Biomedical subjects

Susan G Groshen

Publications and source records attributed to Susan G Groshen.

8 recordsLinked to original sources

PubMed2006

Expression of stress response protein Grp78 is associated with the development of castration-resistant prostate cancer.

BACKGROUND: Induction of molecular chaperone Grp78 (78-kDa glucose-regulated protein) occurs in stress conditions that often characterize tumor microenvironments. We investigated the role of Grp78 in prostate cancer progression and the development of castration resistance, where cancer cells continue to survive despite the stress of an androgen-starved environment. EXPERIMENTAL DESIGN: Immunohistochemistry was done to examine Grp78 expression in 219 prostate cancers from patients with pathologic stage T3N0M0 disease [androgen ablation naive (untreated) and androgen ablation exposed (treated)] and castration-resistant prostate cancer. Classification of tumors was based on intensity of Grp78 cytoplasmic immunoreactivity and percentage of immunoreactive tumor cells. The associations of Grp78 expression with prostate cancer recurrence (clinical and/or serum prostate-specific antigen) and survival were examined in the untreated stage T3N0M0 group. Grp78 expression was also analyzed in the androgen-dependent LNCaP and castration-resistant C42B cell lines. RESULTS: The percentage of tumor cells expressing Grp78 was strongly associated with castration-resistant status (P = 0.005). Increased Grp78 expression was consistently associated with greater risk of prostate cancer recurrence and worse overall survival in patients who had not undergone prior hormonal manipulation. Grp78 expression was also increased in the castration-resistant LNCaP-derived cell line C42B and in LNCaP cells grown in androgen-deprived conditions compared with LNCaP cells grown in androgen-rich media. CONCLUSION: Our findings show that up-regulation of Grp78 is associated with the development of castration resistance, possibly in part by augmenting cell survival as previously suggested, and may serve as an important prognostic indicator of recurrence in a subset of patients with T3N0M0 disease.

Cohort Studies↗

PubMed2006

Phase I study of antisense oligonucleotide against vascular endothelial growth factor: decrease in plasma vascular endothelial growth factor with potential clinical efficacy.

PURPOSE: Vascular endothelial growth factor antisense (VEGF-AS) is an antisense oligonucleotide that targets VEGF, inhibiting angiogenesis and tumor cell proliferation. This study established the safety, biologic effects, and pharmacokinetics of VEGF-AS in 51 patients with advanced malignancies. METHODS: VEGF-AS was administered as a 2-hour infusion daily for 5 consecutive days for only one cycle on the first four dose levels, and then administered daily for 5 days every other week for up to 4 months on subsequent levels. Pharmacokinetics, tumor response, and the effect on plasma VEGF levels were determined. RESULTS: The maximum-tolerated dose was 200 mg/m2. Dose-limiting toxicities included grade 4 fever, and pulmonary embolism in one patient each at 250 mg/m2. Mild anemia, fever, fatigue, and gastrointestinal complaints were the most common adverse events. VEGF-AS t(1/2beta) (beta-phase terminal half-life of drug concentration) was 2.25 hours (range, 1.97 to 2.95 hours). Mean plasma VEGF-A (P = .002) and VEGF-C (P = .01) levels decreased 24 hours postinfusion, with a trend towards greater decreases at higher dose levels. At the maximum-tolerated dose, five of six patients demonstrated reductions in plasma VEGF. Clinical responses included complete remission in one patient with AIDS-Kaposi's sarcoma, a mixed but dramatic response in one patient with cutaneous T-cell lymphoma, and prolongation of progression-free survival compared with that obtained on the immediate prior regimen in six patients (12%) with renal cell, bronchoalveolar, small cell lung, thyroid, and ovarian carcinomas, and chondrosarcoma, respectively. CONCLUSION: VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.

Adult↗

PubMed2006

Early ductal decompression versus conservative management for gallstone pancreatitis with ampullary obstruction: a prospective randomized clinical trial.

OBJECTIVE: To compare the efficacy of endoscopic retrograde cholangiopancreatography +/- endoscopic sphincterotomy (ERCP +/- ES) versus traditional conservative management in early gallstone pancreatitis with persistent ampullary obstruction (GSP + AO). SUMMARY BACKGROUND DATA: The effectiveness of early ERCP +/- ES in this setting is controversial. METHODS: Sixty-one consecutive patients with GSP + AO within 48 hours from the onset of symptoms were randomized to receive either conservative treatment and selective ERCP +/- ES after 48 hours (control group, 31 patients) or initial conservative treatment and systematic ERCP +/- ES within 48 hours if obstruction persisted 24 hours or longer (study group, 30 patients). Patient outcome was compared in relation to treatment groups and to duration of obstruction. RESULTS: In the control group, 22 patients disobstructed spontaneously within 48 hours; 3 of the remaining 9 patients underwent ERCP +/- ES and none had impacted stones. In the study group, 16 patients disobstructed spontaneously and 14 underwent ERCP within 48 hours from the onset of symptoms; impacted stones were found and extracted by ES in 79% (11 of 14) of these. PATIENTS: There were no deaths in either group. Patients in the study group showed a shorter period of obstruction (P = 0.016) and a lower rate of immediate complications (P = 0.026) than controls. Patients with obstruction lasting < or =48 hours regardless of the treatment group had fewer immediate complications than those whose obstruction persisted longer (P < 0.001). CONCLUSIONS: This study shows that in patients with GSP + AO limiting the duration of obstruction to not longer than 48 hours by ERCP + ES decreased morbidity.

