Nicolette K Janzen

University of California, Los Angeles, Los Angeles, CA, United States

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Publications (15)43.86 Total impact

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    ABSTRACT: Carbonic anhydrase-IX (CA-IX) is a cell surface tumor-associated antigen expressed by most clear cell renal cell carcinomas (RCCs). The specificity and the prognostic value of CA-IX provide impetus to create a mouse model of CA-IX-expressing RCC for testing CA-IX-targeted therapies against RCC. A retrovirus encoding the human CA-IX gene was used to transduce the murine RCC line, RENCA. In vivo growth kinetics and CA-IX expression were compared between RENCA and RENCA/CA-IX using heterotopic, metastatic, and orthotopic models. Transduction of RENCA created the RENCA/CA-IX line with nearly 100% CA-IX surface expression. In the heterotopic model, subcutaneous injection of 500,000 and 50,000 cells led to tumor formation at 2 to 2.5 weeks after injection, with similar growth kinetics between the two cell lines at either cell number. In the pulmonary metastatic model, a similar number of metastases was noted after inoculation of RENCA and RENCA/CA-IX. In the orthotopic model, autopsy revealed a CA-IX-expressing renal tumor, as well as CA-IX-expressing metastases to the lungs, liver, contralateral kidney, intestines, and lymph nodes. In all the above models, the RENCA/CA-IX tumors retained expression of CA-IX, as demonstrated by immunohistochemistry staining. RENCA/CA-IX is the first tumor model that manifests in immunocompetent Balb/c mice and stably expresses a defined kidney cancer-associated antigen. It maintains antigen expression, forms metastases, and produces reliable tumor growth kinetics equivalent to that of its parental cell line.
    Urology 12/2006; 68(5):1132-8. · 2.42 Impact Factor
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    ABSTRACT: In a canine model, we evaluated the feasibility of nerve-sparing cryosurgery by active warming of the neurovascular bundle (NVB). Furthermore, our aim was to determine if NVB warming increases the risk of acinar gland and stromal-tissue preservation in adjacent areas of the prostate. The effects of a single versus double freeze-thaw cycle on prostate tissue were also assessed. Ten prostate lobes from five dogs were evaluated. Nine lobes from five dogs were treated with cryoablation using 17-gauge gas-driven cryoneedles. Seven lobes wre treated with active warming of the NVB using helium gas, and two lobes were treated without active warming. A single or double freeze-thaw cycle was utilized. Prostate tissue ablation and NVB preservation were evaluated in histologic sections. All seven prostate lobes treated with active warming demonstrated complete or partial NVB preservation. Four of these lobes had adjacent gland preservation. All lobes treated with a double freeze-thaw cycle showed complete and uniform ablation of prostate tissue. One of the three lobes treated with a single freeze-thaw cycle demonstrated incomplete ablation of the tissue. This is the first study investigating the feasibility of NVB preservation under controlled experimental conditions. In our canine model, NVB preservation with active warming was possible but not consistently reproducible. In some cases, NVB preservation with active warming may result in incomplete peripheral tissue ablation. A double, but not a single, freeze-thaw cycle induces complete and effective necrosis of prostatic tissue. These results have significant clinical applications when attempting nerve-sparing cryosurgical ablation of the prostate.
    Journal of Endourology 06/2005; 19(4):520-5. · 2.07 Impact Factor
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    ABSTRACT: Approximately 30% of renal cell carcinomas (RCCs) present as metastatic disease. Molecular markers have the potential to characterize accurately the biological behavior of tumors and they may be useful for determining prognosis. A custom tissue array was constructed using clear cell RCC from 150 patients with metastatic RCC who underwent nephrectomy prior to immunotherapy. The tissue array was stained for 8 molecular markers, namely Ki67, p53, gelsolin, carbonic anhydrase (CA)9, CA12, PTEN (phosphatase and tensin homologue deleted on chromosome 10), epithelial cell adhesion molecule and vimentin. Marker status and established clinical predictors of prognosis were considered when developing a prognostic model for disease specific survival. On univariate Cox regression analysis certain markers were statistically significant predictors of survival, namely CA9 (p <0.00001), p53 (p = 0.0072), gelsolin (p = 0.030), Ki67 (p = 0.036) and CA12 (p = 0.043). On multivariate Cox regression analysis that included all markers and clinical variables CA9 (p = 0.00002), PTEN (p <0.0001), vimentin (p = 0.0032), p53 (p = 0.028), T category (p = 0.0025) and performance status (p = 0.0013) were significant independent predictors of disease specific survival and they were used to construct a combined molecular and clinical prognostic model. The bias corrected concordance index (C-index) of this combined prognostic model was C = 0.68, which was significantly higher (p = 0.0033) than that of a multivariate clinical predictor model (C = 0.62) based on the UCLA Integrated Staging System (T category, histological grade and performance status). In patients with clear cell RCC a prognostic model for survival that includes molecular and clinical predictors is significantly more accurate than a standard clinical model using the combination of stage, histological grade and performance status.
