p53, bcl-2 and Retinoblastoma Proteins as Long-Term Prognostic Markers in Localized Carcinoma of the Prostate

Purpose

The accumulation of p53 and bcl-2 gene products as well as the loss of the retinoblastoma (Rb) gene product have been associated with prostate cancer progression. We assessed whether the levels of immunoreactivity for p53, Rb and bcl-2 are better long-term predictors of disease specific survival than conventional pathological parameters of the primary tumor, such as Gleason score, capsular penetration, seminal vesicle invasion, and percent tumor in the specimen, in patients with clinically localized prostate cancer treated with radical prostatectomy.

Materials and Methods

A total of 71 patients with clinical stages A1 to B2 adenocarcinoma of the prostate underwent radical prostatectomy after a negative metastatic evaluation. No neoadjuvant or adjuvant treatments were given and causes of death were recorded. Prostatectomy specimens were analyzed to determine the conventional pathological parameters, and p53, Rb and bcl-2 immunohistochemical staining. Univariate and multivariate analyses were done to determine the independent contributions of p53, Rb and bcl-2 in predicting survival.

Results

On multivariate analysis the independent factors predicting disease specific survival were p53 staining score (p <0.001) and Rb staining score (p <0.001). In patients with p53 immunoreactive tumors the 15-year disease specific survival was 38% compared to 87% for those with less immunoreactivity. Analysis of Rb immunoreactivity for 15-year disease specific survival yielded 92 and 66% high and low staining levels, respectively. Best subset analysis revealed that the combination of p53 score and Rb score yielded the best predictive value for disease specific survival.

Conclusions

p53 and Rb immunohistochemical staining scores were independent predictors of disease specific survival and were superior to conventional pathological prognostic factors of the primary tumor. These findings lay the groundwork for the prospective study of these markers in patients treated with radical prostatectomy.     

p53 Mutation Status Predicts Pathological Response to Chemoradiotherapy in Locally Advanced Esophageal Cancer

Background and Objectives

The p53 gene promotes cell-cycle arrest and apoptosis upon DNA damage and is associated with chemo- and radiosensitivity of cancer cells. However, its clinical significance has not been confirmed, especially in squamous cell carcinoma of the esophagus (ESCC). We investigated the correlation between p53 disorders (gene mutation and protein accumulation) and the effects of chemoradiotherapy (CRT).

Patients and Methods

Biopsy specimens obtained before CRT (40–60 Gy; low-dose 5-fluorouracil plus cisplatin) from 64 patients with locally advanced (T2–T4) ESCC were examined for p53 gene mutations (MT) of exons 4–9 by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and protein accumulation by immunohistochemistry (IHC). These were correlated with the pathological effects of CRT and cause-specific survival.

Results

Pathological complete response (pCR) was observed in 21.9% (14/64) patients, who showed better survival than non-pCR patients (2-year survival 78.6% versus 40.5%, P = 0.007). p53 mutation (MT)+ and p53 IHC+ were observed in 31.3% (20/64) and 65.6% (42/64) patients, respectively, and each was significantly associated with non-pCR (P = 0.004 and 0.042, respectively). Combined evaluation of p53 MT and p53 IHC correlated well with pCR frequency, showing 0% (0/12) for MT+/IHC+, 0% (0/8) for MT+/IHC–, 20% (6/30) for MT–/IHC+ and 57.1% (8/14) for MT–/IHC–. These results indicate that presence of p53 mutations was associated with non-pCR regardless of IHC status, and that p53 immunoreactivity was helpful in predicting non-pCR among p53 mutation-negative patients.

Conclusion

Analysis of ESCC biopsy specimens for p53 gene mutation can identify patients who will not achieve pCR by CRT. The results should be confirmed by large cohort prospective studies.     

COMBINED ANALYSIS WITH BCL-2 AND P53 IMMUNOSTAINING PREDICTS POORER PROGNOSIS IN PROSTATIC CARCINOMA

Purpose

The objective of the current study is to investigate the relationship between bcl-2 and p53 expression and prognosis in prostatic carcinoma.

Materials and Methods

One hundred and forty-six needle core biopsy specimens obtained before any treatment were used for immunohistochemical detection of bcl-2 and p53 positivity. The relationship between these proteins was assessed by serial sections. Associations with Gleason score, clinical stage and patient survival were studied. Additionally, multivariate analysis by Cox proportional hazard model was used to determine the prognostic significance of these proteins.