Adult↗

PubMed2005

Influence of quantity of lymph vascular space invasion on time to recurrence in women with early-stage squamous cancer of the cervix.

OBJECTIVE: To determine if the quantity of lymph vascular space invasion (LVSI) correlates with time to recurrence in women with early-stage squamous carcinoma of the cervix. METHODS: 101 consecutive women with Stages IA2, IB, and IIA squamous carcinoma of the cervix who had undergone radical hysterectomy between 1991 and 1997, with previously reported histopathologic quantification of LVSI by four methods, were prospectively followed. The outcome measure was time to recurrence. Univariate and stratified log-rank test analysis was performed to test the association of time to recurrence with prognostic factors. Further analysis was focused on recurrence in those patients who had negative surgical margins and whose tumors contained LVSI, incorporating the four quantification measures. RESULTS: Nineteen (19%) women had cancer recurrence. The presence of LVSI (P = 0.05), cervical stromal invasion (P = 0.01), parametrial involvement (P < 0.001), and positive margins (P < 0.0001) were significantly related to time to recurrence on univariate analysis. In patients whose tumors had negative surgical margins and contained LVSI (65%), percentage of all sections with LVSI >29% and total number of foci with LVSI >5 were significantly related to time to recurrence (P = 0.006). When stratifying for cervical stromal invasion, lymph node status, and parametrial involvement in this group, percentage of all sections with LVSI >29% and total number of foci with LVSI >5 were significantly related to time to recurrence (P = 0.05). CONCLUSION: The quantity of LVSI, as defined by the percentage of all sections with LVSI and total number of foci with LVSI, is an independent prognostic factor for time to recurrence in women with early-stage squamous carcinoma of the cervix.

Carcinoma, Squamous Cell↗

PubMed2005

Radical cystectomy in the elderly: comparison of clincal outcomes between younger and older patients.

BACKGROUND: The authors report their experience with radical cystectomy for transitional cell carcinoma (TCC) of the bladder comparing clinical outcomes, including complication rates, among older patients versus younger patients in a high-volume center specializing in the treatment of patients with advanced carcinoma of the urinary bladder. METHODS: A retrospective review was undertaken of 1054 patients who underwent radical cystectomy for bladder TCC from 1971 through 1997. Four age groups were compared; < 60 years at the time of cystectomy (n = 309 patients), age 60-69 years (n = 381 patients), age 70-79 years (n = 314 patients), and age > or = 80 years (n = 50 patients). RESULTS: The median length of hospital stay in patients ages < 60 years, 60-69 years, 70-79 years, and > or = 80 years was 10 days, 10 days, 11 days, and 11 days, respectively (P < 0.001). The corresponding rates of overall early complications were 24%, 25%, 37%, and 30%, respectively (P = 0.002); whereas the corresponding late complication rates were 36%, 30%, 22%, and 14%, respectively (P < 0.001). The rate of early diversion-related complications did not differ significantly (11%, 8%, 12%, and 6%, respectively; P = 0.14). The operative mortality rates were 1%, 3%, 4%, and 0%, respectively (P = 0.14). There was no difference with respect to early complications, early diversion-related complications, late complications, or operative mortality comparing patients age > 70 years who underwent ileal conduit versus orthotopic urinary diversion (P = 0.20, P = 0.61, P = 0.53, and P = 0.78, respectively). CONCLUSIONS: Elderly patients who underwent cystectomy for TCC had similar mortality and early diversion-related complication rates. Carefully selected elderly patients safely can be offered an orthotopic urinary diversion. Chronological age, per se, is not a contraindication for radical cystectomy in the setting of invasive bladder carcinoma.

Age Factors↗

PubMed2005

Radical cystectomy in the elderly: Comparison of survival between younger and older patients.

BACKGROUND: The authors reported their experience with radical cystectomy for transitional cell carcinoma (TCC) of the bladder. They compared pathologic features and survival rates between older and younger patients. METHODS: The authors retrospectively reviewed the records of 1054 patients who underwent radical cystectomy for bladder TCC between 1971 and 1997. Four age groups were compared: < 60 years old at the time of cystectomy (n = 310), 60-69 years old (n = 381), 70-79 years old (n = 313), and >/= 80 years old (n = 50). RESULTS: There were no significant differences in pathologic features among the groups regarding frequency of carcinoma in situ, high-grade disease, p53 status, and lymph node positivity. However, in the age groups < 60, 60-69, 70-79, and >/= 80, 45%, 49%, 51%, and 72% of patients, respectively, had extravesical TCC (P=0.004). Significant differences also were seen in the proportion of patients who received adjuvant chemotherapy (26%, 26%, 15%, and 6%, respectively; P < 0.001). The 5-year overall survival rates for patients < 60, 60-69, 70-79, and >/= 80 years old were 72%, 58%, 54%, and 33%, respectively (P < 0.001). The 5-year disease recurrence-free survival rates were 75%, 65%, 68%, and 45%, respectively (P = 0.003). The elderly had a lower probability of receiving adjuvant chemotherapy. CONCLUSIONS: Elderly patients undergoing cystectomy for TCC had similar pathologic features (except for disease stage) as younger patients. In the current series, elderly patients undergoing cystectomy had a higher pathologic stage and were less likely to receive adjuvant chemotherapy. The elderly had worse disease recurrence-free survival rates. Further work is needed to identify the causes for this and to develop strategies to improve cancer control in elderly patients.

