Tobias Klatte

Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy.

The mammalian target of rapamycin (mTOR) pathway is up‐regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).

Immunosuppressive plasma cells impede T cell-dependent immunogenic chemotherapy

Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8+ cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IκB kinase α (IKKα)-BMI1 module in prostate cancer stem cells. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent that is effective in aggressive prostate cancer. We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.

Cytogenetic and Molecular Tumor Profiling for Type 1 and Type 2 Papillary Renal Cell Carcinoma

Purpose: The goal of this study was to evaluate immunohistochemical and cytogenetic features and their prognostic value in papillary renal cell carcinoma (PRCC) subtypes. Experimental Design: One hundred fifty-eight cases of PRCC were identified and reclassified by subtype. Tumoral expression of 29 molecular markers was determined by immunohistochemistry. Cytogenetic analyses were done on a prospective series of 65 patients. Associations with clinicopathologic information and disease-specific survival were assessed. Results: Fifty-one patients (32%) had type 1 and 107 (68%) type 2 PRCC. Type 2 patients had worse Eastern Cooperative Oncology Group performance status, higher T stages, nodal and distant metastases, higher grades, and a higher frequency of necrosis, collecting system invasion and sarcomatoid features. Type 2 showed greater expression of vascular endothelial growth factor (VEGF)-R2 in the tumor epithelium, and of VEGF-R3 in both tumor epithelium and endothelium. Loss of chromosome 1p, loss of 3p, and gain of 5q were exclusively observed in type 2, whereas type 1 more frequently had trisomy 17. Type 2 PRCC was associated with worse survival than type 1, but type was not retained as an independent prognostic factor. Lower PTEN, lower EpCAM, lower gelsolin, higher CAIX, and higher VEGF-R2 and VEGF-R3 expression, loss of 1p, 3p, or 9p, and absence trisomy 17 were all associated with poorer prognosis. Conclusions: Type 2 PRCC is associated with more aggressive clinicopathologic features and worse outcome. Molecular and chromosomal alterations can distinguish between PRCC subtypes and influence their prognosis. The effect of 3p loss on survival in PRCC is opposite to the relationship seen in clear cell RCC.

Hypoxia-Inducible Factor 1α in Clear Cell Renal Cell Carcinoma

Purpose: Hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1α in renal cell carcinoma (RCC). Experimental Design: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival. Results: HIF-1α expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1α was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1α was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1α expression predicted outcome in metastatic patients: patients with high HIF-1α expression (>35%) had significantly worse survival than patients with low expression (≤35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1α and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC. Conclusions: HIF-1α is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1α and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.

Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-κB-dependent mechanism

Constitutive nuclear factor-κB (NF-κB) activation is observed in androgen-independent prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. Here, we show that PE inhibited NF-κB and cell viability of prostate cancer cell lines in a dose-dependent fashion in vitro. Importantly, maximal PE-induced apoptosis was dependent on PE-mediated NF-κB blockade. In the LAPC4 xenograft model, PE delayed the emergence of LAPC4 androgen-independent xenografts in castrated mice through an inhibition of proliferation and induction of apoptosis. Moreover, the observed increase in NF-κB activity during the transition from androgen dependence to androgen independence in the LAPC4 xenograft model was abrogated by PE. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence that is driven in part by heightened NF-κB activity. [Mol Cancer Ther 2008;7(9):2662–71]

Laparoscopic Cryoablation Versus Partial Nephrectomy for the Treatment of Small Renal Masses: Systematic Review and Cumulative Analysis of Observational Studies

CONTEXT For small renal masses (SRMs), partial nephrectomy (PN) represents the therapeutic standard of care. Laparoscopic cryoablation (LCA) could be regarded as an alternative to surgical excision in selected patients, if perioperative complication rates and oncologic results are comparable. OBJECTIVE To perform a cumulative analysis of observational studies regarding oncologic outcomes and perioperative complications of both procedures. EVIDENCE ACQUISITION Medline, Embase, and Web of Science searches were performed for clinically localized sporadic SRMs that were treated with PN or LCA. A total of 6785 lesions were analyzed for local and metastatic tumor progression and 10 906 procedures for perioperative complications. EVIDENCE SYNTHESIS Patients undergoing LCA were significantly older, mean tumor sizes were lower, and mean follow-up duration was shorter (each p<0.001). Following LCA and PN, 8.5% and 1.9% developed local tumor progression, respectively (p<0.001). In multivariable analysis, the relative risk for local tumor progression of LCA versus PN was 5.24-fold increased (p<0.001); the risk of metastatic progression was similar. The overall complication rate was higher following PN (23.5% vs 17.0%; p<0.001), especially the rate of major complications (19.2% vs 10.2%; p<0.001). In multivariable analysis, the total risk for complications and major complications for PN versus LCA was 4.6-fold (p=0.004) and 9.71-fold (p<0.001) increased, respectively. Limitations of this analysis include follow-up and selection bias, and lack of standardization reporting complications and outcomes. CONCLUSIONS Both PN and LCA are viable options for the management of SRMs. Compared with PN, LCA results in a higher risk of local tumor progression. The risk of perioperative complications appears to be lower following LCA; however, this difference is strongly influenced by selection bias, and thus limited conclusions can be made regarding true differences in complications. Therefore, PN is the gold standard for SRMs, but LCA may be indicated in selected patients with significant comorbidity.

Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.

BACKGROUND Modern histopathology is able to differentiate chromophobe renal cell carcinomas (cRCCs), oncocytomas, and chromophobe-oncocytic hybrid RCCs; however, the true frequency and clinical courses of these tumors remain unclear. OBJECTIVE To determine the clinical course of hybrid RCC. DESIGN, SETTING, AND PARTICIPANTS Ninety-one surgically treated tumors, originally classified as oncocytoma or cRCC, were slide reviewed and reclassified by an experienced uropathologist. Immunohistochemical cytokeratin-7 (CK7) staining was used to distinguish oncocytoma (CK7 positive in <10% of the cells) and hybrid RCCs (CK7 positive in >10% of the cells). INTERVENTIONS Radical tumor nephrectomy or nephron-sparing surgery. MEASUREMENTS Recurrence-free and tumor-specific survival. RESULTS AND LIMITATIONS Overall, 16 tumors (17.6%) were hybrid RCCs, 32 tumors were cRCCs, and 43 tumors were pure oncocytomas. Perinephric tissue invasion (pT3a) was found in one pure oncocytoma and in two hybrid RCCs. The pathologic stage for cRCC was pT1 in 50% of tumors (n=17), pT2 in 23.5% of tumors (n=8), and pT3a in 26.5% of tumors (n=9). Low-grade RCC was found in 76.5% of tumors (n=26), and vascular invasion was found in 11.8% of tumors (n=4). After a mean follow-up of 50 mo, no oncocytomas or hybrid RCCs were found, but two cRCCs had recurred. The 3-yr tumor-specific survival rates for patients with oncocytoma, hybrid RCCs, and cRCC were 100%, 100%, and 97%, respectively. CONCLUSIONS Hybrid RCCs are more common than expected. The survival rate is 100% for both hybrid RCCs and oncocytomas. Hybrid RCCs may be candidates for active surveillance, and surgery may be unnecessary. CRCCs should be treated because a small proportion of these tumors exhibit aggressive clinical courses.

A Literature Review of Renal Surgical Anatomy and Surgical Strategies for Partial Nephrectomy

CONTEXT A detailed understanding of renal surgical anatomy is necessary to optimize preoperative planning and operative technique and provide a basis for improved outcomes. OBJECTIVE To evaluate the literature regarding pertinent surgical anatomy of the kidney and related structures, nephrometry scoring systems, and current surgical strategies for partial nephrectomy (PN). EVIDENCE ACQUISITION A literature review was conducted. EVIDENCE SYNTHESIS Surgical renal anatomy fundamentally impacts PN surgery. The renal artery divides into anterior and posterior divisions, from which approximately five segmental terminal arteries originate. The renal veins are not terminal. Variations in the vascular and lymphatic channels are common; thus, concurrent lymphadenectomy is not routinely indicated during PN for cT1 renal masses in the setting of clinically negative lymph nodes. Renal-protocol contrast-enhanced computed tomography or magnetic resonance imaging is used for standard imaging. Anatomy-based nephrometry scoring systems allow standardized academic reporting of tumor characteristics and predict PN outcomes (complications, remnant function, possibly histology). Anatomy-based novel surgical approaches may reduce ischemic time during PN; these include early unclamping, segmental clamping, tumor-specific clamping (zero ischemia), and unclamped PN. Cancer cure after PN relies on complete resection, which can be achieved by thin margins. Post-PN renal function is impacted by kidney quality, remnant quantity, and ischemia type and duration. CONCLUSIONS Surgical renal anatomy underpins imaging, nephrometry scoring systems, and vascular control techniques that reduce global renal ischemia and may impact post-PN function. A contemporary ideal PN excises the tumor with a thin negative margin, delicately secures the tumor bed to maximize vascularized remnant parenchyma, and minimizes global ischemia to the renal remnant with minimal complications. PATIENT SUMMARY In this report we review renal surgical anatomy. Renal mass imaging allows detailed delineation of the anatomy and vasculature and permits nephrometry scoring, and thus precise, patient-specific surgical planning. Novel off-clamp techniques have been developed that may lead to improved outcomes.