Results

Bcl-2 positivity was found in 20% and p53 in 27% of 146 prostatic carcinomas. Both bcl-2 and p53 positivity were found only in 5%. They were expressed almost reciprocally in the tumors. P53 positivity correlated with high Gleason grade tumors. Bcl-2 positivity correlated with high T stage. Both bcl-2 and p53 positivity correlated with poor survival and short progression-free period. Multivariate analysis revealed that bcl-2 positivity was an independent prognostic indicator (p = 0.001).

Conclusions

Bcl-2 and p53 were almost independently expressed in prostatic cancer. Both correlated with malignant phenotypes of prostatic cancer. The combined data from this staining further improved the ability to predict the patient prognosis.     

LOCALLY RECURRENT PROSTATE TUMORS FOLLOWING EITHER RADIATION THERAPY OR RADICAL PROSTATECTOMY HAVE CHANGES IN KI-67 LABELING INDEX, P53 AND BCL-2 IMMUNOREACTIVITY

Purpose

We compare the biological phenotype of recurrent prostatic tumors after definitive local therapy (radiation or radical prostatectomy) with that of the same tumors before treatment.

Materials and Methods

Cellular proliferation (Ki-67 labeling index), p53 nuclear reactivity and bcl-2 immunoreactivity were determined in pretreatment and posttreatment tumor specimens from 13 patients with local tumor recurrence following radiation, and in 18 patients with local tumor recurrence following radical prostatectomy.

Results

Mean Ki-67 labeling index increased approximately 2-fold in locally recurrent tumors after radiation (10.5 versus 5.6%, p = 0.0008) or surgery (6.0 versus 3.2%, p = 0.0025) when compared with pretreatment tumors. We noted p53 nuclear reactivity in a significantly higher proportion of recurrences than in pretreatment tumors following radiation (54 versus 8%, p = 0.032) and surgery (39 versus 5%, p = 0.022). Although bcl-2 immunoreactivity was also seen in a higher proportion of recurrent tumors, this difference did not reach statistical significance for either radiation or surgery.

Conclusions

Recurrent tumors following either radiation or surgery differ significantly from the corresponding pretreatment tumors with respect to cellular proliferation and p53 nuclear reactivity.     

Postoperative Radiation Therapy in 26 Patients with Invasive Transitional Cell Carcinoma of the Upper Urinary Tract: No Impact on Survival?

Purpose

To evaluate the role of adjuvant radiation therapy in invasive transitional cell carcinoma of the upper urinary tract, we retrospectively reviewed a series of 26 patients who underwent radical surgery plus postoperative prophylactic irradiation for such a tumor.

Materials and Methods

Between February 1980 and October 1993, 18 men and 8 women (mean age 65 plus/minus 9 years, standard deviation) were treated for an invasive transitional cell carcinoma of the upper urinary tract. Tumor location was the renal pelvis in 15 patients (58 percent). The tumor was pathological stage B in 11 patients (42 percent) and stage C in 15 (58 percent). Tumor grade was 2 in 10 patients, 3 in 15 and unknown in 1. One patient had epidermoid metaplasia of urothelial cancer and 9 had node involvement. All patients underwent surgery followed by radiation therapy to a total dose of 45 Gy. to the tumor bed²³ and/or regional nodes¹⁸.

Results

After a mean followup of 45 months 13 patients (50 percent) were alive and 11 were disease-free at analysis. Local tumor relapse, nodal recurrence and metastasis were noted in 1, 4 (15 percent) and 14 (54 percent) patients, respectively. All patients with nodal recurrence had metastasis. A secondary location was noted frequently (6 bladder, 1 contralateral renal pelvis and 1 urethral tumors). Overall 5-year survival rate and 5-year survival rate with no evidence of disease were 49 percent and 30 percent, respectively. Overall 5-year survival rates were 60 percent for stage B and 19 percent for stage C disease (p = 0.07), 49 percent for node-negative versus 15 percent for node-positive cancer (p = 0.04), and 90 percent for grade 2 and 0 percent for grade 3 tumors (p less than 0.01).

Conclusions

In our trial using a radio-surgical approach, local control of disease and survival rates were similar to those reported previously in surgical series. Prophylactic postoperative radiation therapy is not recommended except in prospective randomized studies.     

RACIAL DIFFERENCES IN CLINICALLY LOCALIZED PROSTATE CANCERS OF BLACK AND WHITE MEN

Purpose

Tumor grade, deoxyribonucleic acid (DNA) ploidy, proliferation, p53 and bcl-2 expression were examined in clinically localized prostate cancers of black and white American men to learn whether these features showed racial differences.

