Metastatic renal cell carcinoma to the brain: optimizing patient selection for gamma knife radiosurgery.

INTRODUCTION: The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. METHODS AND MATERIALS: Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n = 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). RESULTS: One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. CONCLUSIONS: We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.

Adaptive radiosurgery based on two simultaneous dose prescriptions in the management of large renal cell carcinoma brain metastases in critical areas: Towards customization.

BACKGROUND: The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario. CASE DESCRIPTION: A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (<1 cc) in the left temporal lobe (Met 3). Met 2 and Met 3 underwent RRR and SF-GKRS, respectively. RESULTS: Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR. CONCLUSION: Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.

Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-2014.

BACKGROUND AND PURPOSE: Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA). MATERIAL AND METHODS: mRCC patients (n = 117) treated with SRT (n = 57), SM (n = 30) or both modalities sequentially (n = 30) at two oncological centres in Sweden in 2005-2014 were retrospectively included. Median follow-up (mFU) was 63 months. RESULTS: A majority had clear cell histology, 1-3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6-5.2; p < 0.001), intracranial targets (HR 1.8; CI 1.1-3.2; p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2-0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients (n = 60) were relapse-free with mFU of 87 months. CONCLUSIONS: OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

An expression signature at diagnosis to estimate prostate cancer patients' overall survival.

BACKGROUND: This study aimed to identify biomarkers for estimating the overall and prostate cancer (PCa)-specific survival in PCa patients at diagnosis. METHODS: To explore the importance of embryonic stem cell (ESC) gene signatures, we identified 641 ESC gene predictors (ESCGPs) using published microarray data sets. ESCGPs were selected in a stepwise manner, and were combined with reported genes. Selected genes were analyzed by multiplex quantitative polymerase chain reaction using prostate fine-needle aspiration samples taken at diagnosis from a Swedish cohort of 189 PCa patients diagnosed between 1986 and 2001. Of these patients, there was overall and PCa-specific survival data available for 97.9%, and 77.9% were primarily treated by hormone therapy only. Univariate and multivariate Cox proportional hazard ratios and Kaplan-Meier plots were used for the survival analysis, and a k-nearest neighbor (kNN) algorithm for estimating overall survival. RESULTS: An expression signature of VGLL3, IGFBP3 and F3 was shown sufficient to categorize the patients into high-, intermediate- and low-risk subtypes. The median overall survival times of the subtypes were 3.23, 4.00 and 9.85 years, respectively. The difference corresponded to hazard ratios of 5.86 (95% confidence interval (CI): 2.91-11.78, P<0.001) for the high-risk subtype and 3.45 (95% CI: 1.79-6.66, P<0.001) for the intermediate-risk compared with the low-risk subtype. The kNN models that included the gene expression signature outperformed the one designed on clinical parameters alone. CONCLUSIONS: The expression signature can potentially be used to estimate overall survival time. When validated in future studies, it could be integrated in the routine clinical diagnostic and prognostic procedure of PCa for an optimal treatment decision based on the estimated survival benefit.

Treatment and overall survival in renal cell carcinoma: a Swedish population-based study (2000-2008).

BACKGROUND: This retrospective register study assessed overall survival (OS) and influential factors on OS in Swedish renal cell carcinoma (RCC) patients. METHODS: Using three merged national health registers, Cox proportional-hazards analysis was conducted and, in three models, it was used to assess the impact of cytokine (interferon-α and tyrosine kinase inhibitor (TKI; sunitinib or sorafenib) treatment on OS in metastatic (m)RCC. RESULTS: From 2000 to 2008, 8009 patients were diagnosed with RCC and 2753 with mRCC (2002-2008). Median OS in RCC patients diagnosed from 2006 to 2008 compared with 2000-2005 was not reached vs 47.9 months (P<0.001), and in mRCC patients diagnosed from 2006 to 2008 compared with 2002-2005, was 12.4 vs 9.6 months, respectively (P=0.004). Factors associated with significantly improved OS in RCC were female gender, lower age, and previous nephrectomy, and, in mRCC female gender, previous nephrectomy, and any TKI prescription (Model 1: median-adjusted OS, 19.4 months (TKI patients) vs 9.7 months (non-TKI patients); hazard ratio, 0.621; P<0.001). CONCLUSION: OS was improved in Swedish patients diagnosed with RCC and mRCC in the period 2006-2008 compared with 2000-2005 (RCC) and 2002-2005 (mRCC). Although multifactorial in origin, results suggest that increased nephrectomy rates and the use of TKIs contributed to the improvement seen in mRCC patients.

Autoantibodies against the tumour-associated antigen GA733-2 in patients with colorectal carcinoma.