    The Journal of Urology 05/2005; 173(5):1496-501. · 3.75 Impact Factor
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    ABSTRACT: Ablative techniques for the treatment of urological malignancy are gaining acceptance and they are likely to become more widely used in clinical practice. Indications and limitations of the technologies are still evolving. In a porcine model we evaluated the safety and efficacy of cryotherapy and radio frequency ablation (RFA) of cortical and deep renal tissue. In 11 swine argon gas based cryoablation or RFA of renal tissue adjacent to the collecting system was performed using a laparoscopic or percutaneous approach. Lesions created in renal units 30 days or 2 hours prior to harvest were termed chronic or acute. Using single or multiple 17 gauge cryoneedles or 3.0 mm cryoprobes and 2 freeze-thaw cycles (10-minute freeze and 5-minute thaw) 13 acute and 10 chronic cryolesions were made. Using a single 16 gauge umbrella-shaped RFA probe and 2 heating cycles to maximum impedance 13 acute and 4 chronic RFA lesions were made. Gross and microscopic tissue analysis was performed to assess lesion size and renal parenchymal, collecting system and arterial effects. Acute cryolesion size estimation by laparoscopic or transcutaneous ultrasound (US) was compared with pathological lesion size. Acute cryolesions on hematoxylin and eosin staining demonstrated uniform coagulative necrosis of renal parenchyma and chronic cryolesions demonstrated uniform necrosis with fibrous scar formation. Interlobar artery (adjacent to renal pyramid) preservation occurred in 7 of 13 acute and 5 of 9 chronic cryolesions. Urothelial architecture was preserved in 8 of 13 acute and 7 of 9 chronic cryolesions. Acute and chronic RFA lesions demonstrated indeterminate necrosis on hematoxylin and eosin staining, although triphenyl tetrazolium chloride staining of gross specimens confirmed necrosis most definitively in renal cortex. Interlobar artery preservation occurred in 6 of 13 acute and 3 of 4 chronic RFA lesions. Urothelial architecture was preserved in 1 of 13 acute and 2 of 4 chronic RFA lesions. Acute cryolesion dimensions measured by laparoscopic US equaled or underestimated lesion size measured grossly in all 6 cases. Lesion dimensions measured by transcutaneous US equaled or underestimated true lesion size in 3 of 6 cases. In 3 of 6 lesions transcutaneous US overestimated true lesion size by 20%, 76% and 260%, respectively. Renal cortical tissue can be effectively destroyed by cryoablation or RFA. However, treatment of deep parenchymal lesions with either modality may result in incomplete ablation. Cryosurgery but not RFA spares the collecting system in an acute setting. However, healing or regrowth of the urothelium may occur with time after RFA. Laparoscopic US is more accurate for cryolesion monitoring than transcutaneous US.
    The Journal of Urology 05/2005; 173(4):1368-74. · 3.75 Impact Factor
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    ABSTRACT: An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS). A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system. The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (C-index) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P < 0.05) than that of prognostic models based on grade alone (C = 0.65), TNM stage alone (C = 0.73), or the University of California Los Angeles integrated staging system (C = 0.76). Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.
    Clinical Cancer Research 09/2004; 10(16):5464-71. · 7.84 Impact Factor
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    ABSTRACT: Carbonic anhydrase 9 (CA9) is the most promising molecular marker described for renal cell carcinoma (RCC) to date. We investigated whether transduction of monocytes from peripheral blood with adenovirus encoding the CA9 gene (AdV-CA9) could stimulate a T-cell mediated immune response against cancer cells expressing CA9. The ability to consistently generate a T-cell response is an important step toward the development of a CA9-specific RCC vaccine. AdV-CA9 was generated using the AdEasy system. AdV-CA9-transduced peripheral blood mononuclear cell (PBMC)-derived monocytes were used to raise CTLs from autologous peripheral blood lymphocytes (PBLs). The ability of CTLs to lyse targets expressing CA9 was assessed by (51)Cr-release. Monocytes were efficiently transduced with AdV-CA9. In five of six experiments, AdV-CA9-transduced monocytes were able to induce a population of CTLs from bulk PBLs. CTLs were capable of lysing autologous, but not allogeneic monocytes expressing CA9. Furthermore, CTLs were able to lyse autologous RCC tumor cells expressing CA9. The ability of CTLs to lyse relevant targets was blocked by anti-CD3, anti-CD8, and anti-MHC class I antibodies demonstrating a MHC class I restricted response. These results suggest that PBMC-derived monocytes transduced with AdV-CA9 can generate RCC-specific MHC class I restricted CTLs capable of lysing CA9-expressing cancer cells. Transduction of PBMC-derived monocytes with adenovirus provides a simple and effective alternative to the use of dendritic cells for the induction of antigen-specific CTL.