Materials and Methods

A total of 117 prostate cancers (43 black and 74 white patients) obtained at radical prostatectomy for clinically localized disease were assigned Gleason scores by a single pathologist. Enzymatically dissociated nuclei from archival prostate cancers were examined by DNA flow cytometry using propidium iodide staining and the multicycle program to remove debris and sliced nuclei and to perform cell cycle analysis. For immunostaining after microwave antigen retrieval we used a DO-1/DO-7 monoclonal antibody cocktail for p53 and the clone 124 antibody for bcl-2.

Results

Significantly more black than white men had Gleason score 7 tumors. The DNA ploidy distribution of Gleason 6 or less tumors was similar for both races. As anticipated, the ploidy distribution of higher grade prostate cancer in white men was more abnormal but, unexpectedly, this was not found for higher grade prostate cancer in black men. No significant racial differences were found in S phase fractions, p53 or bcl-2 immunopositivity. However, for prostate cancer in black men there was a significant association between bcl-2 immunopositivity and higher S-phase fractions.

Conclusions

The aggressive prostate cancers of black men may be characterized by the 2 features of high proliferation and a block to programmed cell death.     

Relationship of p53 and bcl-2 to Prognosis in Muscle-Invasive Transitional Cell Carcinoma of the Bladder

Purpose

We examined the presence of the p53 and Bcl-2 oncoproteins, as detected by immunohistochemistry, in muscle-invasive bladder cancer and correlated this with survival.

Materials and Methods

Formalin-fixed cystectomy specimens from 41 consecutive patients with mean follow-up of 52 months were used. Five patients were either lost to follow-up or died of other diseases and were not included in the survival evaluation.

Results

Eighteen of 36 patients died of metastatic transitional cell carcinoma. p53 immunostaining was found in 61 percent of patients. In 21 of 23 this staining was homogeneous, with more than 75 percent of cancer cells staining using a DO-1/DO-7 antibody cocktail. p53 staining was not correlated with stage (p greater than 0.25) or grade (p less than 0.10) in these invasive cancer specimens. Contrary to recent studies p53 immunostaining was not correlated with disease-specific survival. Bcl-2 immunostaining was found in 28 percent of patients and was not correlated with grade (p greater than 0.25) or disease-specific survival. No combination of p53 and Bcl-2 staining gave added predictive information.

Conclusions

Cytoplasmic Bcl-2 is found in a small percentage of these cancers and does not correlate with prognosis. Further, p53 molecular overexpression is detected in the majority of muscle-invasive bladder tumors as a field defect. However, in patients undergoing cystectomy, it does not correlate with prognosis.     

Ki-67 Expression is a Prognostic Marker of Prostate Cancer Recurrence after Radical Prostatectomy

Purpose

We assessed the cellular proliferation of clinically localized prostate cancer by immunohistochemistry using the monoclonal antibody MIB to Ki-67 antigen in an attempt to identify associations between proliferative indexes and disease progression following radical prostatectomy.

Materials and Methods

Ki-67 proliferative antigen was evaluated using MIB 1 monoclonal antibody in archival paraffin embedded radical prostatectomy specimens from 180 patients followed for 1 to 9 years (mean 4.4). The percentage of tumor nuclei expressing Ki-67 antigen was measured and assigned an MIB 1 score (none or rare-negative, 1+-low score and 2 to 4+-high score) and analyzed for prostate specific antigen, stage, age, race, grade and serological recurrence postoperatively.

Results

There was a significant association between MIB 1 score and nuclear grade (p less than 0.001), Gleason score (p less than 0.001) and pathological stage (p = 0.01). Patients with a high MIB 1 score had earlier progression and a lower 5-year recurrence-free survival rate (44 percent) than those with negative MIB 1 scores (71 percent, p less than 0.001). In multivariate Cox regression analysis with backward elimination, pathological stage (p less than 0.01), pretreatment prostate specific antigen (p = 0.04) and MIB 1 score (p = 0.05) were statistically significant predictors of disease-free survival, and patients with a high MIB 1 score were 3.1 times as likely to have recurrence as those with a negative score. Controlling for stage, patients with organ confined disease and a high MIB 1 score had a lower 5-year disease-free survival rate (68 percent) than those with a low MIB 1 score (95 percent, p greater than 0.01).

Conclusions

Proliferative activity as measured by the Ki-67 proliferative antigen, MIB 1, appears to be a prognostic marker of recurrent prostate cancer after radical prostatectomy.     

