on staging CT abdomen/pelvis or MR pelvis. HP(5) ranged from 0% to 99% with a median of 48%. IFP ranged from -3 to 48 mm Hg (median 19 mm Hg). Median follow-up was 6.7 years (range 0.9-10.6). RESULTS: Disease-free survival (DFS) at 5 years was 50%. Five year DFS was 42% for patients with hypoxic tumors (HP(5)>50%), and 58% in patients with oxygenated tumors (HR 1.01 per %, p=0.05). DFS at 5 years was 42% for patients with interstitial hypertension (IFP >19 mm Hg), and 63% in patients with IFP <or=19 mm Hg (HR 1.05 per mmHg, p=0.001). In a multivariate analysis only tumor size (HR 1.2, p=0.009) pelvic nodal metastases (HR 3.3, p=0.0004) and IFP (HR 1.06, p=0.0005) were predictive of DFS. Because an interaction between nodal status and oxygenation was observed (p=0.03), further analysis indicated a borderline significant impact of HP(5) in addition to tumor size in node negative patients (HR 1.01, p=0.06). These results were similar when local or distant relapse was used as an endpoint. CONCLUSIONS: These results confirm our initial finding of the strong independent prognostic impact of IFP for relapse and survival in patients with cervix cancer. In contrast, the independent prognostic impact of HP(5) is of borderline significance and is limited to patients without imaging evidence of nodal metastases. However, these findings do not diminish the biologic significance of hypoxia, or the role of hypoxia and IFP as biomarkers of treatment response and as therapeutic targets.

Adult↗

PubMed2006

Similar response rates and superior early progression-free survival with gemcitabine, dexamethasone, and cisplatin salvage therapy compared with carmustine, etoposide, cytarabine, and melphalan salvage therapy prior to autologous stem cell transplantation for recurrent or refractory Hodgkin lymphoma.

BACKGROUND: The objective of this study was to compare the response rates, ability to mobilize autologous hematopoietic (peripheral blood) stem cells (PBSCs), and progression-free survival (PFS) after second-line chemotherapy with either gemcitabine, dexamethasone, and cisplatin (GDP) or carmustine, etoposide, cytarabine, and melphalan (mini-BEAM) followed by high-dose therapy and hematopoietic stem cell transplantation (ASCT) for patients with recurrent or refractory Hodgkin lymphoma. METHODS: The outcomes of 68 consecutive patients who were referred for salvage therapy (34 patients received mini-BEAM, and 34 patients received GDP) were compared retrospectively. Patients received mini-BEAM as inpatient treatment every 3-4 weeks, whereas GDP was administered on an outpatient basis every 3 weeks. Responding patients proceeded to stem cell mobilization, followed by high dose etoposide and melphalan, and ASCT. Patients who had disease bulk at recurrence that measured > 5 cm received involved-field radiation post-ASCT. RESULTS: The response rate to GDP prior to ASCT (complete responses, unconfirmed complete responses, and partial responses) was 62% (95% confidence interval [95% CI], 45-78%) compared with 68% (95% CI, 52-83%) for mini-BEAM (P = 0.61). After mobilizing chemotherapy, the proportion of patients for whom the target PBSC number of > or = 5 x 10(6) CD34-positive cells/kg was obtained was 97% after GDP and 57% after MB (P = 0.0003). More patients completed collection with a single apheresis procedure after GDP than after mini-BEAM (73% vs. 36%; P = 0.004), and fewer patients in the GDP group required bone marrow harvesting to proceed to ASCT. After a median follow-up of 1.8 years after ASCT, PFS was significantly better for patients who received GDP compared with patients who received mini-BEAM (74% vs. 35% at 1.5 yrs, respectively; P = 0.005). Overall survival at 1.5 years was 91% after GDP and 82% after mini-BEAM (P = 0.23). CONCLUSIONS: Although this was a retrospective analysis, response to GDP and early PFS after ASCT compared favorably with mini-BEAM salvage chemotherapy. Based on these data, the authors believe that a Phase III trial comparing GDP with mini-BEAM or other platinum-containing regimens is warranted.

