Mayank Sharma

Trends in multiple myeloma presentation, management, cost of care, and outcomes in the Medicare population: A comprehensive look at racial disparities

Outcomes have improved significantly in multiple myeloma (MM), but racial disparities in health care access and survival exist. A comprehensive analysis exploring MM care and racial disparities is warranted.

Racial disparity in utilization of therapeutic modalities among multiple myeloma patients: A SEER-medicare analysis

Outcomes have improved considerably in multiple myeloma (MM), but disparities among racial‐ethnic groups exist. Differences in utilization of novel therapeutics are likely contributing factors. We explored such differences from the SEER‐Medicare database. A utilization analysis of lenalidomide, thalidomide, bortezomib, and stem cell transplant (SCT) was performed for patients diagnosed with MM between 2007 and 2009, including use over time, use by race, time‐dependent trends for each racial subgroup, and survival analysis. A total of 5338 MM patients were included with median 2.4‐year follow‐up. Within the first year of MM diagnosis, utilization of lenalidomide, bortezomib, SCT, and more than one novel agent increased over time while utilization of thalidomide decreased. There was significantly lower utilization of lenalidomide among African‐Americans (P < 0.01), higher thalidomide use among Hispanics and Asians (P < 0.01), and lower bortezomib use among Asians (P < 0.01). Hispanics had the highest median number of days to first dose of bortezomib (P = 0.02) and the lowest utilization of SCT (P < 0.01). Hispanics and Asians were the only groups without notable increases in lenalidomide and bortezomib use, respectively. SCT utilization increased over time for all except African‐Americans. SCT use within the first year after diagnosis was associated with better overall survival (HR 0.52; 95% CI: 0.4–0.68), while bortezomib use was associated with inferior survival (HR 1.14; 95% CI 1.02–1.28). We noted considerable variability in MM therapeutics utilization with seeming inequity for racial‐ethnic minorities. These trends should be considered to eliminate drug access and utilization disparities and achieve equitable benefit of therapeutic advances across all races.

A pharmacological challenge predicts reversible rectal sensorimotor dysfunctions in women with fecal incontinence

In order to understand the pathophysiology of rectal sensorimotor dysfunctions in women with fecal incontinence (FI) and rectal urgency, we evaluated the effects of a muscarinic antagonist and an adrenergic α2 agonist on these parameters.

Comparison of Therapies for Primary Prevention of Esophageal Variceal Bleeding: A Systematic Review and Network Meta‐analysis

We performed a systematic review with network meta‐analysis (NMA) to compare the efficacy of different approaches in primary prevention of esophageal variceal bleeding and overall survival in patients with cirrhosis with large varices. Thirty‐two randomized clinical trials (RCTs) with 3,362 adults with cirrhosis with large esophageal varices and no prior history of bleeding, with a minimum of 12 months of follow‐up, were included. Nonselective beta‐blockers (NSBB), isosorbide‐mononitrate (ISMN), carvedilol, and variceal band ligation (VBL), alone or in combination, were compared with each other or placebo. Primary outcomes were reduction of all‐cause mortality and prevention of esophageal variceal bleeding. Random‐effects NMA was performed and summary estimates were expressed as odds ratio and 95% confidence intervals (OR; CI). Quality of evidence was critically appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. Moderate quality evidence supports NSBB monotherapy (0.70; 0.49‐1.00) or in combination with VBL (0.49; 0.23‐1.02) or ISMN (0.44; 0.21‐0.93) for decreasing mortality in patients with cirrhosis with large esophageal varices and no prior history of bleeding. Moderate‐quality evidence supports carvedilol (0.21; 0.08‐0.56) and VBL monotherapy (0.33; 0.19‐0.55) or in combination with NSBB (0.34; 0.14‐0.86), and low‐quality evidence supports NSBB monotherapy (0.64; 0.38‐1.07) for primary prevention of variceal bleeding. VBL carries a higher risk of serious adverse events compared with NSBB. Conclusion: NSBB monotherapy may decrease all‐cause mortality and the risk of first variceal bleeding in patients with cirrhosis with large esophageal varices. Additionally, NSBB carries a lower risk of serious complications compared with VBL. Therefore, NSBB may be the preferred initial approach for primary prophylaxis of esophageal variceal bleeding.

