Hypoxia-related carbonic anhydrase 9 induces serpinB9 expression in cancer cells and apoptosis in T cells via acidosis.

Hypoxia is a common feature of solid tumors. However, the impact of hypoxia on immune cells within tumor environments remains underexplored. Carbonic anhydrase 9 (CA9) is a hypoxia-responsive tumor-associated enzyme. We previously noted that regardless of human CA9 (hCA9) expression, hCA9-expressing mouse renal cell carcinoma RENCA (RENCA/hCA9) presented as a "cold" tumor in syngeneic aged mice. This study delves into the mechanisms behind this observation. Gene microarray analyses showed that RENCA/hCA9 cells exhibited elevated mouse serpinB9, an inhibitor of granzyme B, relative to RENCA cells. Corroborating this, RENCA/hCA9 cells displayed heightened resistance to antigen-specific cytotoxic T cells compared with RENCA cells. Notably, siRNA-mediated serpinB9 knockdown reclaimed this sensitivity. In vivo tests showed that serpinB9 inhibitor administration slowed RENCA tumor growth, but this effect was reduced in RENCA/hCA9 tumors, even with adjunctive immune checkpoint blockade therapy. Further, inducing hypoxia or introducing the mouse CA9 gene upregulated serpinB9 expression, and siRNA-mediated knockdown of the mouse CA9 gene inhibited the hypoxia-induced induction of serpinB9 in the original RENCA cells. Supernatants from RENCA/hCA9 cultures had lower pH than those from RENCA, suggesting acidosis. This acidity enhanced serpinB9 expression and T cell apoptosis. Moreover, coculturing with RENCA/hCA9 cells more actively prompted T cell apoptosis than with RENCA cells. Collectively, these findings suggest hypoxia-associated CA9 not only boosts serpinB9 in cancer cells but also synergistically intensifies T cell apoptosis via acidosis, characterizing RENCA/hCA9 tumors as "cold."

Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study.

OBJECTIVES: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment-resistant advanced urothelial cancer in a real-world setting. PATIENTS AND METHODS: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression-free survival (PFS), and overall survival (OS), with treatment-related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median follow-up was 8.9 months (range, 0.1-16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7-9.8), and the median OS was 14.5 months (95% CI: 12.4-not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non-urothelial carcinoma histology, and 40 (38.3%) had at least one pre-existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. CONCLUSIONS: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti-tumor activity and had manageable safety profiles outside the clinical trial setting.

Current status and future perspectives of the managements of metastatic hormone-sensitive prostate cancer.

PURPOSE: The therapeutic landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has changed dramatically. Here, we provide the current status and future prospective of the management of mHSPC. METHODS: We reviewed recent literature of landmark studies on the managements of mHSPC. RESULTS: Upfront docetaxel or androgen receptor signaling inhibitor (ARSi) in addition to ADT has improved survival in mHSPC patients and has become the new standard of care. Triplet therapy with docetaxel, ARSi and ADT also improved survival. In the future, triplet therapy may become the standard of care. Oligometastatic mHSPC patients could benefit from local therapy. The inclusion of risk factors or the genetic biomarkers will provide the best treatment for individual mHSPC patients. CONCLUSION: Strong systemic therapy in the first-line treatment of mHSPC has been shown to improve survival and quality of life. Currently, several clinical trials are evaluating novel compounds such as PARP inhibitor, AKT inhibitor, and immune checkpoint inhibitor. The therapeutic landscape of mHSPC management will change dramatically.

External beam radiotherapy combination is a risk factor for bladder cancer in patients with prostate cancer treated with brachytherapy.

PURPOSE: To investigate the risk of bladder cancer (BCa) in patients treated with brachytherapy for prostate cancer (PCa). METHODS: We retrospectively analyzed 583 patients with PCa who underwent brachytherapy with or without external beam radiotherapy (EBRT). We analyzed the disease-free survival (DFS) of BCa in patients with PCa who underwent brachytherapy with or without EBRT. We performed multivariate Cox regression analyses of DFS using age, EBRT, and Brinkman index (BI) score (number of cigarettes smoked per day × number of years smoking) ≥ 200 as variables for BCa after brachytherapy. RESULTS: Fourteen patients (2.4%) developed BCa after brachytherapy with or without EBRT. The percentage of high-grade urothelial carcinoma (UC) was 63.6%. A total of 85.7% of patients had non-muscle invasive BCa, and 14.3% of patients had muscle invasive BCa. DFS was longer in brachytherapy monotherapy than in combination therapy (brachytherapy + EBRT). Multivariate Cox regression analysis showed that a BI score ≥ 200 (Hazard Ratio (HR 8.61; 95% Confidence Interval (CI) 1.12-65.98) and EBRT combination (HR 3.29; 95% CI 1.03-10.52) were significantly associated with BCa development in patients with PCa treated with brachytherapy. Furthermore, patients with BI score ≥ 200 and EBRT combination had a significantly higher risk of BCa compared with patients with BI score < 200 (HR Log-rank test P = 0.010). CONCLUSION: Most cases of BCa after brachytherapy with or without EBRT are high grade and invasive. We hypothesized that the EBRT combination might be a risk factor for BCa in patients with PCa who underwent brachytherapy.