EXPRESSION OF BCL-2 AND BCL-X IN BLADDER CANCER

Purpose

TP53 and RB1 gene mutations in bladder transitional cell carcinoma (TCC) are correlated with grade, stage, recurrence, and survival and may correlate with tumor cell apoptotic potential. Overexpression of the bcl-2 and bcl-X anti-apoptotic genes has been correlated with poor prognosis and chemotherapy resistance in other systems. Similar studies have not been performed in TCC. We thus sought to determine expression of bcl-2 and bcl-X in TCC and correlate these with stage, survival and abnormal pRb or p53 expression.

Materials and Methods

Forty-two TCC samples (19 Ta and 23 locally advanced tumors) and normal urothelial controls were examined. Immunohistochemistry for p53, pRb, bcl-2 and bcl-X was performed on an automated system using indirect streptavidin biotin/horseradish peroxidase staining. Western immunoblot analysis was performed on bladder cancer cell lines to further characterize bcl-X expression. Recurrence-free and disease-specific survival were retrospectively determined. Kaplan-Meier survival curves were compared using the log rank test, and correlation of abnormal staining with stage and p53 or pRb status was determined using Fisher's exact test.

Results

Bcl-2 was expressed in less than 1% of normal urothelial cells, but moderate expression of bcl-x was found in all normal urothelial samples. Only 7.0% of TCC samples (1/19 Ta and 2/23 locally advanced tumors) demonstrated bcl-2 overexpression. Bcl-X overexpression was observed in 45.2% of TCC (8/19 Ta and 11/23 locally advanced tumors). Western blot analysis also revealed that both the long (29 kDa) anti-apoptotic form and short (19 kDa) pro-apoptotic form were overexpressed in bladder cancer cell lines and normal human urothelial cells. Bcl-X overexpression was weakly correlated with normal p53 expression (p = 0.06). There were no correlations of bcl-2 and bcl-X overexpression with abnormal p53, pRb, or tumor stage. There were no differences in recurrence-free or overall survival in patients with abnormal bcl-X staining.

Conclusions

Bcl-2 overexpression is rare in TCC. Bcl-X overexpression is common, likely reflecting its expression pattern in normal urothelium, but is not correlated with stage or abnormal p53 or pRb staining. Within the power limitations of this small study, bcl-X overexpression is not correlated with recurrence or survival.     

Interleukin-2 Based Home Therapy of Metastatic Renal Cell Carcinoma: Risks and Benefits in 215 Consecutive Single Institution Patients

Purpose

In 215 consecutive patients with advanced metastatic renal cell carcinoma seen at a single institution the efficacy and tolerance of different subcutaneous recombinant interleukin-2 based home therapies were assessed.

Materials and Methods

Treatment consisted of subcutaneous recombinant interleukin-2 alone and subcutaneous recombinant interleukin-2 in combination with recombinant interferon-alpha 2 with or without intravenous 5-fluorouracil.

Results

Overall objective response rate in 215 patients was 33 percent (95 percent confidence interval 26 to 39 percent). Among 16 patients receiving recombinant interleukin-2 alone there was 1 partial remission (overall response 6 percent). In 79 patients receiving recombinant interleukin-2 and interferon-alpha 2 in combination 6 complete and 16 partial remissions occurred (overall response 28 percent). Of 120 patients receiving a combination of recombinant interleukin-2, recombinant interferon-alpha 2 and 5-fluorouracil 13 achieved a complete and 34 a partial remission (overall response 39 percent). Of all patients 5 percent achieved long-lasting remissions and remain disease-free. Multivariate analyses identified pretreatment erythrocyte sedimentation rate greater than 70 mm. per hour and lactic dehydrogenase greater than 280 units per 1. as independent prognostic factors of major significance (p less than or equal to 0.0001) in metastatic renal cell carcinoma. Additionally, neutrophil count greater than 6,000/microliter, hemoglobin less than 100 gm./l., extrapulmonary metastases and bone lesions were identified as minor (p less than or equal to 0.006) prognostic variables. Patients were assigned to 1 of 3 risk categories according to cumulative risk score defined as the function of the sum of all 6 independent variables. In 116 intermediate risk patients 2-year survival was 65 percent (median survival not reached after 32 months) with recombinant interleukin-2, recombinant interferon-alpha 2 and 5-fluorouracil, as opposed to 27 percent 2-year survival (median survival 15 months) with recombinant interleukin-2 and interferon-alpha 2 (p less than 0.0001), and 0 percent (median survival 4.8 months) with single agent recombinant interleukin-2. In the majority of patients systemic toxicity of subcutaneous recombinant interleukin-2 based protocols was limited to grade 1 or 2 constitutional symptoms, that is fever, chills, malaise and anorexia, which allowed for outpatient therapy.