Painful and Painless Constipation: All Roads Lead to (A Change in) Rome

Disease classifications are useful to the extent that they facilitate an understanding of the pathophysiology, guide the diagnosis or treatment, or predict the natural history of the condition. In the field of gastroenterology (GI), disease classifications have long been used for functional syndromes that have largely eluded diagnosis based on conventional criteria such as histological, serological, or biochemical data. The Rome criteria classify chronic constipation as: functional constipation (FC), constipation-predominant IBS (IBS-C), and defecatory disorder (DD). FC is defined by the presence of two or more of six bowel symptoms such as excessive straining to defecate. IBS-C is defined by abdominal pain that is associated, in time, with bowel disturbances (harder or less frequent stools) and/or relief of pain with defecation. DD, which is defined by symptoms of FC or IBS-C combined with objective evidence of impaired rectal evacuation, respond to pelvic floor biofeedback therapy rather than to laxatives. Increased perception of visceral sensations is more prevalent in IBS-C than in FC [1]. The dose and the efficacy of medications such as lubiprostone or linaclotide differ between FC and IBS-C [2]. These features suggest that idiopathic constipation is not a homogenous entity, providing the raison d’être for classifying constipation according to response to therapy. Many patients with FC have abdominal pain, which blurs the distinction between FC and IBS-C. Indeed, in one study, approximately 90% of patients with IBS-C also had criteria for FC and about 44% of the FC patients also had criteria for IBS-C [3]. In patients with overlapping symptoms, a single diagnosis is only possible because the Rome criteria require patients who have symptoms of IBS-C and FC to be designated as IBS-C and not as FC. Moreover, it can be challenging to distinguish between FC and IBS-C in clinical practice [4] because many constipated patients who have infrequent and hard stools even in the absence of abdominal pain are puzzled when asked to relate the hardness and frequency of their bowel movements with the presence of abdominal pain. Lastly, in approximately one-third of patients, symptoms shift over time from CC to IBS-C and vice versa [3]. Hence, the current Rome system for classifying chronic constipation as FC and IBS-C appears to lack specificity and reproducibility; a superior approach is necessary. Beginning with a small case series from the pre-Rome era, several studies in the community and in clinical practice have used abdominal pain to characterize constipated patients as painful or painless constipation (Table 1).1 In the original paper, patients with painful constipation reported more disability, somatic symptoms, and urinary urgency than those with painless constipation; painful constipation resembled IBS-C rather than FC [6]. Remarkably, similar differences between painful and mild pain constipation were observed across studies even though the definition of abdominal pain varied among these studies (Table 1) [7]. Continuing this theme, a meticulous study by Bouchoucha and colleagues in this issue of Digestive Diseases and Sciences not only evaluated symptoms, anxiety, and depression, but also colonic transit and anorectal manometry in 546 consecutive constipated patients referred to a tertiary center [8]. Of these 546 patients, 301 (53%) and 245 (47%), respectively, were classified as having FC and IBS-C. Based on the revised classification, 316 (58%) had “mild pain” and

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti‐CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib‐resistant lines) elicited antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), antibody‐dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI‐WM1‐xenografted mice. CD38 is reported to augment B‐cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib‐resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single‐agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti‐WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co‐targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.