T-cell responses and combined immunotherapy against human carbonic anhydrase 9-expressing mouse renal cell carcinoma.

Renal cell carcinoma (RCC) is known to respond to immune checkpoint blockade (ICB) therapy, whereas there has been limited analysis of T-cell responses to RCC. In this study, we utilized human carbonic anhydrase 9 (hCA9) as a model neoantigen of mouse RENCA RCC. hCA9-expressing RENCA RCC (RENCA/hCA9) cells were rejected in young mice but grew in aged mice. CD8+ T cells were the primary effector cells involved in rejection in young mice, whereas CD4+ T cells participated at the early stage. Screening of a panel of hCA9-derived peptides revealed that mouse CD8+ T cells responded to hCA9288-296 peptide. Mouse CD4+ T cells responded to lysates of RENCA/hCA9, but not RENCA cells, and showed reactivity to hCA9 276-290, which shares three amino acids with hCA9 288-296 peptide. Immunohistochemistry analysis revealed that few T cells infiltrated RENCA/hCA9 tissues in aged mice. ICB therapy of anti-PD-1/anti-CTLA-4 antibodies promoted T-cell infiltration into tumor tissues, whereas no definite antitumor effect was observed. However, additional combination with cyclophosphamide or axitinib, a vascular endothelial growth factor receptor inhibitor, induced complete regression in half of the RENCA/hCA9-bearing aged mice with increased expression of PD-L1 in tumor tissues. These results indicate that hCA9 can be a useful model neoantigen to investigate antitumor T-cell responses in mice with RCC, and that RENCA/hCA9 in aged mice can serve as a non-inflamed 'cold' tumor model facilitating the development of effective combined immunotherapies for RCC.

Disseminated intravascular coagulation induced by pazopanib following combination therapy of nivolumab plus ipilimumab in a patient with metastatic renal cell carcinoma.

Recently, combination therapy including immune checkpoint inhibition (ICI) has proven to be effective as first-line therapy for patients with metastatic renal cell carcinoma. Although the first-line combination therapies with ICI have shown clinical benefit, a number of patients require second-line treatment. We report a 60-year-old man with metastatic renal cell carcinoma who was treated with pazopanib soon after nivolumab plus ipilimumab combination therapy. He experienced Grade 3 disseminated intravascular coagulation (DIC). We suspect that this was caused by an interaction between pazopanib and nivolumab even though ICI therapy was discontinued. He was treated with thrombomodulin and platelet transfusion and recovered from DIC. Treatment with pazopanib was subsequently restarted. No evidence of DIC was observed thereafter. This severe adverse reaction may have been induced by an interaction between activated proinflammatory immune cells and cytokines from an exacerbated inflammatory state and pazopanib. This report highlights the need to perform careful monitoring of patients who receive molecular targeted therapy after ICI-based immunotherapy.

Predictive factors for the efficacy of abiraterone acetate therapy in high-risk metastatic hormone-sensitive prostate cancer patients.

PURPOSE: There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period. METHODS: Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80 mg/day) in combination with ADT. RESULTS: OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients. CONCLUSION: The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

Real-world efficacy and safety of nivolumab plus ipilimumab in untreated metastatic renal cell carcinoma, and the impact of previous nephrectomy on clinical outcome: Japanese multi-institutional retrospective study.