Conclusions

The present outpatient recombinant interleukin-2 triple drug combination protocol was as effective as the most aggressive intravenous recombinant interleukin-2 regimen available. Combination home therapy eliminated the need for inpatient and/or intensive care as required for intravenous cytokine administration and, thereby, it substantially improved the therapeutic index and cost-effectiveness of recombinant interleukin-2 therapy in metastatic renal cell carcinoma stratified for risk.     

Primary Cisplatin, Methotrexate and Vinblastine Aiming at Bladder Preservation in Invasive Bladder Cancer: Multivariate Analysis on Prognostic Factors

Purpose

Although radical cystectomy is the standard therapy for invasive bladder cancer, cisplatin based multi-drug chemotherapy has proved to be effective for advanced transitional cell urothelial carcinoma. The potential for bladder preservation with neoadjuvant chemotherapy is currently under investigation.

Materials and Methods

A phase 2 protocol is presented for conservative treatment of muscle invasive transitional cell carcinoma of the bladder consisting of primary cisplatin, methotrexate and vinblastine chemotherapy followed by reevaluation for bladder sparing surgery and surveillance. A total of 61 patients completed the protocol with a mean followup of 41.4 months.

Results

Initial complete response to chemotherapy associated with tumor stage, size and configuration was noted in 20 patients (33 percent). Bladder preservation, intended only for the complete response group, was achieved in 16 patients (26 percent) but only 11 (18 percent) were alive with the bladder intact at study closure. Disease-free 5-year survival rate was 47 percent (95 percent confidence interval 65 to 26 percent). Tumor stage (p = 0.0007), size (p = 0.0003), response to chemotherapy (p = 0.002), patient age (p = 0.039) and tumor grade (p = 0.048) influenced survival. Multivariate analysis revealed response to chemotherapy (beta = 0.988, p = 0.034) and tumor size (beta = 0.978, p = 0.042) to be the only independent predictors.

Conclusions

Induction of cisplatin, methotrexate and vinblastine chemotherapy is helpful in identifying patients with a greater chance for survival among those with locally advanced bladder cancer. However, a bladder preservation strategy based on this therapy is only of limited success.     

p53 Immunohistochemical and Genetic Alterations are Associated at High Incidence with Post-Irradiated Locally Persistent Prostate Carcinoma

Purpose

Several reports have shown that cells with p53 mutations display increased resistance to ionizing radiation, a treatment often used clinically for localized prostate carcinoma.

Materials and Methods

Totals of 18 post-irradiated locally recurrent prostatic carcinoma specimens and 25 (no radiation) stage D1 node-positive (TxN+MO) primary prostatic carcinoma specimens were tested for p53 immunoreactivity by immunohistochemistry. Of the 18 post-radiation locally recurrent prostatic carcinomas 10 were further analyzed by single strand conformational polymorphism to assess the validity of using this immunohistochemistry approach in irradiated tissue for detecting p53 alterations. Specimens showing p53 alterations by single strand conformational polymorphism were subjected to nucleotide sequence analysis or tested for loss of heterozygosity at a locus within the p53 gene.

Results

Of the 25 stage TxN+MO prostatic carcinomas without radiation 5 (20 percent) were immunoreactive (consistent with the reported incidence of positive immunoreactivity in clinical/surgical stage TxN+MO primary prostatic carcinomas). In contrast, 13 of 18 post-radiation locally recurrent prostatic carcinoma specimens (72 percent) were immunoreactive. Multivariate logistic regression analysis showed no dependence of p53 immunoreactivity to grade, stage or androgen status in the post-radiation locally recurrent prostatic carcinoma group, while 8 of 10 hormone naive prostatic carcinoma specimens (80 percent) were immunoreactive. The temporal relationship between p53 alterations and radiotherapy was assessed. Pre-irradiation prostatic carcinomas available from 5 patients with immunoreactive post-radiation locally recurrent disease were analyzed and all were immunoreactive.

Conclusions

p53 Alteration in localized prostatic carcinoma is uncommon. Our study confirms others in that even aggressive locally advanced nonirradiated primaries (stage TxN+MO) contain only a 20 percent incidence of p53 alterations. However, our study demonstrates that p53 alterations are found in the preponderant majority of post-radiation locally recurrent prostatic carcinoma specimens. Limited evaluation of pretreatment prostatic carcinoma biopsies uniformly documented the presence of p53 alterations before ionizing radiation, thereby demonstrating that p53 alteration was already present and was not radiation-induced or only correlated with late stage disease. This finding suggests a potential for p53 immunoreactivity to be used as a pretreatment marker that might predict local treatment failure with ionizing radiation. Large scale prospective trials would appear warranted to evaluate conclusively the potential prognostic applicability of p53 pre-screening before enrollment in definitive radiotherapy.     

