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Biomedical subjects

Richard J Bold

Publications and source records attributed to Richard J Bold.

At least 19 recordsLinked to original sources
PubMed2006

Upstaging and improved survival of early breast cancer patients after implementation of sentinel node biopsy for axillary staging.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has become a standard for axillary staging for early breast cancer patients. Prior studies suggest that SLNB may be more sensitive for the identification of lymph node disease than axillary lymph node dissection (ALND). We hypothesized that SLNB use increases the incidence of node-positivity in early breast cancer patients compared to ALND. Furthermore, survival improves due to more accurate staging (stage migration). METHODS: Registry data from an NCI-designated cancer center was reviewed for breast cancer patients with T1 and T2 tumors for two 5-year periods: before (1993-1997) and after (2000-2004) SLNB implementation (1998). TNM staging was updated to conform to American Joint Committee on Cancer (AJCC) 2003 guidelines. RESULTS: There were no differences in tumor size or stage groupings between the two time periods (n = 316 and 577). There was a non-significant increase in the proportion of patients with lymph node involvement (32 vs. 27%; P = .16) after SLNB implementation; though a trend of increased incidence of single-node positive patients was observed (13 vs. 8%; P = .07). This was significant in patients with T1A/T1B tumors (10 vs. 3%; P = .04), though not seen in T1C or T2 tumors. Stage II survival improved in the later time period (P = .02). CONCLUSIONS: The increase in single-node positivity after SLNB implementation supports the theory that SLNB is more sensitive than ALND. Improvements in survival are likely due to the stage migration of patients who would have been node-negative by ALND (but were found to be node-positive by SLNB) in addition to improvements in adjuvant therapy.

Adult↗
PubMed2005

Targeting BCL-2 overexpression in various human malignancies through NF-kappaB inhibition by the proteasome inhibitor bortezomib.

BACKGROUND: BCL-2 overexpression occurs in many cancer types and is associated with chemoresistance and radioresistance. The mechanisms responsible for its aberrant expression are thought to be transcriptionally mediated but remain unclear. We examined the cell type-specific mechanism of BCL-2 gene transcription in various solid organ malignancies. METHODS: Regulation of BCL-2 gene transcription was examined in seven different human cancer cell lines including two pancreatic (MIA-PaCa-2, PANC-1), two prostate (LNCaP, PC-3), two lung (Calu-1, A549) and one breast (MCF-7) cancer cell line. Cells were treated with inhibitors of phosphatidylinositol-3 kinase (PI3K), MEK/ERK, and p38MAPK. The effect of mutation of a NF-kappaB site in the BCL-2 promoter was determined, as was the effect of inhibition of NF-kappaB function using a 26S proteasome inhibitor (bortezomib) on both BCL-2 transcription and induction of apoptosis. RESULTS: BCL-2 expression varied both between and within tumor types; four of seven cell lines demonstrated high BCL-2 levels (MIA-PaCa-2, PC-3, Calu-1 and MCF-7). No signaling pathway was uniformly responsible for overexpression of BCL-2; however, mutation of the NF-kappaB site decreased BCL-2 promoter activity in all cell lines. Inhibition of NF-kappaB activity decreased BCL-2 protein levels independently of the signaling pathway involved in transcriptional activation of the BCL-2 gene. CONCLUSIONS: Diverse signaling pathways variably regulate BCL-2 gene expression in a cell type-specific fashion. Therapy to decrease BCL-2 levels in various human cancers would be more broadly applicable if targeted to transcriptional activation rather than signal transduction cascades. Finally, the apoptotic efficacy of proteasome inhibition with bortezomib paralleled the ability to inhibit NF-kappaB activity and decrease BCL-2 levels.

Boronic Acids↗
PubMed2005

A young surgeon's perspective.

The environment of health care delivery is responding to a variety of external forces that are changing the practice of surgery. Only when we look back at this period can any assessments be made to determine whether the changes were beneficial or detrimental. The observation that surgeons are retiring at an earlier age may be a reflection of the negative effect of the changing culture of surgery on career satisfaction. As a young surgeon who anticipates an additional 20+ years of a surgical career, these changes are important to me and will clearly affect my practice as well as my satisfaction. This special article provides my personal perspective on some of the current and anticipated changes in surgery that are a manifestation of cultural changes in health care delivery.

Attitude of Health Personnel↗
PubMed2005

Experience and attitudes of surgeons toward palliation in cancer.