Adult↗

PubMed2006

Outcome of hyperfractionated radiotherapy in chemotherapy-resistant non-Hodgkin's lymphoma.

PURPOSE: Patients with chemotherapy-resistant lymphoma have rapidly progressive disease and a poor prognosis. Local symptoms are treated with radiotherapy (RT) for local control. We have reviewed local control and toxicity in patients treated with hyperfractionated accelerated RT. METHODS AND MATERIALS: A total of 34 patients received hyperfractionated RT between 1997 and 2003. The radiation dose was 39.9-40.5 Gy in 30 fractions. The median treatment time was 22 days with twice-daily involved-field RT. The median follow-up was 4.4 years. Response was assessed <3 months after RT and was classified as a complete response, a complete response-unconfirmed, a partial response, or no response. Local control was defined as maintenance of local complete response, complete response-unconfirmed, or lack of local progression with a partial response. Recurrence or progression outside the RT volume was regarded as distant disease. RESULTS: The median age was 53 years; 20 patients were men and 14 were women. The initial diagnosis was Stage I-II in 56% and Stage III-IV in 44%. The disease bulk was > or =10 cm in 35% (n = 12). The histologic features at diagnosis were follicular in 11 (Grade 1 in 4, Grade 2 in 3, and Grade 3 in 4), diffuse large B-cell in 14, peripheral T-cell lymphoma in 2, Burkitt-like in 1, mantle cell in 2, natural killer cell in 2, plasmacytoma/lymphoma in 1, and T-cell lymphoblastic in 1. The initial treatment was chemotherapy in 32 patients (94%); 71% were refractory to initial chemotherapy and 29% developed a relapse after an initial response. The RT response was complete in 24% (n = 8), complete, unconfirmed in 26% (n = 9), partial in 47% (n = 16), and none in 3% (n = 1). The local control rate was 73% at 1, 2, and 3 years. Grade 1 dermatitis was the most common side effect. CONCLUSION: Hyperfractionated RT provided good local control and was well tolerated. This encouraging result requires additional study with comparison to conventional fractionation regimens.

Adult↗

PubMed2005

Comparison of late toxicity between continuous low-dose-rate and pulsed-dose-rate brachytherapy in cervical cancer patients.

PURPOSE: To compare survival and severe late radiation toxicity between patients who received continuous low-dose-rate (LDR) brachytherapy (BT) and pulsed-dose-rate (PDR) BT for cervical cancer. METHODS AND MATERIALS: A retrospective review of cervical cancer patients who underwent primary radiotherapy with or without concurrent cisplatin was performed. Late Grade 3 or worse toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. The study endpoints were overall and disease-free survival and the probability of severe late toxicity. RESULTS: A total of 109 patients (65.7%) received LDR BT and 57 (34.3%) received PDR BT. Seventy patients received concurrent chemotherapy with cisplatin. The 3-year overall survival and disease-free survival rate was 70% and 57% for the LDR group and 82% and 70% for the PDR group, respectively (p = 0.25 and p = 0.19). The 3-year probability rate for late Grade 3 or worse toxicity was 7.4% for LDR BT patients and 7.6% for PDR BT patients, respectively (p = 0.69) and 6.9% and 7.6%, respectively, for concurrent chemotherapy vs. none (p = 0.69). CONCLUSION: No difference was found in severe late toxicity, overall survival, or disease-free survival between the LDR and PDR groups.

Adult↗

PubMed2005

Consolidative abdominopelvic radiotherapy after surgery and carboplatin/paclitaxel chemotherapy for epithelial ovarian cancer.