Prevalence and Clinical Significance of Her-2/neu, p53 and Rb Expression in Primary Superficial Bladder Cancer

Purpose

The usefulness of the expression of HER2/neu oncoprotein and of p53 and Rb suppressor gene product as predictors of tumor recurrence was evaluated by using a bank of prospectively collected primary papillary bladder tumors treated initially only by transurethral resection.

Materials and Methods

The expression of HER-2/neu oncoprotein and of p53 and Rb suppressor genes was evaluated by immunohistochemistry in 256, 265 and 74 specimens of primary Ta/T1 superficial bladder tumors obtained from patients enrolled in a prospective study from 1990 to 1992. Survival analysis was used to evaluate the association between time to first recurrence and expression of each marker, the follow-up period extending to March 1994. Immunostaining for p53 and HER-2/neu was performed on paraffin-embedded tissue and, for Rb, on frozen tissue only.

Results

Her-2/neu was expressed in 21 (8.2 percent) cases and p53 in 39 cases (14.7 percent); Rb expression was altered in 12 (16.2 percent). In this study, p53 expression was only related to earlier recurrence in a univariate analysis. Multivariate analysis, however, failed to recognize p53 expression as an independent predictor of recurrence.

Conclusions

Our study demonstrate the low prevalence of HER2/neu, p53 and altered Rb expression in superficial TCC at initial resection. Only p53 expression was significantly associated with an earlier first tumor recurrence, but this association was not independent of other prognostic factors.     

Post-Transplant Renal Artery Stenosis: Impact of Therapy on Long-Term Kidney Function and Blood Pressure Control

Purpose

We assessed the long-term outcome of different treatment methods for transplant renal artery stenosis.

Materials and Methods

Outcome data for 23 patients with transplant renal artery stenosis treated during a 16-year period were reviewed and analyzed.

Results

There was a higher incidence of renal artery stenosis in cadaveric donor kidneys compared to living donor kidneys (2 percent versus 0.3 percent, p less than 2), and in cadaveric kidneys from pediatric donors less than 5 years old compared to those from adults (13.2 percent versus 1.3 percent, p less than 0.01). Six patients underwent primary medical treatment for renal artery stenosis, with a successful outcome in 4 (mean followup plus or minus standard error 57 plus/minus 22 months) and failure in 2. Of the patients 16 were treated with percutaneous transluminal angioplasty, including 12 who were cured or improved with respect to hypertension (followup 44.7 plus/minus 7.6 months). Five patients underwent surgical revascularization for renal artery stenosis with postoperative improvement of hypertension (followup 18.8 plus/minus 11.6 months). Overall, 21 of 23 patients (91 percent) were treated successfully for transplant renal artery stenosis with cure or improvement of associated hypertension. Posttreatment renal function was stable or improved in 18 patients, while renal function deteriorated due to parenchymal disease in 3.

Conclusions

Most patients with transplant renal artery stenosis can be treated successfully. Percutaneous transluminal angioplasty is the initial interventive treatment of choice for high grade renal artery stenosis. Surgical revascularization is indicated if percutaneous transluminal angioplasty cannot be done or is unsuccessful.     

p53 Protein and Gene Alterations in Pathological Stage C Prostate Carcinoma

Purpose

We determined the extent of p53 immunoreactivity in pathological stage C prostate cancer as well as its correlation to tumor grade, substage, recurrence and proliferation rate. To define better the temporal relationship of p53 nuclear reactivity in prostate cancer p53 immunoreactivity was evaluated in all associated prostatic intraepithelial neoplasia lesions.

Materials and Methods

Using immunohistochemistry p53 status and proliferation rate were determined in 96 tumors from patients with pathological stage C prostate cancer. Single strand conformational polymorphism in exons 5 to 8 was used in a subset of specimens to assess the association of p53 nuclear accumulation with mutations in the p53 gene.

Results

p53 Nuclear reactivity was demonstrated in 10 tumors (10.4%), including 6 with high and 4 with low level nuclear reactivity. Of the tumors 86 (89.6%) had no evidence of p53 immunoreactivity. Each of the 6 tumors with high level p53 reactivity had associated areas of prostatic intraepithelial neoplasia that also showed p53 nuclear reactivity. Furthermore, pathological stage C substage (C1, 2 or 3) was significantly associated with p53 nuclear reactivity (p = 0.04). Proliferation rates were correlated with p53 nuclear reactivity (p = 0.09), while there was no association with tumor grade or recurrence. p53 Gene alterations were noted in 2 of the 3 p53 positive tumors versus no alterations in the p53 gene of 3 p53 negative tumors.