The tumour-associated antigen (TAA) GA733-2 is expressed as a non-secreted surface molecule on the majority of human colorectal carcinoma cells. The antigen has been used as a target for passive and active immunotherapy during the last decade. To determine the incidence of autoantibodies against this antigen, sera from 1068 patients with colorectal carcinoma were analysed for naturally occurring IgG antibodies against the baculovirus-produced GA733-2E protein. A total of 14.5% of the patients had IgG antibodies against the antigen. In 519 patients, sera were collected at the time of diagnosis and 15% of those patients had anti-GA733-2E IgG antibodies. There was a tendency to a higher frequency of patients with antibodies among those in the advanced Dukes stages: 11% in stage A and 32% in stage D respectively (P = 0.06). Antibodies could be detected for up to 10 years after the diagnosis. Patients with Crohn's disease or colitis ulcerosa (n = 20) did not elicit anti-GA733-2E antibodies. No healthy control donor (n = 45) had detectable antibodies against the antigen. The specificity of GA733-2E-reactive serum IgG was indicated by significant inhibition of mAb17-1A (originally used to define GA733-2) binding to the GA733-2E antigen. Sera of positive patients bound to the GA733-2-expressing human colorectal carcinoma cell line, SW948. No significant correlation was found between the presence of antibodies and survival in the present patient population. However, the high incidence of autoantibodies against this tumour antigen in colorectal carcinoma patients confirms its antigenicity in humans and supports the use of the GA733-2 antigen as a target for immunotherapy.

T-cell-epitope mapping of the idiotypic monoclonal IgG heavy and light chains in multiple myeloma.

The idiotypic structures of the myeloma protein might be regarded as tumor-specific antigens. The present study was designed to map T-cell epitopes of the idiotypic myeloma protein to prove the existence of naturally occurring major-histocompatibility-complex-dependent idiotype (peptide)-specific T cells in multiple myeloma. The fine specificity of idiotype-reactive, interferon-gamma-producing blood T cells of a patient with multiple myeloma stage I was characterized by identification of idiotype (heavy and light chains)-derived MHC-restricted T-cell epitopes. T cells specifically reacting with peptides corresponding to each of the 3 complementarity-determining regions (CDRs) of the heavy-chain variable part (V(H)) of the autologous idiotype were found. In contrast, none of the peptides corresponding to the 3 CDRs of the light chain (V(L)) induced a specific T-cell response. The idiotype amino-acid sequence corresponding to the junction of the V(H), diversity (D), and joining (J) gene segments of the VH appeared to be an important target for T cells, since the sequence expressed MHC-class-I- as well as MHC-class-II-restricted epitopes. The study provides further support for the existence of MHC-restricted idiotype-specific T cells, which may target immunogenic CDR peptides in multiple myeloma. Such T cells could be an important part of the specific anti-tumor immune responses induced in idiotype vaccination protocols.

Clonal CD8+ and CD52- T cells are induced in responding B cell lymphoma patients treated with Campath-1H (anti-CD52).

Five patients with non-Hodgkin's lymphoma (NHL) and 4 patients with chronic lymphocytic leukaemia (CLL) were treated with the CDR-grafted (rat x human) monoclonal antibody (mAb) Campath-1H (anti-CD52). Tumour regression was noted preferentially in peripheral blood and in the bone marrow but lymph nodes were less affected. Normal blood B and T cells were profoundly reduced in all patients whereas CD16+ NK cells and CD14+ monocytes decreased marginally. In all responding CLL patients CD52-negative T but not B cells appeared during treatment and persisted for several months (4-19+) during unmaintained follow-up. Clonal T cells defined as a predominance of a single T cell receptor (TCR) V gene usage, in one case verified by TCR CDR3 fragment analysis and nucleotide sequencing, emerged within the CD52-/CD8+ cell population during Campath-1H therapy in 2 CLL patients, both achieving a long-lasting remission. The increase in CD8+ T cell expansions (up to 23-fold) during unmaintained remission and follow-up suggest that the clonal CD8+ cells may represent regulatory T cells controlling the growth of the tumour B cell clone. Clonal T cells might thus be a target for an immune therapeutic intervention in B cell tumours.

Serum levels of CA 19-9 and CA 50 in relation to Lewis blood cell status in patients with malignant and benign pancreatic disease.

Serum expression of the cancer-associated antigens CA 19-9 and CA 50 and their relation to Lewis blood cell status were studied in 26 patients with pancreatic duct carcinoma and 26 patients with pancreatitis. The discriminating capacity between benign and malignant disease was high for both tumor markers. The correspondence between serum levels of CA 19-9 and CA 50 was close irrespective of the Lewis phenotype of the patient. All cancer patients with normal levels of CA 19-9 and CA 50 were of the phenotype Le(a-b-). Knowledge of the Lewis phenotype may therefore add vital information when tumor marker assays are used for diagnosis and monitoring of malignant pancreatic disease.