PURPOSE: To assess the feasibility and morbidity of sequential cytoreductive surgery, carboplatin/paclitaxel chemotherapy, and consolidative abdominopelvic radiotherapy (APRT) in ovarian cancer. METHODS AND MATERIALS: Between 1998 and 2000, 29 patients with optimally cytoreduced epithelial ovarian cancer were treated with carboplatin (135 mg/m2) and paclitaxel (area under the curve [AUC] of 6) followed by APRT in a prospective protocol. All patients were clinically, radiographically, and biochemically (CA-125) free of disease at the completion of chemotherapy. Abdominopelvic radiotherapy was delivered using 6 MV anterior-posterior photon fields to encompass the peritoneal cavity. Median follow-up was 4 years. RESULTS: Two patients experienced Radiation Therapy Oncology Group Grade 3 gastrointestinal toxicity during APRT; 6 patients, Grade 3 or 4 neutropenia; and 3 patients, Grade 3 or 4 thrombocytopenia. Overall, 10 patients had Grade 3 or 4 acute toxicity. All of the acute side effects resolved after treatment was completed, and there were no serious consequences such as sepsis or hemorrhage. Abdominopelvic radiotherapy was abandoned prematurely in 3 patients. Late side effects were seen in 5 patients, including 1 small bowel obstruction, 2 symptomatic sacral insufficiency fractures, 1 case of severe dyspareunia, and 1 case of prolonged fatigue. All resolved with supportive management. The 4-year actuarial disease-free survival was 57%, and the overall survival was 92%. Eleven of 12 patients who relapsed received salvage chemotherapy, which was well tolerated. CONCLUSIONS: Abdominopelvic radiotherapy after optimal surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute and late side effects and does not limit subsequent salvage chemotherapy. Consolidative APRT warrants further investigation as a means of improving the outcome of patients with ovarian cancer.

Adult↗

PubMed2005

Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature.

PURPOSE: This meta-analysis was performed to compare the activity, efficacy and toxicity of platinum-based versus non-platinum-based chemotherapy in patients with advanced non-small-cell lung cancer. METHODS: Randomized phase II and III clinical trials comparing first-line palliative platinum-based chemotherapy with the same regimen without platinum or with platinum replaced by a nonplatinum agent were identified by electronic searches of Medline, Embase, and Cancerlit, and hand searches of relevant abstract books and reference lists. Response rates, 1-year survival, and toxicity were analyzed. Subgroups of trials using third-generation agents were compared. RESULTS: Thirty-seven assessable trials were identified including 7,633 patients. A 62% increase in the odds ratio (OR) for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46 to 1.8; P < .0001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% v 29%; OR, 1.21; 95% CI, 1.09 to 1.35; P = .0003). No statistically significant increase in 1-year survival was found when platinum therapies were compared to third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96 to 1.28; P = .17). The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nephrotoxicity, and nausea and vomiting, but not for neurotoxicity, febrile neutropenia rate, or toxic death rate. CONCLUSION: Response is significantly higher with platinum-containing regimens. One-year survival was not significantly prolonged when platinum-based therapies were compared with third-generation-based combination regimens. Toxicity is generally higher for platinum-based regimens.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Relations between non-protein sulfydryl levels in the nucleus and cytoplasm, tumor oxygenation, and clinical outcome of patients with uterine cervical carcinoma.

PURPOSE: The non-protein sulfydryls (NPSH) glutathione and cysteine are able to effect chemical repair of radiation-induced DNA damage, particularly under hypoxic conditions, and are implicated in radioresistance. The levels of NPSH in the nucleus are predicted to be more important than those in cytoplasm. We, therefore, investigated the relation between nuclear NPSH and the clinical outcome of radical radiotherapy (RT). METHODS AND MATERIALS: A fluorescence image analysis technique to measure nuclear NPSH was developed, based on the SH-reactive probe 1(4-chloromercuryphenyl-azo-2-naphthol) and the DNA dye 4,6-diamidino-2-phenylindole. This was used to measure nuclear and tissue NPSH levels in biopsies obtained from 58 patients with locally advanced uterine cervical carcinoma, treated with radical RT. RESULTS: An approximately twofold range in the nuclear and tissue NPSH levels between individual tumors was found, although the intratumoral heterogeneity was much smaller. Nuclear and tissue NPSH values correlated closely in all cases. No statistically significant associations were noted between NPSH levels and tumor size, stage, or tumor hypoxia as determined at the time of biopsy using an Eppendorf po(2) probe. The response to RT and patient survival did not correlate with tumor NPSH. CONCLUSION: These results did not support the existence of an independently regulated nuclear pool of NPSH and showed that tissue and nuclear NPSH are not predictive of the outcome of patients with locally advanced cervical carcinomas treated with RT.

