Jatinder Goyal

Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases

Patients with castration-resistant prostate cancer (CRPC) frequently have metastases to the bone, which may cause pain and lead to a deterioration in quality-of-life. Bone-seeking radiopharmaceuticals are agents which, when administered systemically, localize to the site of bone metastases and deliver focal radiation there. In this review, we will summarize the current literature on bone-targeting radiopharmaceuticals for CRPC, focusing on strontium-89, samarium-153, rhenium-186 and radium-223. We will discuss their indications, clinical efficacy, and toxicities and highlight some of the challenges in optimizing treatment with these agents. Historically, clinical trials with these drugs have failed to demonstrate survival improvements, restricting their use for palliative purposes only. Radium-223 is the first agent in this class to show an overall survival advantage in CRPC patients with bone metastases. This landmark finding will likely have a considerable impact on the treatment paradigm of bone-metastatic CRPC, and will pave the way for further developments in the future.

Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy

BACKGROUND Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. PATIENTS AND METHODS Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. RESULTS The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS ≥ 1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS ≥ 1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. CONCLUSIONS In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS ≥ 1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors.

Relapses of Thrombotic Thrombocytopenic Purpura after Treatment with Rituximab

Rituximab has been added to therapeutic plasma exchange (TPE) in the last 10 years for refractory thrombotic thrombocytopenic purpura (TTP). We performed a retrospective single institution study to determine if patients with TTP treated with TPE and rituximab experienced relapses. We reviewed the electronic and apheresis records of patients treated between 2003 and 2008 and collected the following parameters: demographics, laboratory results, treatment characteristics, and follow‐up. We identified 12 patients with ADAMTS13 <5% due to an inhibitor who received TPE and rituximab during the study period. The mean number of TPEs required to achieve remission was 24 ± 3, time to remission was 28 ± 3 days, and hospital length of stay was 36 ± 4 days. During a mean follow‐up of 73.4 ± 6 months, four patients (33%) relapsed. On average, relapse occurred at 62 ± 8.5 months postachievement of remission. The one‐year, three‐year, and five‐year relapse free‐survival (RFS) rates were 92%, 75%, and 75%, respectively. On multivariate analysis, we failed to identify independent predictors of relapse. This retrospective analysis does not support the notion that rituximab prevents or decreases the rate of relapse in TTP. Prospective randomized studies are needed to confirm this observation. J. Clin. Apheresis, 28:390–394, 2013.

Peering into the future: Hepcidin testing

Hepcidin, a small 25 amino acid peptide, has been well established as the iron regulatory hormone. Its expression is upregulated in response to iron and inflammatory cytokines, and downregulated in anemic or hypoxic states. Hepcidin decreases iron export into the plasma by binding to and inducing the degradation of ferroportin, an iron channel located on macrophages and the basolateral surface of enterocytes. This leads to decreased absorption of parental iron by the enterocytes, reduced recycling of erythrocyte iron by macrophages, and increased iron stores in the hepatocytes. Although hepcidin assays are not currently approved for clinical use in the United States, there is much interest in the potential use of this biomarker for management of iron related medical conditions. This review briefly summarizes the current hepcidin test platforms under investigation and the challenges associated with development of a clinical assay for this biomarker. In addition, selected potential future applications hepcidin testing in the clinical setting are addressed. Am. J. Heamtol. 88:976–978, 2013.

Analysis of a grading system to assess the quality of small-bowel preparation for capsule endoscopy: in search of the Holy Grail.