Clinical relevance of tumour markers CA 19-9 and CA-50 in sera from patients with pancreatic duct carcinoma.

Serum levels of the tumour antigens CA 19-9 and CA-50 and their relation to the extent of the disease were studied in 97 patients with carcinoma of the pancreas. Of 13 patients with normal serum concentrations of CA 19-9, 11 (84.6%) had irresectable disease, whereas 87.5% of the patients with resectable disease expressed antigen levels above cut-off. Following attempted radical surgery, preoperatively elevated serum levels decreased in eight patients (50%). Unchanged and high levels were associated with residual disease and early death. Clinical signs of recurrence were preceded by elevated serum levels of both tumour antigens.

Identification and characterization of alkaline phosphatase isozymes in human colorectal adenocarcinomas.

Using alkaline phosphatase isozyme-specific immunocatalytical assays, the content of isozymes was determined in normal mucosas and adenocarcinomas from human colon or rectum. Tumor levels of both the tissue (liver)-unspecific and the placental-like alkaline phosphatase (PLAP-like) were elevated compared to normal mucosas of the same patients. Such elevations have been reported previously, particularly in seminomas and ovarian tumors. In several tumors, moreover, the intestinal isozyme was expressed in lesser amounts than in the adjacent mucosa. The present results indicate that the activation of two of the phosphatase isozymes, including expression of the typical germ cell line phosphatase (the PLAP-like isozyme), may occur even in nongonadal tumors. This may reflect an induction pattern of phosphatase isozymes, with implications for malignant transformation also in other tumors.

Search for epitopic sites of antibodies to germ cell alkaline phosphatase.

This study comprises a search for epitopic sites of the germ cell alkaline phosphatase by the use of polyclonal and monoclonal antibodies. The aim of this study was to define epitopes of the germ cell alkaline phosphatase molecule by synthetic peptides representing the known sequence of the molecule. The amino acid sequences of the epitopes to which antisera react were not known. We used overlapping peptides covering the whole 532 amino acid germ cell alkaline phosphatase molecule, including the signal 19 amino acid peptide. A polyclonal, and three monoclonal, antibodies known to react equally well with placental alkaline phosphatase isozyme (PLAP), but which differ in their reactivities with the germ cell alkaline phosphatase isozyme, were used. We have revealed potential epitopic sites of the germ cell alkaline phosphatase molecule using first polyclonal anti-PLAP, followed by monoclonal antibodies for the mapping. We could also show that the antibodies exhibited higher reactivities with such sites if they were combined in a linear synthesis. This indicates that the germ cell alkaline phosphatase molecule has discontinuous epitopes.

Tumor-associated antigens common to humans and chemically induced colonic tumors of the rat.

The expression of human tumor-associated antigens CO17-1A, GA73-3, BR55-2, GICA 19-9, and CA50 and of carcinoembryonic antigen was immunohistochemically studied in the colonic mucosa of 70 Sprague-Dawley rats. Fifty were treated with 1,2-dimethylhydrazine (DMH) (with EDTA as a vehicle), ten were treated with EDTA only, and ten were untreated normal rats. The tumors were histogenetically divided as: (a) adenocarcinomas arising from villous adenomas; (b) adenocarcinomas arising from lymphoid-associated mucosa (LAM); and (c) adenocarcinomas arising in flat mucosa. Of 44 colonic adenocarcinomas, BR55-2 was expressed in 41 tumors, CO17-1A in 40 tumors, GA73-3 in 38 tumors, and GICA 19-9 in 38 tumors. CA50 and carcinoembryonic antigen were not expressed in the tumors. The highest antigenic expression (number of cells) was observed in adenocarcinomas arising in villous adenomas and the lowest in those arising in flat mucosa. Adenocarcinomas arising in LAM had an intermediate expression. The expression of these antigens had no correlation to the localization of the tumor and to the differentiation. The expression of these antigens was similar in the non-lymphoid-associated normal colonic mucosa of the untreated, EDTA-treated, and DMH-treated rats. In DMH-treated rats, LAM demonstrated increased expression (number of cells) and increased staining intensity of these tumor-associated antigens. In six of the 50 DMH-treated rats, only LAM expressed carcinoembryonic antigen. CA50 was not expressed in the normal colon of untreated, of EDTA-treated, and of DMH-treated rats, nor was it in DMH-induced tumors. None of the tumor-associated antigens (GICA 19-9 and CA50 and carcinoembryonic antigen) was detected in serum. It is concluded that this animal model would be of value in the preclinical evaluations of monoclonal antibodies for therapy in humans.