BACKGROUND: Surgery can effectively palliate symptoms in patients with advanced malignancy and thereby maintain quality of life. However, the goal of surgical palliation should be balanced with the associated risks, and the decision to operate can be challenging for even the most experienced surgeon. HYPOTHESIS: There are significant deficiencies in training during residency and in continuing medical education in palliative surgical care leading to a lack of agreement for treatment recommendations. DESIGN AND SETTING: A survey of general surgeons involving 4 clinical vignettes of patients with advanced malignancies and varying degrees of symptoms. Respondents were asked to select the best treatment option for each patient from a list of 6 alternatives. Furthermore, respondents identified the clinical factors that most influenced the decision, as well as the major goal of the palliative intervention. SUBJECTS: Surgeons in a midsized urban setting and its surrounding region. RESULTS: Of 124 surveys sent out, 70 (56%) were completed. Significant deficiencies in education were identified; 59 (84%) of the respondents did not receive any education in palliative surgical care during residency and 28 (44%) lacked continuing medical education. A consensus treatment recommendation was not selected in 3 of the 4 clinical vignettes, but the respondents used similar clinical factors and goals of treatment for selection of the specific recommendation. CONCLUSIONS: Palliative care is a major deficiency of postgraduate surgical training. A more focused effort in training surgeons in palliative care may allow for the more uniform and standard provision of palliative surgical care to patients with advanced cancer.

Adult↗
PubMed2005

An analysis of cost and clinical outcome in palliation for advanced pancreatic cancer.

BACKGROUND: The optimal palliative method for patients with unresectable pancreatic cancer remains controversial. METHODS: A retrospective chart review evaluated patients who underwent exploration for presumed resectable pancreatic cancer. Cost-based analysis was performed using relative value units (RVUs) that included the initial surgical procedure and any additional procedure required to achieve satisfactory palliation. RESULTS: Of 96 patients (1993--2002), 6% had biliary bypass, 42% had duodenal bypass, 40% had double bypass, and 13% had no procedure with equivalent clinical outcomes. If biliary bypass was not initially performed, there was a significant incidence of biliary complications before definitive endoscopic stenting (P=.01). If duodenal bypass was not initially performed, 11% developed duodenal obstruction (P=.04). Total RVUs was highest for a double bypass and lowest for no initial surgical palliative procedure. CONCLUSIONS: Although surgical bypass procedures at initial exploration provide durable palliation, these procedures are associated with greater costs.

Aged↗
PubMed2005

Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer.

Overexpression of the anti-apoptotic protein BCL-2 is frequently observed in small cell lung cancers (SCLC) and is associated with chemoresistance. We examined the signaling pathways involved in upregulation of BCL-2 in SCLC, and whether inhibition of NF-kappaB using the 26S proteasome inhibitor bortezomib had any effect on BCL-2 levels or apoptosis. Mutation of a NF-kappaB site in the BCL-2 promoter reduced promoter activity to less than 20% of the wild-type promoter. Treatment with bortezomib resulted in decreased transcription of the BCL-2 promoter, decreased BCL-2 levels, and induced apoptosis. These data provide the necessary laboratory background for further investigation of bortezomib in the treatment of SCLC.

Apoptosis↗
PubMed2005

Bortezomib-based combinations in the treatment of non-small-cell lung cancer.

Lung cancer is the most common cause of cancer-related death among men and women in the United States. Current trials are focusing on the integration of novel therapeutic agents into current non-small-cell lung cancer (NSCLC) treatment paradigms. Bortezomib, a small-molecule proteasome inhibitor, has single-agent activity in NSCLC and in combination with agents commonly used in NSCLC. This article will review the rationale and preclinical data supporting bortezomib combinations and the clinical trials with bortezomib alone and in combination in NSCLC to date.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Proteasome inhibition in small-cell lung cancer: preclinical rationale and clinical applications.

Small-cell lung cancer (SCLC) is a tobacco-related malignancy that usually presents in an extensive and therefore incurable stage. Although initially sensitive to platinum agent-based therapy, SCLC rapidly becomes refractory to chemotherapy, leading to disease recurrence and ultimately patient death. Treatment options following failure of first-line platinum agent-based therapy are limited. Small-cell lung cancer is characterized by molecular aberrancies such as overexpression of the antiapoptotic protein Bcl-2, which is regulated in part by the inhibitory IkappaB, a target of the ubiquitin-proteasome degradative pathway. Bortezomib is a proteasome inhibitor that can decrease Bcl-2 expression through diminished IkappaB degradation. Efforts to promote apoptosis in SCLC through the integration of bortezomib into therapy are under way.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has a poor prognosis. Despite advances in therapy, survival has improved only slightly. The 26S proteasome regulates multiple cellular processes through degradation of ubiquitin-tagged proteins. The proteasome inhibitor, bortezomib (Velcade, formerly PS-341), has been shown to be an active anticancer agent both in vitro and in vivo in multiple tumor types. PURPOSE: To determine the molecular and cellular effects of the proteasome inhibitor in NSCLC as well as to evaluate the effectiveness of sequential treatment with bortezomib and gemcitabine/carboplatin (G/C) chemotherapy both in vitro and in vivo. METHODS: All experiments were performed in the A549 NSCLC cell line. MTT assays were used to evaluate cytotoxicity. Western blotting evaluated protein levels. Measures of apoptosis included FACS analysis, DAPI staining and caspase-3 cleavage. Long-term cell viability was determined using an anchorage-dependent clonogenic assay. Sequential studies were performed in vitro and in vivo. RESULTS: Bortezomib increased p21(waf1/cip1), induced G(2)/M arrest, and triggered a small amount of apoptosis. The apoptotic effect of G/C chemotherapy was eliminated when bortezomib was administered prior to the chemotherapy; however, it was accentuated when the bortezomib was given simultaneously or after the chemotherapy. CONCLUSIONS: Bortezomib improves efficacy in combination with gemcitabine and carboplatin in NSCLC, but sequential effects are important and must be considered when developing therapeutic regimens.