Age Factors↗

PubMed2004

The management of urethral transitional cell carcinoma after radical cystectomy for invasive bladder cancer.

PURPOSE: Previous reports have identified risk factors for urethral recurrence following radical cystectomy for transitional cell carcinoma (TCC). However, reports of the clinical presentation, treatment and outcome in these patients are lacking. We report our experience with the diagnosis, management and outcome of urethral TCC after radical cystectomy for bladder cancer. MATERIALS AND METHODS: A database of 1,054 patients who underwent radical cystectomy and urinary diversion for TCC from 1971 to 1997 was retrospectively reviewed. All patients with urethral TCC after surgery were identified. RESULTS: Urethral TCC was diagnosed in 47 men a median of 18.5 months (range 2 to 116) after cystectomy with 20 (42%) diagnosed within 1 year. Symptomatic recurrence developed in 24 of 42 evaluable patients (57%), 21 had bloody urethral discharge and 7 had pain or a palpable mass. A total of 13 patients (31%) were asymptomatic with abnormal cytology. The remaining 5 patients underwent prophylactic urethrectomy based on cystectomy pathology. Overall 41 patients underwent urethrectomy, which was total in 36 and distal with perineal urethrostomy in 5, including later conversion to total urethrectomy in 2. Overall at a median followup of 26 months (range 3 to 275) since diagnosis 36 of 47 patients (76%) were dead, including 25 of metastatic disease. Only 10 patients (21%) remained disease-free. Median overall survival in patients with urethral TCC after radical cystectomy was only 28 months after the diagnosis of urethral TCC. Urethral stage (superficial vs invasive disease) at diagnosis was the most import predictor of overall survival in this cohort of patients. CONCLUSIONS: Most patients with urethral recurrence present with symptoms. However, screening cytology alone still detects a significant proportion. The median survival of patients with urethral TCC after radical cystectomy is only 28 months after diagnosis. Urethral stage (superficial vs invasive disease) at diagnosis is the most import predictor of overall survival in this cohort of patients.

Adult↗

PubMed2003

Granulocyte-macrophage-colony-stimulating factor added to a multipeptide vaccine for resected Stage II melanoma.

BACKGROUND: Forty-eight patients with resected Stages IIA and IIB melanoma were immunized with two tumor antigen epitope peptides derived from gp100(209-217) (210M) (IMDQVPSFV) and tyrosinase(368-376) (370D) (YMDGTMSQV) emulsified with incomplete Freund's adjuvant (IFA). Patients were assigned randomly to receive either peptides/IFA alone or with 250 microm of granulocyte-macrophage-colony-stimulating factor (GM-CSF) subcutaneously daily for 5 days to evaluate the toxicities and immune responses in either arm. Time to recurrence and survival were secondary end points. METHODS: Immunizations were administered every 2 weeks x 4, then every 4 weeks x 3, and once 8 weeks later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses and skin testing with peptides and recall reagents was performed before and after eight vaccinations. RESULTS: Local pain and granuloma formation, fever, and lethargy of Grade 1 or 2 were observed. Transient vaccine-related Grade III and no Grade IV toxicity was observed. Seventeen of the 40 patients for whom posttreatment skin tests were performed developed a positive skin test response to the gp100 peptide, but only 1 of the 40 patients developed a positive skin test response to tyrosinase. Immune responses were measured by release of interferon-gamma (IFN-gamma) in an enzyme-linked immunosorbent assay (ELISA) by effector cells in the presence of peptide-pulsed antigen-presenting cells, by cytokine release of IFN-gamma, GM-CSF, and tumor necrosis factor-alpha in a Luminex assay, or by an antigen-specific tetramer flow cytometry assay. Thirty-four of the 39 patients for whom the ELISA data were performed demonstrated an immune response after vaccination, as did 37 of 42 patients by tetramer assay. Enzyme-linked immunosorbent assay, Luminex, and tetramer responses in the GM-CSF/peptide/IFA group were higher than in the peptide/IFA group. Epitope spreading to the MART-1/MelanA 27-35 and 26-35 (27L) epitopes was detected by tetramer assay in 10 patients. Seven of 48 patients experienced disease recurrence with a median of 24 months of follow-up and 2 patients in this intermediate to high risk group have died. CONCLUSION: These data suggest a significant number of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine. There is a trend for GM-CSF to modestly increase the immune response and support further development of GM-CSF as a vaccine adjuvant.

Antibodies, Neoplasm↗