Significance of alkaline phosphatase isozymes in the monitoring of patients with colorectal carcinoma.

The clinical course of colorectal carcinoma may be monitored by tumor markers such as carcinoembryonic antigen (CEA), carcinoma antigen (CA) 19-9 and CA-50. Alkaline phosphatase isozymes were previously used to study the clinical course of testicular and gynecologic tumors. In this study we investigated 8 patients with advanced colorectal carcinoma. Their sera were analyzed for the tumor markers CEA, CA 19-9, CA-50 and three alkaline phosphatase isozymes: the nonspecific liver isozyme LAP, the intestinal isozyme IAP and the placental isozyme PLAP. Rising levels of CEA, CA 19-9 and CA-50 were seen as expected, and PLAP also showed rising levels during tumor progression. LAP remained elevated. This indicates an association between progression of colorectal carcinoma and a raised serum content of alkaline phosphatase isozymes.

Clinical effects of monoclonal antibodies (MAb 17-1A) in patients with metastatic colorectal carcinomas.

Ten patients with metastatic colorectal carcinoma were treated with MAb 17-1A (IgG2A). Before infusion, MAb was incubated in vitro with isolated autologous blood mononuclear cells. Treatment was given in repeated courses (2-4 times) to a maximum dose of 1000 mg of MAb 17-1A. One patient achieved a clinical complete remission, two patients had a minor response and one patient had stable disease for 5 months. The median survival for the four responders was 19 months compared to 7 months for the six non-responders. Therapy was well tolerated. In this series, 32 infusions of MAb 17-1A were given. The serum half-life of MAb 17-1A was approximately 22 hours. All patients developed anti-mouse antibodies of both IgG and IgM classes. No relation between adverse reactions and anti-mouse antibodies was seen. At 3 occasions allergic reactions were noted. Skin test with MAb 17-1A seems to reliably predict for allergic reactions.

Tumor markers carbohydrate antigens CA 19-9 and CA-50 and carcinoembryonic antigen in pancreatic cancer and benign diseases of the pancreatobiliary tract.

Sera from patients with diseases in the pancreas, gallbladder, and bile duct were analyzed for the tumor markers CA 19-9, CA-50, and carcinoembryonic antigen. In particular CA 19-9 and CA-50 appear to be valuable in differentiating malignant from benign disease in these organs. Our sample of 72 patients with pancreatic cancer also indicates that CA 19-9 and CA-50 complement each other in 21% of the cases. They are also shown to be reliable for monitoring disease: following radical surgery for pancreatic cancer low levels of CA 19-9 and CA-50 were noted, while progressive rises of these tumor markers were related to disease progression.

Polyclonal and monoclonal anti-CEA antibodies in immunolocalization of colorectal cancer.

Antibodies to carcinoembryonic antigen (CEA) from sheep and monkey were immunoadsorbent purified. Mouse monoclonal antibody (MAb) anti-CEA I-38S1 and Fab fragments of this antibody were prepared from mouse ascitic fluid. The IgG preparations were labelled with 123I or 131I, the Fab fragments with 131I. The antibody reactivity was unchanged after labelling. Patients with advanced colorectal carcinomas received an intravenous injection of 50-200 MBq 123I or 30-160 MBq 131I coupled to 250-500 micrograms antibody or antibody fragment. Patient examinations were performed using emission tomography (SPECT) and/or conventional gamma camera scintigraphy. The specific localization of labelled anti-CEA to tumor was compared to known tumor localized by CAT-scan, other x-ray methods or laparotomy, 50% of known tumors were accurately localized with sheep anti-CEA. In contrast, 70-80% of known tumor sites were correctly localized with polyclonal monkey anti-CEA antibodies, with monoclonal anti-CEA antibodies or with Fab fragments of the latter. A few previously unknown tumors were detected.

Improved radioimmunolocalization of carcinomas using Fab fragments with anti-CEA specificity.

A model system with human colonic grafts containing carcinoembryonic antigen (CEA) in nude mice was used to improve specificity and sensitivity of the radioimmunolocalization method. Monoclonal antibody MAb I-38S1 and monkey anti-CEA appeared to have high in vitro and in vivo specificity. Fab fragments of MAb I-38S1 improved localization ratios. A reduced time for optimal immunolocalization was obtained with Fab compared with MAb of the same specificity. Combinations of Fab:s, vasoactive compounds or anti-IgG treatment to reduce background levels did not further improve speed of localization or sensitivity.