    Clinical Cancer Research 03/2004; 10(4):1421-9. · 7.84 Impact Factor
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    ABSTRACT: The purpose of the study was to evaluate unilocular and multilocular cystic renal cell carcinoma (cRCC). These tumors are a rare entity, comprising approximately 1 to 2% of all renal tumors, and their true biologic behavior is not well-known. Initial review of renal cell carcinoma (RCC) cases treated at our institution between 1989 and 2001 identified 39 cases of cRCC. However, histopathologic review of these cases by 2 pathologists revealed that only 18 cases met the criteria that all tumors have a cystic component that constitutes at least 75% of the total lesion without evidence of necrosis. These cases were compared to 614 conventional clear cell RCC cases with regards to clinical outcomes. All 18 patients presented with localized (N0M0) disease. Thirteen (72%) of the tumors were Fuhrman Grade 1, while the remaining 5 (28%) were Fuhrman Grade 2. By comparison, only 60% of the clear cell RCC tumors were Grade 1 or 2. Similarly, 83% of cRCC were pT1 tumors compared to only 35% of conventional clear cell tumors. Mean tumor size for the cRCC tumors was 4.9 cm compared to 7.4 cm for conventional clear cell tumors. Cystic RCC patients had an 82% four-year disease-specific survival (DSS). Unilocular and multilocular cRCC is a distinct subtype of clear cell RCC. Its biology appears to be more favorable with regards to important prognostic factors such as metastatic presentation, Fuhrman grade, 1997 T stage, and tumor size. These findings suggest that cRCC patients may benefit from nephron sparing surgery.
    Urologic Oncology 01/2004; 22(5):410-4. · 3.65 Impact Factor
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    ABSTRACT: Outcome prediction for patients with renal cell carcinoma is based on a combination of factors. In this study a previously published clinical outcome algorithm based on 1997 T stage, Fuhrman grade and performance score is validated using an international database. A total of 1,060 patients from Nijmegen, the Netherlands (NN), MD Anderson (MDA) and University of California, Los Angeles (UCLA) who had localized renal cell carcinoma were evaluated for outcome prediction using a clinical outcome algorithm previously shown to stratify patients into low, intermediate and high risk groups. Validation was performed by comparing the 3 risk groups separately within the 3 centers as well as by comparing hazard ratios and concordance indices among the 3 centers. Estimated disease specific survival rates at 5 years for the low risk groups were 94% (NN), 92% (MDA) and 93% (UCLA). The 5-year disease specific survival rates for the intermediate risk groups were 65% (NN), 73% (MDA) and 78% (UCLA), while the rates for the high risk groups were 40% (NN), 30% (MDA) and 48% (UCLA). The concordance indices for each of the databases were 79% (NN), 86% (MDA) and 84% (UCLA). A clinical algorithm that uses only 3 prognostic variables (1997 T stage, Fuhrman grade and performance status) to stratify patients with localized renal cell carcinoma into 3 risk groups has been shown to be applicable to external databases. This algorithm may be useful for patient counseling, surveillance and identification of high risk patients for enrollment in clinical trials.
    The Journal of Urology 01/2004; 170(6 Pt 1):2221-4. · 3.75 Impact Factor
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    ABSTRACT: Surveillance after surgery for RCC is important because approximately 50% of these patients will develop a disease recurrence, two thirds of who will recur within the first year. Although the prognosis is generally poor in these patients, some may respond favorably to immunotherapy. The small subset of patients who develop solitary metastases has the greatest chance to achieve long-term survival. Aggressive surgical resection is an integral part of this success. Proposed surveillance protocols using a stage-based approach or an integrated approach combining stage with other important prognostic factors attempt to provide a rational approach to identifying treatable recurrences while minimizing unnecessary examinations and patient anxiety. However, strict adherence to follow-up guidelines may not be appropriate for all patients. Factors including patient comorbidities and patient willingness to pursue aggressive management in the event of recurrence may alter the follow-up for each individual.