Animals↗
PubMed2004

Immediate breast reconstruction after mastectomy increases wound complications: however, initiation of adjuvant chemotherapy is not delayed.

BACKGROUND: Immediate breast reconstruction is being increasingly used after mastectomy, although it may increase the incidence of wound complications. The indications for chemotherapy in breast cancer are expanding and wound complications following mastectomy may delay the initiation of adjuvant chemotherapy. HYPOTHESIS: Immediate breast reconstruction after mastectomy for breast cancer does not lead to an increased incidence of wound complications nor delay the initiation of systemic chemotherapy. DESIGN AND SETTING: Retrospective medical record review at a tertiary care center. PATIENTS: One hundred twenty-eight women treated with a mastectomy for breast cancer over an 8-year period (January 1, 1995, through December 31, 2002). MAIN OUTCOME MEASURES: Surgical site complications (infectious and noninfectious) and time to initiation of postoperative chemotherapy. RESULTS: One hundred forty-eight mastectomy procedures in 128 women with breast cancer were evaluated. We analyzed 4 subgroups according to whether or not immediate breast reconstruction was part of the surgical procedure (76 or 72 procedures, respectively) and whether or not postoperative adjuvant chemotherapy was administered (81 or 47 patients, respectively). There was an increased incidence of wound complications in patients who underwent immediate breast reconstruction compared with those who did not (6/72 [8.3%] vs 17/76 [22.3%]; P = .02). However, these complications did not delay initiation of postoperative chemotherapy. CONCLUSIONS: Although we observed an increased incidence of wound complications when immediate breast reconstruction was combined with mastectomy, there was no delay in the initiation of adjuvant therapy. Immediate breast reconstruction should remain an important treatment option after mastectomy even when postoperative chemotherapy is anticipated.

Adult↗
PubMed2004

Inhibition of AKT abrogates chemotherapy-induced NF-kappaB survival mechanisms: implications for therapy in pancreatic cancer.

BACKGROUND: When activated, the nuclear factor (NF)-kappaB pathway is a potent cellular signal that inhibits apoptotic cell death. Pancreatic cancer is resistant to the apoptotic effect of chemotherapy, though it is unclear whether this is an inherent feature or a survival signal engaged in response to chemotherapy. We investigated whether pancreatic cancer cells activate the NF-kappaB pathway in response to chemotherapy and whether inhibition of this response altered the apoptotic efficacy of chemotherapy. STUDY DESIGN: We determined NF-kappaB activity after chemotherapy treatment of the MIA-PaCa-2 human pancreatic cancer cell line using both physical (electrophoretic mobility shift assay) and functional (luciferase) techniques. The effect of chemotherapy on transcription of the antiapoptotic gene BCL-2, a target of NF-kappaB, was determined. We examined the effect of inhibition of Akt, an upstream activator of NF-kappaB, on the molecular (NF-kappaB function and BCL-2 transcription) and cellular (apoptosis) effect of chemotherapy. RESULTS: Both the chemotherapeutic agents gemcitabine and paclitaxel activated NF-kappaB and stimulated BCL-2 gene promoter activity. The stimulation of BCL-2 promoter function was directly regulated by NF-kappaB. These cellular responses were blocked by inhibition of Akt. The apoptotic effect of gemcitabine and paclitaxel also was enhanced after Akt inhibition. CONCLUSIONS: Part of the apoptotic resistance of pancreatic cancer may be mediated by activation of the NF-kappaB survival pathway in response to chemotherapy. Inhibition of this response may be an important adjunct to increase the efficacy of chemotherapy.

Antineoplastic Agents↗
PubMed2004

Hilar cholangiocarcinoma: surgical and endoscopic approaches.