BACKGROUND: In metastatic renal-cell carcinoma (mRCC), recent clinical trials have shown efficacy of first-line combination therapy, as evidenced by better clinical outcome over target therapy. However, there are insufficient real-world evidences in mRCC patients in Japan. METHODS: We performed a multicenter retrospective study of 72 mRCC patients who received nivolumab plus ipilimumab as first-line treatment between September 2018 and July 2021. Patient's characteristics, clinical outcomes and safety were retrospectively reviewed. We analyzed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients treated with combination therapy. RESULTS: Of all patients, the median age was 70 years (range, 36-86) and the major type of histology was clear cell RCC (n = 55; 76.4%). Progressive disease (n = 25; 34.8%) and irAEs (n = 22; 30.6%) were the most common causes for discontinuing treatment. Median PFS and OS seemed similar between patients who discontinued treatment because of irAEs and for patients who did not (p = 0.360 and p = 0.069, respectively). Importantly, for patients with synchronous metastatic disease at diagnosis (n = 56), nephrectomy before initiating nivolumab plus ipilimumab had a significantly positive impact on better OS when compared to that in patients without nephrectomy (p = 0.028). CONCLUSION: This study confirms efficacy and safety of nivolumab plus ipilimumab for mRCC patients in real-world settings. Furthermore, nivolumab plus ipilimumab was associated with a better outcome in patients who had undergone nephrectomy at diagnosis for synchronous mRCC.

[Gas-Producing Splenic Abscess after Spleen Metastasis of Left Renal Cell Carcinoma Spleen Metastasis Successfully Treated with Sunitinib].

A 67-year-old man underwent open radical left nephrectomy for left renal cell carcinoma [pT4N0M1 (right lower lobe of lung)] and thoracoscopic partial right lung resection for lung metastasis. The patient subsequently developed a solitary lung metastasis at 10 months and then at 26 months postoperatively. He underwent partial lung resection on each occasion. During the 28 months postoperatively, he was found to have a 12 mm middle mediastinal lymph node metastasis and a 30 mm splenic metastasis, which gradually increased in size. Three months after discovery, sunitinib was initiated at 37.5 mg 2 weeks on/1 week off. Twelve days later, the patient presented with complaints of fever. A gas-producing splenic abscess was diagnosed and he was admitted on the same day. His condition improved with antibiotics and splenic drainage. On day 35 of hospitalization, he underwent laparoscopic splenectomy. The patient's postoperative clinical course was uneventful and he was discharged 7 days after the surgery.

Regional differences in the prevalence of sensitization to environmental allergens: Analysis on IgE antibody testing conducted at major clinical testing laboratories throughout Japan from 2002 to 2011.

BACKGROUND: Identification of sensitized allergens for patients with respiratory allergy is an important step in disease care and environmental allergen control. The Japanese archipelago belongs to various climate categories due to its length from north to south which transverse the subarctic in the north to the subtropical in the south, suggesting substantial regional differences in dominant environmental allergens. However, few studies have assessed the regional differences in the prevalence of sensitization to environmental allergens. METHODS: We requested three major clinical testing laboratories to provide us with summarized results of antigen-specific IgE-antibody (Ab) measurements. These measurements were collected for clinical purposes throughout Japan from 2002 through 2011. The prevalence of positivity for IgE-Ab against 19 environmental allergens was calculated for each prefecture in order to evaluate regional differences. RESULTS: Test data on specific IgE-Ab of 19,969,753 orders were analyzed. The prevalence of positivity for house dust mites was high and the regional difference was low, whereas apparent regional differences were found for pollen, insects, and fungi. The prevalence of positivity for Japanese cedar was low in Hokkaido and Okinawa, while those to alder was highest in Hokkaido. Higher prevalence for insects was observed in southern areas (Okinawa and prefectures in Kyusyu). CONCLUSIONS: Findings of this study clearly demonstrated regional differences in the prevalence of sensitization to environmental allergens in Japan and the study also provides useful information for the clinician when deciding which allergens should preferentially be measured for IgE-Ab after considering regional difference.

The Change in Neutrophil Lymphocyte Ratio from the First to the Last Repeat Prostate Biopsy Proposed as a Marker of Carcinogenesis.