    Urologic Clinics of North America 12/2003; 30(4):843-52. · 1.39 Impact Factor
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    ABSTRACT: PurposeUpper pole tumors with direct extension into the adrenal gland are currently staged as pT3a tumors in the 1997 TNM staging system. To determine whether the clinical behavior of pT3a adrenal tumors differs from that of tumors with perinephric fat invasion (also stage pT3a) a retrospective analysis was performed.Materials and MethodsOf 1,087 patients who underwent nephrectomy 27 were identified with direct adrenal involvement and 187 were identified with perinephric fat or renal sinus involvement. Variables and outcomes analyzed in each group included the percent of patients with metastatic disease at presentation, lymph node involvement, Eastern Cooperative Oncology Group score, response to immunotherapy, and median and overall survival using Kaplan-Meier curves.ResultsMedian survival for patients with pT3a disease and perinephric or renal sinus fat involvement was 36 months with a 36% 5-year cancer specific survival rate. In contrast, patients with adrenal gland invasion had significantly worse survival at a median of 12.5 months and a 0% 5-year cancer specific survival rate (p <0.001), which was similar to median survival of those with stage pT4 disease (11 months).ConclusionsUpper pole tumors with direct extension into the adrenal gland predict significantly worse survival than similarly staged tumors with fat invasion and they have a prognosis similar to that of stage pT4 disease. While these data await external validation, consideration should be given to re-categorizing tumors with direct adrenal gland involvement as stage pT4 or in a subcategory such as pT4a.
    The Journal of Urology 04/2003; · 3.75 Impact Factor
  • Nicolette K Janzen, Kent T Perry, Peter G Schulam
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    ABSTRACT: Radical nephrectomy has long been the gold standard for the management of renal tumors since Robson and colleagues reported increased survival in that group as compared to those who underwent simple nephrectomy1.Over the last decade, however, the surgical management of renal tumors has changed with emergence of laparoscopy as an alternative to open surgery. The short-term benefits of laparoscopic radical nephrectomy (LRN) in the form of reduced morbidity were clearly established soon after its inception. However, the long-term benefits and particularly the oncological efficacy of LRN were not established until very recently. Mature data from several groups provide evidence that LRN appears to have equivalent oncological efficacy to open radical nephrectomy, establishing it as a new standard of care in select cases.
    Cancer treatment and research 02/2003; 116:99-117.
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    ABSTRACT: Advances in imaging technologies have readily been incorporated into the practice of urology and have led to important advances in patient care and outcomes. In the area of oncology, advances in radiologic imaging are improving the ability of the urologist to diagnose and monitor urologic malignancies. Some of these technologies include positron emission tomography (PET), intraoperative ultrasound (IUS), 3-dimensional computerized tomography (3D-CT), and magnetic resonance spectroscopy (MRS). We provide an overview of these four emerging imaging modalities and their potential applications and limitations in the diagnosis and management of urologic malignancy.
    Urologic Oncology 01/2003; 21(5):317-26. · 3.65 Impact Factor
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    ABSTRACT: Ablative techniques for the treatment of renal cell carcinoma (RCC) are an extension of nephron-sparing surgery and include cryoablation, radiofrequency ablation (RFA), and high-intensity focused ultrasound (HIFU). Although experimental, these are evolving treatment modalities. The widespread use of computed tomography scans, ultrasound, and magnetic resonance imaging caused an increase in the diagnosis rate of small renal masses amenable to nephron-sparing surgery. The same imaging modalities permit interactive monitoring both during the delivery of ablative measures and at postoperative follow-up. Cryosurgery is the most studied of the ablative approaches, and clinical studies have demonstrated promising short-term results and a remarkable safety profile. Long-term studies, however, are needed in order to determine the appropriate selection criteria and to confirm a response as durable as that for partial and radical nephrectomy. More data are needed to evaluate the efficacy of RFA. Currently, preclinical results with HIFU do not justify its use for treating RCC in humans.
    Current Urology Reports 03/2002; 3(1):13-20.
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    ABSTRACT: Widespread use of computed tomography, ultrasound, and magnetic resonance imaging has led to an increase in detection of relatively small renal masses, and approaches to managing them have evolved in the last two decades. Indications for nephron-sparing surgery have expanded, and minimally invasive procedures, which can confer advantages over open surgery, are now available. Ablative techniques offer a combination of nephron-sparing and minimally invasive approaches. Ablative techniques include cryoablation, radiofrequency ablation (RFA), and high-intensity focused ultrasound (HIFU). Cryoablation and RFA have been relatively safe. HIFU has been associated with serious side effects in animal models, and is not yet acceptable for use in humans. Ablative techniques require long-term studies to confirm lasting efficacy. The best modality for tumor targeting, monitoring of therapy, and follow-up is still under investigation. Debate exists regarding the best method for ensuring adequate intraoperative tumor cryoablation. For minimally invasive ablative measures to gain a place as nephron-sparing approaches, they should show both equivalent efficacy and reduced morbidity relative to those of open partial nephrectomy. These techniques should currently be reserved for selected patients and should be compared to the evolving modality of laparoscopic partial nephrectomy.
    Reviews in urology 02/2002; 4(3):103-11.