Conclusions

p53 Nuclear accumulation is uncommon in pathological stage C prostate cancer and its presence in premalignant prostatic intraepithelial neoplasia lesions suggests that it may be an early event in a subset of prostate cancers.     

Radiotherapy for High Grade Clinically Localized Adenocarcinoma of the Prostate

Purpose

We defined the efficacy of radiotherapy for the treatment of high grade (Gleason scores 8 to 10) adenocarcinoma of the prostate.

Materials and Methods

A total of 50 patients underwent radiotherapy with curative intent for clinically localized prostate cancer with Gleason scores of 8 to 10 at 1 of 4 facilities affiliated with the University of California San Francisco. Patients were considered to have biochemical failure if they had a significant increase in prostate specific antigen (PSA) of 0.5 ng./ml. per year, an increase in PSA to greater than 1.0 ng./ml. or a positive biopsy.

Results

Among the 50 patients median PSA was 22.7 ng./ml. (range 1.3 to 93.4). Tumors were clinical stage T1 or T2 in 46 percent of the cases and stage T3 or T4 in 54 percent. The overall actuarial probability of freedom from biochemical failure at 4 years was 23 percent. In a multivariate analysis including all patients pretreatment PSA was the only predictor of PSA failure, with 64 percent free of progression if the pretreatment PSA was 10 ng./ml. or less compared to only 16 percent at 3 years if PSA was more than 10 ng./ml. (p = 0.01). In a multivariate analysis restricted to patients with PSA less than 20 ng./ml. 83 percent of those treated to more than 71 Gy. were free of progression compared to 0 percent for those treated to less than 71 Gy. (p = 0.03). In a multivariate analysis PSA 10 ng./ml. or less (related risk 11.4, p = 0.02), T stage 1 or 2 (relative risk 3.8, p = 0.05) and radiation dose more than 71 Gy. (relative risk 4.0, p = 0.06) were associated with a favorable outcome.

Conclusions

At 4 years the freedom from PSA failure following radiotherapy for high grade prostate cancer was comparable to previously reported surgical series. The high failure rate among patients with PSA greater than 20 ng./ml. suggests that these patients should be considered for investigational approaches. The apparent improvement in freedom from progression with the use of higher doses provides reason for optimism.     

Retropharyngeal Parathyroid Glands: Important Differences

Introduction

In primary hyperparathyroidism (PHPT), parathyroid ectopia is seen in up to 22% leading to more difficult surgery. We aimed to determine the rate and characteristics of retropharyngeal (RP) parathyroid glands.

Methods

A prospective database was queried for patients with sporadic PHPT who had surgery from 1997 to 2016. The data of RP patients were compared to those who had surgery for sporadic PHPT over the same time period with hyperfunctioning parathyroids in anatomically normal positions (N).

Results

RP glands occurred in 47/3006 (1.6%) patients and were more common at reoperative than initial surgery (5.5 vs 1.4%, p < 0.01). RP patients had prior failed surgery more often than N patients (17 vs 3.1%, p < 0.01). Preoperative calcium levels (p = 0.06), PTH levels (p = 0.15), and mean gland weights (p = 0.07) were similar among groups. For RP glands, ultrasound imaging was negative in all but one patient, while 99mTc-sestamibi accurately indicated a posterior midline position in only 13/47 (28%) and was negative in 21%. All RP glands were anatomically superior. RP patients more often required > 1 post-resection intraoperative PTH level (36 vs 21%, p = 0.02). Failure due to persistent PHPT was more likely in RP patients (4.7 vs 2.1%, p = 0.2).

Conclusion

In PHPT, hyperfunctioning RP glands are seen in 1.6% of cases and often associated with initial failure (17%). At reoperation, RP ectopia is 4X more common. RP glands are associated with a high rate of negative imaging, but imaging results suggestive of a midline abnormality can guide exploration. The RP space should be evaluated prior to ending an otherwise unfruitful surgery.

     

Prostate specific antigen nadir following external beam radiation therapy for clinically localized prostate Cancer: The relationship between nadir level and disease-free survival

Purpose

We determined whether the prostate specific antigen (PSA) nadir achieved following external beam radiation therapy alone predicts biochemical disease-free survival in a large cohort of men with clinically localized prostate cancer.