Impact of psychiatric comorbidities on health care utilization and cost of care in multiple myeloma

Approximately one third of cancer patients suffer from comorbid mood disorders that are associated with increased cost and poorer outcomes. The majority of patients with multiple myeloma (MM) are treated with corticosteroids; as many as three fourths of those taking corticosteroids develop neuropsychiatric complications, likely increasing morbidity and cost of care. MM patients diagnosed between 1991 and 2010 and reported in the Surveillance Epidemiology, and End Results-Medicare database were characterized as MM-Only, MM+Psychiatric (any psychiatric condition, preexisting or post-MM), or MM+Depression (depression as the only psychiatric diagnosis, preexisting or post-MM). Differences in demographic characteristics, occurrence of clinical myeloma-defining events (MDEs), health care utilization (inpatient, outpatient, ambulatory claims), and cost of care during the first 6 months of MM diagnosis were analyzed. Psychiatric comorbidities were reported more frequently in females, and racial minorities had lower rates of psychiatric comorbidities. All clinical MDEs were more common in the MM+Psychiatric and MM+Depression groups; within them, the majority were more common in patients diagnosed with the psychiatric condition or depression after MM compared with it being a preexisting condition. Health care utilization in all treatment settings was higher in those with psychiatric comorbidities. Cost of care within the first 6 months after MM diagnosis was significantly higher in the MM+Psychiatric and MM+Depression groups. This increase in cost was more pronounced for patients from racial minorities diagnosed with a psychiatric condition, including depression. Psychiatric comorbidities significantly impact the clinical presentations, health care utilization, and cost among patients with MM. These findings need to be addressed for improved survivorship of MM patients.

PSYCHIATRIC COMORBIDITIES ARE ASSOCIATED WITH SIGNIFICANTLY INCREASED COST OF CARE AND HEALTHCARE UTILIZATION IN MULTIPLE MYELOMA (MM) PATIENTS