Background: The diagnostic yield of capsule endoscopy is vulnerable to inadequate visualization related to residual bile or chyme remaining in the lumen despite intestinal lavage. It has been challenging to determine the optimal lavage preparation of the bowel and patient diet before capsule endoscopy, as well as the timing of the procedure, because no well-accepted, validated grading system for assessing the quality of intestinal lavage before capsule endoscopy is available. There remains no consensus on the reliability of qualitative, quantitative, or computer-derived assessments of the quality of preparation for capsule endoscopy. This study evaluates intra-observer and interobserver agreement for a previously validated scale. Materials and methods: The digital images of 34 patients who underwent capsule endoscopy were independently reviewed by two blinded physicians according to a previously validated grading scale. One of the physicians reviewed and graded the patients a second time. The quality of the bowel luminal preparation was assessed with a qualitative parameter (fluid transparency) and a more quantitative parameter (mucosal invisibility) for each of three small-intestinal segments, and an overall small-bowel score for each parameter was assigned as well. A weighted kappa coefficient was used to calculate intra-observer (observer 1A and 1B) and interobserver (observer 1A and observer 2) agreement. A kappa value of 0.60 or more suggests strong agreement, 0.40 to 0.60 moderate agreement, and less than 0.40 poor agreement. Results: The intra-observer weighted kappa index for both fluid transparency and mucosal visibility was 0.52, which is consistent with moderate agreement. The interobserver weighted kappa indices for fluid transparency and mucosal invisibility were 0.29 and 0.42, respectively, demonstrating suboptimal interobserver agreement. The individual segment interobserver kappa indices were better for mucosal visibility (0.52, 0.39, and 0.47 for small-bowel segments 1, 2, and 3, respectively) than for fluid transparency (0.18, 0.38, and 0.31). Conclusions: The proposed grading scale for assessing the quality of preparation for capsule endoscopy has inadequate interobserver and intra-observer agreement. Capsule endoscopy preparation grading scales that focus more on quantitative than on qualitative assessment may demonstrate more reliable performance characteristics. Optimizing the quality of preparation and diagnostic yield of capsule endoscopy will first require the development of a well-validated grading scale.

Acquired von Willebrand's disease in myelofibrosis and essential thrombocythemia

J. GOYAL,* V. V. B. REDDY† and M. B. MARQUES†*Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; and †Department of Pathology, University of Alabama atBirmingham, Birmingham, AL, USAAcquired von Willebrand’s disease (AVWD) is a rare coagulopathysecondary to a variety of conditions such as hypothyroidism, abnormalheart valves and lymphoproliferative and autoimmune disordersamong others [1]. AVWD, like the inherited form of VWD, may becharacterized by quantitative or qualitative abnormalities of vonWillebrand factor (VWF). Few reports have linked AVWD to myelo-proliferative neoplasms (MPN) [2]. We hereby report a patient withAVWD in association with essential thrombocythemia (ET) andmyelofibrosis, who was asymptomatic. In such cases, unless otherwisesuspected and tested for, the condition may be missed and bleedingcould ensue if an invasive procedure becomes necessary. We haveattempted to highlight the importance of keeping AVWD in mindwhenever significant thrombocytosis is present. Although bleeding/thrombotic complications do not occur in all patients with this presen-tation, early recognition and prompt treatment are important [3].

Association of the Charlson comorbidity index and hypertension with survival in men with metastatic castration-resistant prostate cancer.

OBJECTIVES The independent prognostic effect of comorbidities on outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) is unclear. We sought to determine whether the Charlson comorbidity index (CCI) and hypertension (HTN) are associated with overall survival (OS) independent of known clinical prognostic factors in mCRPC. PATIENTS AND METHODS A retrospective analysis was conducted on 221 patients with mCRPC treated with docetaxel plus prednisone combined with AT-101 (bcl-2 antagonist) or placebo on a prospective randomized phase II trial. The Cox regression analysis was performed to identify whether the CCI or HTN or both (by medical history) independently predicted OS after adjusting for baseline variables known to be associated with OS. The Wilcoxon rank sum test and the Fisher exact test were used to compare data by comorbidity groups (CCI as a continuous variable, CCI = 6 vs. CCI ≥ 7 and HTN vs. no HTN). RESULTS The CCI was 6 in 116 patients (52.7%), 7 in 70 (31.8%), 8 in 23 (10.5%), 9 in 4 (1.8%), and 10 in 7 patients (3.2%). HTN was present in 107 (48.6%) patients. Patients with CCI of ≥ 7 were older and exhibited worse performance status and anemia than patients with CCI of 6 (P<0.05). The CCI was not independently predictive of OS on univariable and multivariable analyses. HTN alone or in combination with the CCI was borderline significantly associated with OS (P ~ 0.09) on both univariable and multivariable analyses. CONCLUSIONS The CCI did not predict OS independent of known prognostic factors in mCRPC. Age, performance status, and anemia may adequately capture comorbidities in the context of mCRPC, given their association with higher CCI. Further prospective study of comorbidities in a larger data set may be warranted. The study of HTN in a larger data set may also be warranted given its borderline-independent association with OS.