Fluorescence Cystoscopy with High-Resolution Optical Coherence Tomography Imaging as an Adjunct Reduces False-Positive Findings in the Diagnosis of Urothelial Carcinoma of the Bladder

BACKGROUND The advantage of photodynamic diagnosis in detecting urothelial cell carcinoma (UCC) of the bladder has been demonstrated clearly, but it comes at the price of a higher false-positive rate. Optical coherence tomography (OCT) is a noninvasive, real-time, microstructural imaging modality that uses near-infrared light for a point analysis of the bladder-wall microstructure. OBJECTIVE To evaluate whether adding targeted OCT analysis of lesions that are suspicious at white-light (WL) and hexaminolevulinate (HAL) fluorescence cystoscopy improves diagnostic accuracy in the detection of UCC. DESIGN, SETTING, AND PARTICIPANTS In this prospective single-center study with same-patient comparison, patients with suspected UCC first received an intravesical instillation of HAL. Cystoscopy was performed in WL, followed by blue-light inspection and OCT scanning. INTERVENTION Suspicious lesions identified by WL or HAL were evaluated by OCT and were subsequently resected or biopsied. MEASUREMENTS We measured changes in sensitivity and specificity in detecting UCC using WL, HAL, and targeted OCT. RESULTS AND LIMITATIONS In 66 patients studied, 232 lesions were detected, were scanned by OCT, and were subsequently resected or biopsied. Additionally, 132 areas of normal-appearing urothelium were investigated by all three methods and biopsied. On a per-lesion basis, sensitivity and specificity were respectively 69.3% and 83.7% for WL, 97.5% and 78.6% for HAL, and 97.5% and 97.9% for HAL combined with OCT. Overall, UCC was diagnosed in 58 patients (87.9%), with a per-patient sensitivity of 89.7% for WL and 100% for both HAL alone and HAL with targeted OCT. Per-patient specificity for HAL alone and targeted HAL was 62.5% and 87.5%, respectively. The limitation of OCT results from poor visualization of flat lesions in WL, making scanning a time-consuming procedure. CONCLUSIONS Combining fluorescence cystoscopy with targeted OCT increases the specificity of fluorescence cystoscopy significantly, with no added morbidity, and reduces the need for unnecessary (false-positive) biopsies.

Systematic Review and Meta-Analysis of Perioperative and Oncologic Outcomes of Laparoscopic Cryoablation Versus Laparoscopic Partial Nephrectomy for the Treatment of Small Renal Tumors

PURPOSE For the minimally invasive treatment of small renal tumors, laparoscopic cryoablation has emerged as an alternative procedure to minimally invasive partial nephrectomy (laparoscopic, robot-assisted laparoscopic) for selected patients, but there are still limited data regarding its safety and oncologic efficacy. We compare perioperative and oncologic outcomes of laparoscopic cryoablation and laparoscopic partial nephrectomy/robot-assisted laparoscopic partial nephrectomy. MATERIALS AND METHODS We searched the literature published until September 2013 from MEDLINE®, Web of Science® and major conference proceedings. We included studies comparing laparoscopic cryoablation and laparoscopic partial nephrectomy/robot-assisted laparoscopic partial nephrectomy if they reported oncologic or perioperative outcomes. RESULTS Overall 13 retrospective, nonrandomized, observational studies met our inclusion criteria. According to the modified NOS (Newcastle-Ottawa Scale) 7 studies (53%) were considered to be of higher quality. Compared with laparoscopic partial nephrectomy/robot-assisted laparoscopic partial nephrectomy, laparoscopic cryoablation was associated with significantly shorter operative times (weighted mean difference [WMD] 35.45 minutes), lower estimated blood loss (WMD 130.11 ml), shorter length of stay (WMD 1.22 days), and a lower risk of total (RR 1.82), urological (RR 1.99) and nonurological complications (RR 2.33). Patients undergoing laparoscopic cryoablation had a significantly increased risk of local (RR 9.39) and metastatic tumor progression (RR 4.68). CONCLUSIONS This analysis provides fair evidence that oncologic outcomes are substantially worse for laparoscopic cryoablation than for laparoscopic partial nephrectomy/robot-assisted laparoscopic partial nephrectomy, but laparoscopic cryoablation may be associated with improved perioperative outcomes. Therefore, surgical resection may be encouraged in the majority of cases. Balancing cancer control with the risk of perioperative complications is crucial for patient counseling and selection of the appropriate procedure. Prospective, randomized controlled studies with long-term followup are needed to confirm our findings.