C antiphospholipid syndrome (CAPS) is a systemic autoimmune disease which occurs in <1% of patients with Antiphospholipid syndrome (APS). It is the most severe variant of the classic APS, characterized by histopathologic and clinical evidence of widespread small vessel microthrombi. The resulting inflammatory cytokine storm causes multi-organ failure over a short period and laboratory confirmation of high antiphospholipid antibody titers. Sarcoidosis is a systemic inflammatory disorder characterized by granulomatous inflammation of various organs. Although the association of APS and sarcoidosis may be explained by shared immune dysregulation, cases with concurrent sarcoidosis and APS are extremely rare. Here, we present the 12th reported case, presenting with digital gangrene and review the literature on CAPS. A 66 year-old gentleman presented with rapidly progressive ischemic changes of extremities with skin ulcerations and gangrene of peripheral digits. Autoantibodies testing revealed elevated levels of anti-beta2 glycoprotein IgM and anti-cardiolipin IgM antibodies. Skin ulceration biopsy showed vasculitis with intravascular microthrombi deposition. First-line treatment was initiated for “Probable CAPS” with anticoagulation, glucocorticoids and therapeutic plasma exchange. Subsequent, bone marrow biopsy workup for acute leucopenia with lymphopenia, revealed non-necrotizing granuloma, suggestive of sarcoidosis. This was further substantiated with high serum Angiotensin converting enzyme level. CAPS is a challenging systemic disease requiring a high index of clinical awareness, as outcomes are poor without prompt recognition and early initiation of targeted multimodal therapy. This case highlights the need for a collaborative team approach. It is also the first case reported of probable CAPS associated with sarcoidosis of bone marrow.The thrombotic microangiopathies are a complex group of disorders that typically present with a schistocytic hemolytic anemia and associated thrombocytopenia with ensuing microvascular occlusion leading to tissue ischemia and end organ damage. Central nervous system, renal, gastrointestinal and cardiac microcirculations are frequent targets. Signs and symptoms related to organ dysfunction may evolve over weeks to months and may not be present simultaneously. Lactic dehydrogenase enzyme elevation due to microvascular ischemia is frequently disproportionate to elevation of bilirubin or reticulocyte count. The major thrombotic microangiopathies include Thrombotic thrombocytopenic purpura, Disseminated intravascular coagulation/sepsis, and Hemolytic Uremic Syndrome. Hemolytic Uremic Syndrome may be further divided into “typical”, related to Shiga toxin, “atypical”, related to dysregulation or over-activation of Complement, and secondary, including disorders of pregnancy such as the Hepatic enzyme elevation low platelet syndrome or pre-eclampsia, certain other infections such as Streptococccus pneumonia, auto-immune disorders such as Sjogren’s syndrome, cancer, chemotherapy, or other medications, such as quinine and calcineurin inhibitors. These disorders can provoke direct microvascular damage and present as a thrombotic microangiopathy or act as a trigger for a microangiopathic syndrome in individuals with a genetic predisposition. The level of ADAM-TS 13, Von Willebrand Factor cleaving enzyme, is a key discriminator between Thrombotic thrombocytopenic purpura and HUS being severely reduced in Thrombotic thrombocytopenic purpura but not Hemolytic Uremic Syndrome. Plasma exchange with or without steroids is the mainstay of treatment for Thrombotic Thromobocytopenic Purpura. Anti C5 complement antibody therapy has evolved as an important treatment for atypical Hemolytic Uremic Syndrome. Although we have gained significant insight into the pathophysiology of many of these disorders, given the complex interplay between genetic factors, acquired factors, the roles of the humoral, cellular, and innate immune systems, the inflammatory response, and the coagulation system, thrombotic microangiopathies remain clinically challenging. This review will focus on a summary of our current knowledge with regard to diagnosis and treatment of Thrombotic thrombocytopenic purpura and Hemolytic Uremic Syndrome and how they relate to each other and the broader family of thrombotic microangiopathies. Three clinical cases will be used to illustrate key points.Treatment of steroid resistant ITP in adults can be challenging in patients who are actively bleeding. The majority of novel therapies that have been developed in the last few years including anti CD 20 monoclonal antibody therapy (Rituximab) and the thrombopoietic growth factors romiplostim and eltombopag, take time to work. Combinations of active agents may accelerate the response rate. Splenectomy and the use of immunosuppressive agents may still have an important role in the acute management. A case of resistant ITP will be discussed in the context of currently available treatment modalities. *Correspondence to: James Granfortuna, Associate Professor of Clinical Medicine, Cone Health affiliate of University of North Carolina Chapel Hill Medical Center, USA, Tel: +1 336-832-8062; E-mail: James.Granfortuna@ conehealth.com Received: July 30, 2018; Accepted: August 10, 2018; Published: August 13, 2018 Introduction Immune Thrombocytopenia is an autoantibody mediated blood disorder characterized by both increased platelet destruction and decreased platelet production. The estimated incidence is 9.5 cases per 100,000 population with an estimated 200,000 cases per year in the United States. Median age at presentation is 56 with 2 peaks: age 20-40 and age over 60. There is no male/female predominance in adults. The disorder is self-limited in 70-80% of children. Immune thrombocytopenia typically presents with bleeding from mucosal surfaces which may include epistaxis, oral mucosal bleeding, or bleeding from the GI or Genitourinary tracts. Critical site bleeding, including the brain, may occur. Spontaneous bruising and a petecchial rash are common presenting complaints. Many patients present with an isolated abnormality found on routine laboratory analysis [1-6]. An International consensus panel redefined the older terminology of ITP (Idiopathic Thrombocytopenic Purpura) into Primary and Secondary Immune Thrombocytopenia. Primary immune thrombocytopenia is a diagnosis of exclusion with isolated thrombocytopenia in the absence of other causes or disorders that may be associated with thrombocytopenia. Secondary immune thrombocytopenia comprises all forms of immune thrombocytopenia except primary ITP. Treatment is targeted to the underlying disease or offending medication/drug and usually has a different natural history compared with primary ITP (Table 1 and Figure 1) [2,7,8]. There are no robust laboratory or clinical parameters available to establish the diagnosis with accuracy. The platelet threshold for diagnosis was changed from ≤ 150,000 to ≤ 100,000 based on worldwide epidemiologic observations that there was only a 6.9% 10 year probability that a platelet count in the 100-150,000 range would get worse over time. Testing for the presence of anti-platelet antibodies has not been informative to date [9,10].