Materials and Methods

Between January 1986 and October 1993, 364 men with clinically localized, stages T1 to T3 adenocarcinoma of the prostate received definitive external beam radiation therapy with no prior, concomitant or adjuvant endocrine therapy. PSA was measured before treatment in 326 men (90 percent) and serial PSA was measured following treatment in all patients. All men were followed continuously for at least 24 months (median 44 months, range 24 to 90, mean 46). Biochemical failure after irradiation was defined as PSA of 1.5 ng./ml. or more and 2 consecutive serum PSA elevations.

Results

The 5-year overall biochemical disease-free survival rate for the entire group was 56 percent. PSA nadir was predictive of subsequent biochemical disease-free survival. The biochemical disease-free survival rate at 3 years was 93, 49 and 16 percent for PSA nadirs of 0 to 0.99, 1 to 1.99 and 2 or more ng./ml., respectively (p = 0.0001). In a multivariate analysis PSA nadir (0 to 0.99 versus 1.0 to 1.99 versus 2 or more ng./ml.) was an independent predictor of biochemical disease-free survival along with pretreatment PSA, central axis dose, Gleason grade and T stage.

Conclusions

PSA nadir after radiation therapy is an indicator of subsequent biochemical disease-free survival. Patients who achieve a nadir of less than 1 ng./ml. following external beam radiation therapy have a favorable biochemical disease-free survival rate, while those with a nadir of greater than 1 ng./ml. have a high subsequent failure rate. Strategies to improve results should focus on techniques to increase the likelihood of achieving a PSA nadir of less than 1 ng./ml.     

Neoadjuvant chemohormonal therapy followed by robot-assisted and minimum incision endoscopic radical prostatectomy in patients with high-risk prostate cancer: comparison of perioperative and oncological outcomes at single institution

Purpose

Optimal management strategies for patients with high-risk prostate cancer (PCa) have not been established. This study aimed to estimate the impact of surgical procedures on perioperative and oncological outcomes in patients with high-risk PCa who received neoadjuvant chemohormonal therapy (CHT) prior to radical prostatectomy (RP).

Methods

In this retrospective study, we focused on patients with high-risk PCa who received neoadjuvant CHT followed by RP. The enrolled patients were divided into the following two groups according to surgical procedure: the robot-assisted RP (RARP) group and minimum incision endoscopic RP (MIE-RP) group. The primary endpoint was biochemical recurrence-free survival (BRFS).

Results

A total of 522 high-risk PCa patients were enrolled in this study. The median operating time was significantly shorter in the MIE-RP group than in the RARP group. The median estimated blood loss was significantly lower in the RARP group than in the MIE-RP group. The rates of positive surgical margins (PSMs) were not statistically significant in either group. During the follow-up period, biochemical recurrence (BCR) without clinical recurrence occurred in 60 (23.9%) patients in the MIE-RP group and 5 (1.8%) in the RARP group. The 5-year BRFS rate was 76.5% in the MIE-RP group and 97.6% in the RARP group (P?<?0.001). On multivariate analysis, RARP, PSM, pathological T stage, and initial prostate-specific antigen were significantly associated with BCR.

Conclusions

Neoadjuvant CHT with subsequent RARP may decrease the risk of BCR when compared to MIE-RP.

     

National trends and differences in morbidity among surgical approaches for radical prostatectomy in Germany

Objective

In this study, we document trends in radical prostatectomy (RP) employment in Germany during the period 2005–2012 and compare the morbidity of open (ORP), laparoscopic and robotic-assisted RP based on nationwide administrative data of Allgemeine Ortskrankenkassen (AOK) German local healthcare funds.

Materials and methods

Administrative claims data of all AOK patients subjected to RP during 2005–2012 (57,156 cases) were used to evaluate the employment of minimally invasive RP (MIRP) procedures, pelvic lymph node dissection (PLND) and nerve-sparing approaches during this period. In addition, data from the most recent three-year period of our dataset (2010–2012) were used to compare the morbidity among the different surgical approaches. Study end points comprised 30-day mortality, 30-day transfusion, 1-year reintervention and 30-day adverse events, as well as 1-year overall complications.

Results

A 20 % reduction in RP utilization from 2007 to 2012 was documented. ORP remained the predominant RP approach in Germany. MIRP approaches carried a lower risk of 30-day transfusions, 1-year reinterventions and 1-year overall complications than ORP when adjusting for confounding factors. PLND was associated with an increased risk of complications, while age in the highest quintile and the presence of comorbidities were independent risk factors for morbidity and mortality. Lack of pathological data was the main limitation of the study.

Conclusions

RP utilization in Germany is dropping, but the use of MIRP has risen steadily during the years 2005–2012, which is expected to have a positive impact on the morbidity of the operation.