INTRODUCTION: We investigated whether the change in the neutrophil lymphocyte ratio (NLR) from the first to the last repeat prostate biopsy (ΔNLR) could be the diagnostic tool or not for prostate cancer (PCa) detection. MATERIALS AND METHODS: We retrospectively evaluated medical records of men who had undergone repeat prostate biopsy. The investigated parameters were white blood cell, neutrophil, lymphocyte counts, NLR at the last prostate biopsy, ΔNLR, prostate-specific antigen (PSA), PSA density (PSAD), and PSA velocity. Exclusion criteria were the presence of cancers other than prostate origin, medication, and diseases which induce the change of NLR. RESULTS: A total of 301 men who had undergone repeat prostate biopsy were selected for this study. After applying exclusion criteria, 223 patients were included. Of these patients, 94 were diagnosed with PCa (Group I) and 129 with no malignancy (Group II). Only a single patient had metastasis. On evaluating the area under the receiver operating characteristic curve of all study parameters, ΔNLR was the most accurate marker, followed by PSAD and then NLR measured at the last biopsy. CONCLUSIONS: ΔNLR was the most accurate marker to improve the total predictive value in repeat prostate biopsy for diagnosing PCa.

Hand eczema as a risk factor for food allergy among occupational kitchen workers.

BACKGROUND: An increasing number of studies in children is highlighting the importance of transdermal routes of exposure to food allergens through damaged skin in the pathogenesis of food allergies. However, data on this in adults are limited. A few case-series studies has documented development of food allergy among kitchen workers with hand eczema after direct contact exposure to foods. METHODS: To explore the significance of hand eczema as a risk factor for food allergies in adults at the epidemiological level, we performed a cross-sectional web-based questionnaire survey on kitchen workers whose exposures were classed as occupational (cooks and food handlers, n = 1592) or non-occupational (housewives, n = 1915). Logistic regression was used to explore the association between the presence/severity of hand eczema and the risk of food allergy after adjustment for potential confounders. RESULTS: Current hand eczema and current diagnosed food allergy were more common among occupational kitchen workers (OKW) than among non-occupational kitchen workers (NOKW) (32.3%-vs-29.9% and 9.9%-vs-3.8%, respectively). Current hand eczema was significantly associated with increased risk of current diagnosed food allergy in OKW (adjusted odds ratio 2.4, 95% CI 1.6-3.7). Those with more severe hand eczema were more likely to suffer from allergic symptoms for foods, and diagnosed food allergy. CONCLUSIONS: This study illustrates a significant public health problem in the adult population, documenting a major impact of hand eczema on the ongoing adult food allergy epidemic.

[SENSITIVITY OF FRUIT-SPECIFIC IgE SCREENING IN MULTI-PANEL ANTIBODY TESTING].

BACKGROUND: One of the strengths of multi-panel IgE testing is that it facilitates screening for IgE antibodies (Abs) in allergic patients by providing data on levels of IgE Abs to multiple allergens at the same time. Nonetheless, its diagnostic sensitivity for clinical use has not been well-studied. METHODS: We tested sera from 33 fruit-allergic patients. The sensitivity of determining IgE Abs to fruit allergens using the MAST Immunosystems (MAST) system and the View Allergy 39 (VA) system was calculated separately in patients sensitized to PR-10 or to profilin, and compared with that of single-panel IgE testing (ImmunoCAP system). RESULTS: In both the PR-10 sensitized and 31 profilin sensitized groups, the sensitivity of the IgE Abs to apple measured by VA (87%, and 83%, respectively) was almost identical to that of ImmunoCAP. On the other hand, the sensitivity of IgE Abs to peach measured by MAST (23% and 25%, respectively) was markedly lower than that of ImmunoCAP. CONCLUSIONS: The sensitivity of fruit IgE Abs in the MAST system was remarkably lower than that of the ImmunoCAP system. Caution is necessary in clinical practice when interpreting of the results of some multipanel IgE testing.

[Four Cases of Resected cN2 Stage III A Non-Small-Cell Lung Cancer after Induction Chemotherapy].

Four patients with non-small-cell lung cancer(NSCLC), diagnosed with cN2 stage III A disease, by using CT and FDG-PET/ CT imaging, received 2 or 3 courses of platinum-based combination chemotherapy.The patients achieved partial response after chemotherapy and underwent surgery.Complete tumor resection was performed via upper lobectomy for 3 patients, but in 1 patient, interlobar metastatic lymph nodes remained after middle and lower bilobectomy.Two courses of postoperative chemotherapy were administered to 3 patients, but 1 patient could not receive postoperative chemotherapy due to complications.One patient, in whom lymph node metastasis completely disappeared after induction chemotherapy, is still alive and without disease recurrence for 7 years.Another patient, with the presence of only one intralobar metastatic lymph node after chemotherapy, died of brain and meningeal metastases, 3 years after surgery.Two other patients, with multiple pN2 lymph nodes after chemotherapy, died of early intrathoracic local relapse, indicating that prognosis is influenced by response to chemotherapy, especially in patients with poor N-downstaging.Improvements in response to induction therapy by using intensive chemotherapeutic regimens, concurrent radiotherapy, and strict patient selection, limited to N-downstaged cases, are needed for successful surgery outcomes in patients with cN2 stage III A NSCLC who have received induction therapy.