Update in Systemic Therapy of Urologic Malignancies

Abstract Systemic therapy of advanced prostate and renal cancers has gained several recent additions to the therapeutic armamentarium. Treatment of patients with castration–resistant prostate cancer now includes additional immunotherapy (sipuleucel–T), chemotherapy (cabazitaxel), androgen–signaling inhibitors (abiraterone acetate, enzalutamide), and a radiopharmaceutical (alpharadin), based on extension of patient survival. Similarly, therapy for patients with renal cell carcinoma, a chemoresistant malignancy, has undergone dramatic changes based on an understanding of the role of angiogenesis. Multiple vascular endothelial growth factor inhibitors (sorafenib, sunitinib, pazopanib, axitinib, bevacizumab) and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) have been added to the therapeutic arsenal. Additionally, immunotherapy retains an important treatment role, with a continuing application of high–dose interleukin–2 in select patients and the emergence of novel immunotherapeutic agents that may have significant benefit. Other major urologic malignancies, including urothelial, testicular, and penile cancers, have witnessed relatively few or no recent advances in therapy, although testicular germ cell tumors are one of the most curable malignancies. An agent for treatment of advanced urothelial cancer now has commercial approval, the chemotherapeutic agent, vinflunine, as second–line therapy in multiple countries—but not in the United States. Our review summarizes and updates the field of systemic therapy for advanced urologic malignancies, with a focus on castration–resistant prostate cancer and renal cell carcinoma.

Acquired haemophilia in a patient treated with interferon-α for hepatitis C infection.

Acquired factor VIII inhibitor (FEI) due to the development of autoantibodies in patients without a history of haemophilia A is unusual, occurring at an incidence of 0.2–1 case per million each year [1]. Acquired haemophilia due to these antibodies usually develops idiopathically but certain conditions like pregnancy along with lymphoproliferative and solid malignancies have been frequently reported to be associated with it. However, there is only one other instance in the published literature describing the development of FEI secondary to interferon-a exposure for the treatment of chronic hepatitis C virus (HCV) infection in a patient without any co-infection or history of coagulopathy [2]. We report the initial presentation, treatment and follow-up details of another such case.

Predictability of capsule endoscopy referred to a tertiary care center for double-balloon enteroscopy.

Objectives Patients with obscure gastrointestinal bleeding with ‘positive’ findings on video capsule endoscopy (VCE) by gastroenterologists practicing in the community are often referred to tertiary care centers for double-balloon enteroscopy (DBE). Our study explores the degree of concordance between these two procedures performed in two different clinical settings. Methods Concordance between the procedures was estimated using a &kgr;-coefficient. Results A total of 73 patients with obscure gastrointestinal bleeding were referred to our center for DBE after undergoing VCE elsewhere. Ten of these patients (10/73 or 13.7%) had been found to have bleeding in the small bowel on VCE without any concrete diagnosis. DBE revealed the source of bleeding in 17 of the 22 patients (77.3%) with normal VCE. The referral diagnosis was correct in 31 cases (31/73 or 42.5%). The &kgr;-coefficient for VCE and DBE for the 63 patients was 0.28, suggesting poor agreement between the two procedures. However, most patients with a referral diagnosis of vascular pathology were confirmed to have vascular disease on DBE (19/23 or 82.6%). Conclusion Our study shows that there is a poor concordance between capsule endoscopy performed in the community and confirmatory DBE performed at our tertiary care center.