Cell Nucleus↗

PubMed2005

DJ-1, a novel regulator of the tumor suppressor PTEN.

The phosphatidylinositol 3' kinase (PI3'K) pathway, which regulates cell survival, is antagonized by the PTEN tumor suppressor. The regulation of PTEN is unclear. A genetic screen of Drosophila gain-of-function mutants identified DJ-1 as a suppressor of PTEN function. In mammalian cells, DJ-1 underexpression results in decreased phosphorylation of PKB/Akt, while DJ-1 overexpression leads to hyperphosphorylation of PKB/Akt and increased cell survival. In primary breast cancer samples, DJ-1 expression correlates negatively with PTEN immunoreactivity and positively with PKB/Akt hyperphosphorylation. In 19/23 primary non-small cell lung carcinoma samples, DJ-1 expression was increased compared to paired nonneoplastic lung tissue, and correlated positively with relapse incidence. DJ-1 is thus a key negative regulator of PTEN that may be a useful prognostic marker for cancer.

Animals↗

PubMed2005

Fractures following radiotherapy and limb-salvage surgery for lower extremity soft-tissue sarcomas. A comparison of high-dose and low-dose radiotherapy.

BACKGROUND: The purpose of the present retrospective study was to determine the correlation between radiation therapy and the risk of postradiation fracture following combined therapy for the treatment of soft-tissue sarcomas of the lower extremity. METHODS: Three hundred and sixty-four patients with lower extremity sarcomas that had been treated with combined external beam radiation therapy and limb-salvage surgery were evaluated on the basis of a combined chart and data-base review. For the purposes of analysis, high-dose radiation was defined as 60 or 66 Gy and low-dose radiation was defined as 50 Gy. The timing of irradiation was defined as preoperative, postoperative, or preoperative followed by a postoperative boost. Univariate and multivariate analyses were used to determine which factors were associated with fracture risk. RESULTS: Twenty-seven fractures occurred in twenty-three patients. Twenty-four fractures occurred in twenty patients who had been managed with high-dose radiation. Seventeen of these patients had received postoperative radiation (with fifteen patients receiving 66 Gy and two receiving 60 Gy), and three had received preoperative radiation with a postoperative boost (total dose, 66 Gy). Three fractures occurred in three patients who had received preoperative, low-dose radiation (50 Gy). Of the twenty-three patients who sustained a pathologic fracture, eighteen were female and five were male. The crude median time to fracture was forty-three months. Most fractures occurred in the femoral shaft (thirteen) or the femoral neck (eight). High-dose radiation was associated with a greater risk of fracture when compared with low-dose radiation (p = 0.007). CONCLUSIONS: Women more than fifty-five years of age who are managed with removal of a thigh sarcoma combined with radiation therapy have a higher risk of pathologic fracture. The frequency of pathologic fractures associated with higher doses (60 or 66 Gy) of radiation is significantly higher than that associated with lower doses (50 Gy).

Adolescent↗

PubMed2004

Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.

BACKGROUND: We determined the effect of breast irradiation plus tamoxifen on disease-free survival and local relapse in women 50 years of age or older who had T1 or T2 node-negative breast cancer. METHODS: Between December 1992 and June 2000, 769 women with early breast cancer (tumor diameter, 5 cm or less) were randomly assigned to receive breast irradiation plus tamoxifen (386 women) or tamoxifen alone (383 women). The median follow-up was 5.6 years. RESULTS: The rate of local relapse at five years was 7.7 percent in the tamoxifen group and 0.6 percent in the group given tamoxifen plus irradiation (hazard ratio, 8.3; 95 percent confidence interval, 3.3 to 21.2; P<0.001), with corresponding five-year disease-free survival rates of 84 percent and 91 percent (P=0.004). A planned subgroup analysis of 611 women with T1, receptor-positive tumors indicated a benefit from radiotherapy (five-year rates of local relapse, 0.4 percent with tamoxifen plus radiotherapy and 5.9 percent with tamoxifen alone; P<0.001). Overall, there was a significant difference in the rate of axillary relapse at five years (2.5 percent in the tamoxifen group and 0.5 percent in the group given tamoxifen plus irradiation, P=0.049), but no significant difference in the rates of distant relapse or overall survival. CONCLUSIONS: As compared with tamoxifen alone, radiotherapy plus tamoxifen significantly reduces the risk of breast and axillary recurrence after lumpectomy in women with small, node-negative, hormone-receptor-positive breast cancers.