Lower Airway Inflammation in Eosinophilic Chronic Rhinosinusitis as Determined by Exhaled Nitric Oxide.

BACKGROUND: Chronic rhinosinusitis (CRS) is classified into eosinophilic CRS (ECRS) and non-ECRS. The objectives of this study were to evaluate lower airway inflammation by measuring the fractional concentration of exhaled nitric oxide (FeNO) and to examine the effects of endoscopic sinus surgery (ESS) on FeNO in patients with ECRS compared to non-ECRS. METHODS: CRS patients with nasal polyps (23 with ECRS and 22 with non-ECRS) were enrolled into this study. ECRS was diagnosed based on the definition proposed by the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) study group. Several clinical markers including blood eosinophil counts, percent of eosinophils in white blood cells (WBC), number of eosinophils in nasal polyps, JESREC scores, total IgE, FeNO, and Lund-Mackay paranasal sinus CT scores were compared between ECRS and non-ECRS. These markers were also tested before and 2 months after ESS. RESULTS: FeNO was significantly higher in patients with ECRS than in non-ECRS patients. When all CRS patients were tested, a significant correlation was found between FeNO and eosinophilic markers including blood eosinophil counts, percent of eosinophils in WBC, number of eosinophils in nasal polyps, and JESREC scores. FeNO showed a significant correlation with Lund-Mackay scores only in ECRS patients. Blood eosinophil counts, percent of eosinophils in WBC, and FeNO decreased after ESS only in ECRS patients. CONCLUSIONS: ECRS patients had lower airway inflammation as revealed by an elevated FeNO, which was parallel to the Lund-Mackay CT scores. ESS decreased the blood eosinophils and FeNO, leading to an improvement of the occult pulmonary dysfunction in ECRS patients.

Axitinib-induced proteinuria and efficacy in patients with metastatic renal cell carcinoma.

BACKGROUND: No report has evaluated axitinib-induced proteinuria as a biomarker for predicting treatment efficacy and survival of patients with metastatic renal cell carcinoma (mRCC). METHODS: The subjects were patients with mRCC treated with axitinib at Kinki University Hospital from February 2008 to November 2014. Clinical records were retrospectively reviewed including baseline patient characteristics, time-dependent changes of urinary protein status, computed tomography scans of metastatic lesions, treatment duration with axitinib, and survival time. RESULTS: A total of 45 patients were evaluable. Median tumor shrinkage rates were 32.3 and 35.0 % in patients with urinary protein increases ≥+2 and <+2, respectively (p = 0.496). Objective response rates were also similar between the two groups. Median progression-free survival (PFS) times with axitinib were 13.5 months [95 % confidence interval (CI) 0.0-27.5] and 11.0 months (95 % CI 0.0-26.7) in patients with urinary protein increases ≥+2 and <+2, respectively (p = 0.975). The maximum tumor shrinkage rate with axitinib was significantly associated with PFS with axitinib as a result of multivariate analysis (p = 0.002). Median overall survival (OS) times were 39.8 months (95 % CI 12.7-67.0) and 25.4 months (95 % CI 11.2-39.6) in patients with axitinib-induced urinary protein increases ≥+2 and <+2, respectively (p = 0.250). The number of metastatic sites (p = 0.006), the MSKCC risk (p = 0.009), and the maximum tumor shrinkage rate with axitinib (p = 0.019) were significantly associated with OS as a result of multivariate analysis. CONCLUSIONS: The degree of urinary protein increase during axitinib treatment was not associated with objective response, PFS, and OS in mRCC patients treated with axitinib.

[Long-Term Local Control with Radiofrequency Ablation or Radiotherapy for Second, Third, and Fourth Lung Tumors after Lobectomy for Primary Lung Cancer].

