Atypical hemolytic uremic syndrome and complement blockade: established and emerging uses of complement inhibition.

PURPOSE OF REVIEW: Atypical hemolytic uremic syndrome (aHUS) is a diagnosis that has captured the interest of specialists across multiple fields. The hallmark features of aHUS are microangiopathic hemolysis and thrombocytopenia, which creates a diagnostic dilemma because of the occurrence of these findings in a wide variety of clinical disorders. RECENT FINDINGS: In most of the instances, aHUS is a diagnosis of exclusion after ruling out causes such as Shigella toxin, acquired or genetic a disintegrin and metalloproteinase thrombospondin motif 13 deficiency (thrombotic thrombocytopenic purpura), and vitamin B12 deficiency. In the purest sense, aHUS is a genetic condition that is activated (or unmasked) by an environmental exposure. However, it is now evident that complement activation is a feature of many diseases. Variants in complement regulatory genes predispose to microangiopathic hemolysis in many rheumatologic, oncologic, and drug-induced vascular, obstetric, peritransplant, and infectious syndromes. SUMMARY: Many 'hemolysis syndromes' overlap clinically with aHUS, and we review the literature on the treatment of these conditions with complement inhibition. New reports on the treatment of C3 glomerulopathy, Shiga toxin-related classic hemolytic uremic syndrome, and medication-related thrombotic microangiopathy will be reviewed as well.

Proteasome inhibitor-based therapy for treatment of newly diagnosed multiple myeloma.

Multiple myeloma is a hematologic malignancy that is unable to be cured and has significant impact throughout the world. Front line treatment has shifted but ultimately has landed on a bortezomib-based combination therapy. Carfilzomib is a next-generation proteasome inhibitor shown to improve both progression-free and overall survival in relapsed and refractory multiple myeloma in combination with lenalidomide and dexamethasone (KRd). Given the favorable response rates seen in phase II trials treating newly diagnosed myeloma, this combination is listed as a viable option for upfront treatment. This systematic review compares pharmacologic properties, clinical efficacy, and toxicities of carfilzomib- and bortezomib-based regimens.

ASCO Plenary Sessions: impact, legacy, future.

The ASCO annual meeting draws a large crowd of physicians, cancer researchers, policy makers, and industry representatives. The crown jewel of the annual events is the Plenary session where impactful, influential and visible abstracts are selected for the largest audience. Plenary topics are frequently paired with concurrent New England Journal or Lancet publications.  Here, we review 9 years of ASCO plenary sessions.  Several themes emerge.  First, many of the topics selected have indeed been practice changing, such as the use of ALK inhibitors for ALK rearranged NSCLC, or checkpoint inhibitors in metastatic melanoma.  Second, although some plenary topics seemed destined to change practice, they ultimately falter, such as the use of Cetuximab in NSCLC, vaccine therapy for follicular lymphoma, and even Bevacizumab in metastatic renal cell cancer. Who could have forseen bevacizumab displaced by several VEGF TKIs?  Third, negative trials are rare among Plenary sessions, but when they are presented they are immensely important.  Examples include a seminal study using CA-125 levels to guide treatment of relapsed ovarian cancer, the use of lapatinib combined with traztuzumab in the adjuvant treatment of HER2 + disease, and studies showing no survival benefit to upfront bevacizumab in glioblastoma multiforme.   Fourth, we note a large industry presence among Plenary sessions, as the Industry in part sponsored 62% of Plenary abstracts.  Ultimately a review of 9 years of ASCO plenary reveals the plenary for what it is: a conservative selection of abstracts that, at the time, are thought to change the face of oncology.  Time, however, is the true arbiter, and some succeed in this quest, while others falter.  ASCO plenary sessions reveal the influence, legacy and future of cancer care.

Characteristics of Exceptional or Super Responders to Cancer Drugs.

OBJECTIVE: To summarize case reports of exceptional and super responders already published in the biomedical literature. PATIENTS AND METHODS: We searched for published case reports or abstracts of exceptional or super responders to a cancer drug using PubMed and Google Scholar search engines. Pooling such reports is widely considered a promising research strategy and the subject of several ongoing investigations, including the National Cancer Institute's Exceptional Responders Initiative. All articles were read in full, including relevant references. We extracted clinical characteristics of exceptional or super responders, including age, tumor type, drug, genetic mutations, depth of response, duration of response, number of previous lines of therapy, duration of response to a previous line of therapy, and the number of patients treated similarly to identify the exceptional case. This study was performed between March 1, 2015, and April 30, 2015. RESULTS: Among 489 articles, 32 exceptional responders were identified. The most common malignancies described were renal cell cancer (5 of 32 [16%]) and urothelial carcinoma (4 of 32 [13%]). The use of targeted agents was common in these cases (26 of 32 [81%]), particularly inhibitors of the mTOR pathway (16 of 32 [50%]). The median duration of response among responders was 17.5 months, and 59% (19 of 32) of the patients were last known to be alive with continuing response or stable disease. Notably, 46% (12 of 26) of the patients had received 2 or more previous lines of therapy and 6 of the 32 cases (19%) did not report this information. Few authors report the number of patients treated similarly to observe the super response (12 of 32 [38%]). CONCLUSION: Exceptional or super responders to cancer drugs have been described in the literature; however, there is incompleteness in the reporting of relevant data that may help clarify whether such responses are secondary to treatment or reflect underlying biology.