HCCa remains an uncommon malignancy, though increasing use of more radical surgery has led to prolonged survival in those patients who undergo curative resection. The extent of these resections suggest that the best results are likely to be obtained in centers with the resources and experience to conduct these operations in a safe fashion. Until major advances in the systemic therapy of HCCa are made, however, the management should focus on optimal preoperative imaging and palliation of jaundice with improvement in quality of life.

Bile Duct Neoplasms↗
PubMed2004

Proteasome inhibition with PS-341 (bortezomib) in lung cancer therapy.

PS-341 (bortezomib) represents a new class of therapeutics that targets the ubiquitin-proteasome pathway. It has broad-spectrum single-agent anticancer activity and can potentiate chemotherapy and radiation in preclinical models. Early phase clinical studies have shown tolerability and activity in multiple myeloma, lymphoma, prostate cancer, and lung cancers. By its mechanism of inhibiting protein degradation, PS-341 targets a wide range of pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27(Kip1), p53, nuclear factor-kappaB, Bcl-2, and Bax. PS-341 is currently in phase I/II clinical development in both non-small cell lung cancer and small cell lung cancer. This article will review the preclinical and clinical experience with PS-341 as it relates to lung cancer.

Antineoplastic Agents↗
PubMed2003

Utility of tumor markers in determining resectability of pancreatic cancer.

HYPOTHESIS: Despite advances in preoperative radiologic imaging, a significant fraction of potentially resectable pancreatic cancers are found to be unresectable at laparotomy. We tested the hypothesis that preoperative serum levels of CA19-9 (cancer antigen) and carcinoembryonic antigen will identify patients with unresectable pancreatic cancer despite radiologic staging demonstrating resectable disease. DESIGN AND SETTING: Academic tertiary care referral center. PATIENTS: From March 1, 1996, to July 31, 2002, 125 patients were identified who underwent surgical exploration for potentially resectable pancreatic cancer based on a preoperative computed tomographic scan; in 89 of them a preoperative tumor marker had been measured. MAIN OUTCOME MEASURES: Preoperative tumor markers (CA19-9 and carcinoembryonic antigen) were correlated with extent of disease at exploration. As CA19-9 is excreted in the biliary system, CA19-9 adjusted for the degree of hyperbilirubinemia was determined and analyzed. RESULTS: Of the 89 patients, 40 (45%) had localized disease and underwent resection, 25 (28%) had locally advanced (unresectable) disease, and 24 (27%) had metastatic disease. The mean adjusted CA19-9 level was significantly lower in those with localized disease than those with locally advanced (63 vs 592; P =.003) or metastatic (63 vs 1387; P<.001) disease. When a threshold adjusted CA19-9 level of 150 was used, the positive predictive value for determination of unresectable disease was 88%. Carcinoembryonic antigen level was not correlated with extent of disease. CONCLUSIONS: Among the patients with resectable pancreatic cancer based on preoperative imaging studies, those with abnormally high serum levels of CA19-9 may have unresectable disease. These patients may benefit from additional staging modalities such as diagnostic laparoscopy to avoid unnecessary laparotomy.

Adenocarcinoma↗
PubMed2003

Schedule-dependent molecular effects of the proteasome inhibitor bortezomib and gemcitabine in pancreatic cancer.

BACKGROUND: 26S proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumor sensitivity to standard chemotherapy. We determined the effect of alternate sequencing regimens of a proteasome inhibitor and gemcitabine on molecular and cellular responses in pancreatic cancer cells. MATERIALS AND METHODS: MIA-PaCa-2 human pancreatic cancer cells were treated with the proteasome inhibitor bortezomib either before, simultaneously or following exposure to gemcitabine. Expression of the cell cycle proteins p21(WAF1/CIP1) and p27(KIP1), and the anti-apoptotic protein BCL-2 were determined by Western blotting. Cell cycle changes and immediate or delayed induction of apoptosis were quantitated. RESULTS: Gemcitabine followed by bortezomib induced the greatest induction of apoptosis and long-term inhibition of cell growth. Bortezomib treatment led to accumulation of p21(WAF1/CIP1) and p27(KIP1) and decreased BCL-2; gemcitabine decreased p27(KIP1), induced BCL-2 and had no effect on p21(WAF1/CIP1). When these agents were given in combination or sequence, intermediate changes in these proteins were observed, and the alterations did not correlate with immediate or delayed induction of apoptosis. CONCLUSIONS: Inhibition of the 26S proteasome following chemotherapy appears to be the most effective regimen, though changes in BCL-2, p21(WAF1/CIP1), p27(KIP1) do not necessarily correlate with the cellular effects when various sequences are examined. Therefore, these proteins may not be the most appropriate surrogate markers of efficacy of this regimen. These data provide the background for the development of the optimal regimen to be used in clinical trials.

Adenocarcinoma↗