A 78-year-old woman developed second, third, and fourth lung tumors at intervals of 1-3 years after left upper lobectomy for primary lung cancer. The tumors were controlled with radiofrequency ablation(RFA)or conventionalconformalradiotherapy for 9 years postoperatively. For the treatment of second primary lung cancer or lung metastasis after surgical resection of the primary lung cancer, reoperation is not recommended because of the impaired respiratory reserve. Thus, local therapy such as radiotherapy or RFA is applied in some cases. Among these, stereotactic body radiotherapy(SBRT)is a feasible option because of its good local control and safety, which is comparable with surgery. On the other hand, for cases of multiple lesions that are not suitable for radiotherapy or combination therapy, RFA could be an option because of its short-term local control, easiness, safety, and repeatability. After surgery for primary lung cancer, a second lung tumor could be controlled with highly effective and minimally invasive local therapy if it is recognized as a local disease but is medically inoperable. Therefore, longterm postoperative follow-up for primary lung cancer is beneficial.

Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer.

BACKGROUND: Despite recent advances in the treatment for advanced prostate cancer, outcomes remain poor. This lack of efficacy has prompted the development of alternative treatment strategies. In the present study we investigate the effects of the multikinase inhibitor sorafenib in a genetically engineered mouse model of prostate cancer and explore the rational combination with the mTOR inhibitor everolimus. METHODS: Conditional prostate specific PTEN-deficient knockout mice were utilized to determine the pharmacodynamic and chemopreventive effects of sorafenib. This mouse model was also used to examine the therapeutic efficacy of sorafenib alone or in combination with everolimus. Preclinical efficacy was assessed by comparing the reduction of tumor burden, proliferation, angiogenesis and the induction of apoptosis. Molecular responses were assessed by immunohistochemical, TUNEL and western blot assays. RESULTS: Pharmacodynamic analysis revealed that a single dose of sorafenib decreased activation of the PI3K/AKT/mTOR signaling axis at doses of 30-60 mg/kg, but activated JAK/STAT3 signaling. Levels of cleaved casapase-3 increased in a dose dependent manner. Chemoprevention studies showed that chronic sorafenib administration was capable of inhibiting tumor progression through the reduction of cancer cell proliferation, angiogenesis and the induction of apoptosis. In intervention models of established castration-naïve and castration-resistant prostate cancer, treatment with sorafenib provided modest but statistically insignificant reduction in tumor burden. However, sorafenib significantly inhibited cancer cell proliferation and MVD but had minimal effects on the induction of apoptosis. Interestingly, the administration of sorafenib increased the expression levels of the androgen receptor, p-GSK3ß and p-ERK1/2 in castration-resistant prostate cancers. In both intervention models, combination therapy demonstrated a clear tendency of enhanced antitumor effects over monotherapy. Notably, the treatment combination of sorafenib and everolimus overcame therapeutic escape from single agent therapy in castration-resistant prostate cancers. CONCLUSIONS: In summary, we provide insights into the molecular responses of sorafenib therapy in a clinically relevant model of prostate cancer and present preclinical evidence for the development of targeted treatment strategies based on the use of multikinase inhibitors in combination with mTOR inhibitors for the treatment of advanced prostate cancer.

IgE Abs to Der p 1 and Der p 2 as diagnostic markers of house dust mite allergy as defined by a bronchoprovocation test.

BACKGROUND: Limited information is available regarding the clinical usefulness of measuring the levels of IgE to allergen components from house dust mites (HDMs) in the diagnosis of genuine HDM allergy. METHODS: To evaluate the diagnostic usefulness of measuring levels of serum IgE antibodies (Abs) to allergen components from Dermatophagoides pteronyssinus (DP) as a predictor of immediate asthmatic response (IAR) to bronchoprovocation, we studied 55 DP-sensitized asthmatic patients who underwent a bronchoprovocation test using crude DP extract. The levels of IgE Abs to crude DP, nDer p 1, rDer p 2, and rDer p 10 in patients who showed IAR (n = 41) were compared with those in patients who showed no IAR (n = 14). RESULTS: While the frequencies of positivity for IgE Abs to nDer p 1 and rDer p 2 among the entire study population were 89 and 86%, respectively, all patients with IAR tested positive for both of them with high IgE concentrations. The areas under the receiver operating characteristic curves for IgE to nDer p 1 and rDer p 2 as predictors of IAR were 0.913 and 0.906, respectively. The specificity of IgE to nDer p 1 and rDer p 2 was higher than IgE to crude DP even at low cut-off points. CONCLUSIONS: IgE to nDer p 1 and/or rDer p 2 was highly predictive of allergen-induced IAR. These findings validate the clinical usefulness of measuring the levels of IgE to nDer p 1 and rDer p 2 as a diagnostic tool for genuine HDM allergy.