The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses.

IMPORTANCE: The strength of association between surrogate end points and survival in oncology is important to understand because surrogate end points are frequently used in oncology clinical trials, supporting US Food and Drug Administration approvals and National Comprehensive Cancer Network guideline recommendations. OBJECTIVE: To identify and evaluate trial-level meta-analyses of randomized clinical trials quantifying the association between a surrogate end point and overall survival in medical oncology. Trial-level correlations test whether treatments that improve the surrogate end point also improve the final end point and are widely considered the strongest evidence to validate a surrogate end point. EVIDENCE REVIEW: Our literature search was built on earlier reported data sets and updated with Google Scholar and MEDLINE searches conducted on December 26, 2014. For MEDLINE, search terms included ("regression" or "correlation") and "surrogate" and "end point [or endpoint]" and ("oncology" or "cancer"). For Google scholar, search terms included ("regression" or "correlation") and "surrogate end point [or endpoint]" and "overall survival" and "trial level." A total of 108 abstracts were retrieved, and 62 articles were read in full in addition to articles identified through prior reviews. FINDINGS: We found 36 articles in which 65 specific correlations between a surrogate end point and survival were identified. Surrogate end points were studied in the neoadjuvant, adjuvant, locally advanced, and metastatic settings. The most common sources for trials included in the 36 articles were systematic reviews of the published literature (10 of 36; 28%), and published literature and meeting abstracts (14 of 36; 39%). Four meta-analyses (11%) used a convenience sample, and only 5 studies (14%) attempted to include unpublished trials by surveying clinical trial registries. Among these 5 studies, only 352 of 684 eligible trials (51.1%) were included in the analyses. More than half of reported correlations (34 of 65; 52%) were of low strength (r ≤ 0.7). Approximately a quarter (16 of 65; 25%) were of medium strength (r > 0.7 to r < 0.85), and 15 of 65 (23%) were highly correlated (r ≥ 0.85) with survival. CONCLUSIONS AND RELEVANCE: Most trial-level validation studies of surrogate end points in oncology find low correlations with survival. All validation studies use only a subset of available trials. The evidence supporting the use of surrogate end points in oncology is limited.

Can a resident's publication record predict fellowship publications?

BACKGROUND: Internal medicine fellowship programs have an incentive to select fellows who will ultimately publish. Whether an applicant's publication record predicts long term publishing remains unknown. METHODS: Using records of fellowship bound internal medicine residents, we analyzed whether publications at time of fellowship application predict publications more than 3 years (2 years into fellowship) and up to 7 years after fellowship match. We calculate the sensitivity, specificity, positive and negative predictive values and likelihood ratios for every cutoff number of application publications, and plot a receiver operator characteristic curve of this test. RESULTS: Of 307 fellowship bound residents, 126 (41%) published at least one article 3 to 7 years after matching, and 181 (59%) of residents do not publish in this time period. The area under the receiver operator characteristic curve is 0.59. No cutoff value for application publications possessed adequate test characteristics. CONCLUSION: The number of publications an applicant has at time of fellowship application is a poor predictor of who publishes in the long term. These findings do not validate the practice of using application publications as a tool for selecting fellows.

A decade of reversal: an analysis of 146 contradicted medical practices.

OBJECTIVE: To identify medical practices that offer no net benefits. METHODS: We reviewed all original articles published in 10 years (2001-2010) in one high-impact journal. Articles were classified on the basis of whether they addressed a medical practice, whether they tested a new or existing therapy, and whether results were positive or negative. Articles were then classified as 1 of 4 types: replacement, when a new practice surpasses standard of care; back to the drawing board, when a new practice is no better than current practice; reaffirmation, when an existing practice is found to be better than a lesser standard; and reversal, when an existing practice is found to be no better than a lesser therapy. This study was conducted from August 1, 2011, through October 31, 2012. RESULTS: We reviewed 2044 original articles, 1344 of which concerned a medical practice. Of these, 981 articles (73.0%) examined a new medical practice, whereas 363 (27.0%) tested an established practice. A total of 947 studies (70.5%) had positive findings, whereas 397 (29.5%) reached a negative conclusion. A total of 756 articles addressing a medical practice constituted replacement, 165 were back to the drawing board, 146 were medical reversals, 138 were reaffirmations, and 139 were inconclusive. Of the 363 articles testing standard of care, 146 (40.2%) reversed that practice, whereas 138 (38.0%) reaffirmed it. CONCLUSION: The reversal of established medical practice is common and occurs across all classes of medical practice. This investigation sheds light on low-value practices and patterns of medical research.

Cardiovascular primary prevention: how high should we set the bar?

Recent trials in cardiovascular medicine have contradicted current practice, and, accordingly, are medical reversals. Extended-release niacin and fenofibrate have failed to provide mortality benefit when added to statin therapy, though both drugs have been used for this purpose for years. Cardiovascular primary prevention is no small matter. Annual spending on statins exceeded $19 billion in 2005, ezetimibe cost over $5 billion in 2007, and fenofibrate costs passed $1 billion in 2009. Given the tremendous price of these medications, and recent trials that have undermined years of practice, we propose that the bar for cardiovascular primary prevention has been raised. Large studies must show improvements in overall mortality before novel agents are recommended and used. The implications of this proposal are considered.