Aged↗

PubMed2004

Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcoma.

PURPOSE: Hypoxia is associated with malignant progression and poor outcome in several human tumors, including soft tissue sarcoma. Recent studies have suggested that carbonic anhydrase (CA) IX is an intrinsic marker of hypoxia, and that CA IX correlates with poor prognosis in several types of carcinoma. The aim of this study was to quantify the extent of CA IX expression and to investigate whether CA IX is a marker for poor prognosis in soft tissue sarcoma patients at high risk of developing metastasis. EXPERIMENTAL DESIGN: Archival paraffin-embedded blocks were retrieved from 47 patients with deep, large, high-grade soft tissue sarcoma. Sections from two separate and representative tumor areas were immunostained for CA IX, and the CA IX-positive area fraction was quantified by image analysis, excluding areas of normal stroma and necrosis that were identified from serial H&E-stained sections. Patients were then subject to survival analysis. RESULTS: CA IX-positive area fractions of viable tumor tissue varied significantly between tumors (range, 0-0.23; median, 0.004), with positive membranous CA IX staining in 66% (31 of 47) of the tumors. Patients with CA IX-positive tumors had a significantly lower disease-specific and overall survival than patients with CA IX-negative tumors (P = 0.033 and P = 0.044, respectively). CONCLUSIONS: These data suggest that CA IX, a potential intrinsic marker of hypoxia, predicts for poor prognosis in patients with deep, large, high-grade soft tissue sarcoma. Larger studies are required to determine whether CA IX has independent prognostic value in this group of tumors.

Adult↗

PubMed2004

Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor.

PURPOSE: Microvascular permeability changes and loss of blood-brain barrier integrity are important features of central nervous system (CNS) radiation injury. Expression of vascular endothelial growth factor (VEGF), an important determinant of microvascular permeability, was examined to assess its role in CNS radiation damage. Because hypoxia mediates VEGF up-regulation through hypoxia-inducible factor-1alpha (HIF1alpha) induction, we studied the relationships of hypoxia, HIF1alpha expression, and expression of VEGF in this damage pathway. EXPERIMENTAL DESIGN: Expression of HIF1alpha, VEGF, and another hypoxia-responsive gene, glucose transporter-1, was assessed in the irradiated rat spinal cord using immunohistochemistry and in situ hybridization. Hypoxic areas were identified using the nitroimidazole 2-(2-nitro-1H-imidazole-L-yl)-N-(2,2,3,3,3,-pentafluoropropyl) acetamide. To determine the causal importance of VEGF expression in radiation myelopathy, we studied the response of transgenic mice with greater (VEGF-A(hi/+)), reduced (VEGF-A(lo/+)), and wild-type VEGF activity to thoracolumbar irradiation. RESULTS: In rat spinal cord, the number of cells expressing HIF1alpha and VEGF increased rapidly from 16 to 20 weeks after radiation, before white matter necrosis and forelimb paralysis. A steep dose response was observed in expression of HIF1alpha and VEGF. HIF1alpha and VEGF expressing cells were identified as astrocytes. Hypoxia was present in regions where up-regulation of VEGF and glucose transporter-1 and increased permeability was observed. VEGF-A(lo/+) mice had a longer latency to development of hindlimb weakness and paralysis compared with wild-type or VEGF-A(hi/+) mice. CONCLUSIONS: VEGF expression appears to play an important role in CNS radiation injury. This focuses attention on VEGF and other genes induced in response to hypoxia as targets for therapy to reduce or prevent CNS radiation damage.

Animals↗