Acute myocardial infarction in an untreated patient with acute myeloid leukemia.

Key Clinical Message: Acute leukemia, particularly AML, is closely associated with thrombotic events, driven by complex factors like coagulation system changes, endothelial dysfunction, and leukemic cell interactions with the vascular system. Certain chemotherapy drugs can exacerbate the prothrombotic state. Understanding these dynamics is crucial for effective thromboprophylaxis in carefully selected patients with leukemia. Abstract: Thrombosis is a significant complication of acute leukemia. Thrombotic events mostly occur at diagnosis or during induction therapy. Here we report the occurrence of myocardial infarction (MI) before initiation of therapy, in a patient with acute myeloid leukemia not otherwise specified (AML NOS) who had no other significant risk factors for coronary artery disease. The occurrence of MI in this patient limited the choice of induction therapy and resulted in mortality. We discuss the pathogenesis and risk factors associated with increased thrombosis in AML and advocate for risk-adapted thromboprophylaxis in this patient population.

Advances in Immunology: A Cornerstone in Diagnosis and Therapy of Merkel Cell Carcinoma.

Merkel cell cancer (MCC) is a rare cutaneous malignancy arising from neuroendocrine cells. This rare but lethal malignancy (mortality greater than 30%) has also tripled in incidence over the last two decades. The role of immunodeficiency in pathogenesis of this rare malignancy is well established, with elucidation of viral pathogenesis by Merkel cell polyoma virus (MCPyV), a novel polyoma virus, in a majority of patients. Viral neoantigens while playing an important role in oncogenesis can also aid in early immunologic detection of recurrent disease. Viral neoantigens can also be targets for immunotherapy. Immune checkpoint inhibitors (ICI) have established role in frontline therapy in addition to recurrence of metastatic MCC. ICI therapy is being explored in adjuvant and neoadjuvant settings as well. We would like to illustrate curative potential of early diagnosis of recurrence and prompt use of ICI in treatment of oligometastatic disease in our case presentation.

A rare case of chordoma presenting as a Pancoast tumor.

The notochord is the defining structure of all chordate embryos. It is a midline structure ventral to the ectoderm, neural plates, and neural arch. Remnants of the notochord ultimately give rise to the nucleus pulposus. The function of the notochord is to organize the surrounding structures. Chordoma is a rare malignant bone tumor arising from remnants of the notochord. These tumors are indolent and can present as incidental or locally advanced involving adjacent structures. These tumors typically present at the skull base and sacral spine but more rarely can be seen on the cervical and thoracic spine. Rare cases of chordoma invading the brachial plexus have been recorded. Surgical resection is the mainstay of treatment for chordomas. We would like to discuss a novel presentation of a chordoma as a Pancoast tumor, and aim to highlight the clinical importance of accurate diagnosis and planning therapy along with poor prognosis of incomplete surgical resection.

Recurrent Colon Cancer: Presentation With Disseminated Intravascular Coagulation From Disseminated Carcinomatosis of the Bone Marrow.

Diffuse carcinomatosis of the bone marrow (DCBM) is a rare clinical condition characterized by diffuse bone marrow involvement with hematological changes. This case study concerns a patient who presented with DCBM secondary to colon cancer with diffuse intravascular coagulation. This is a rare presentation of DCBM in colon cancer. The case study also elaborates on clinical features, pathogenesis, and therapy of this unique presentation.

Chronic Myelomonocytic Leukemia Presenting With Polyserositis and Seropositivity for Rheumatoid Arthritis.

Chronic myelomonocytic leukemia (CMML) is a rare clonal stem cell disorder associated with clinical and pathologic of myelodysplasia and myeloproliferation. Systemic autoimmune/inflammatory disorders (SAID) and polyserositis have been associated with CMML. These manifestations can be observed concomitantly, shortly before diagnosis or anytime along the course of illness. We report a case of myeloproliferative CMML who presented with polyserositis and positive serology for rheumatoid arthritis. Retrospective studies of myelodysplasia/CMML have reported 15% to 25% incidence of SAID. The most commonly observed disorders include systemic vasculitis, connective tissue diseases, polychondritis, seronegative arthritis, and immune thrombocytopenia. SAID does not confer adverse prognosis in retrospective studies. Polyserositis is less common; this may result from leukemic infiltrate or result from autoimmunity. Treatment of serositis includes steroids and cytoreductive agents. Serositis may confer poor prognosis and hypomethylating therapy may improve the outcome.

Statin-Induced Rhabdomyolysis Due to Pharmacokinetic Changes From Biliary Obstruction in a Patient With Metastatic Prostate Cancer.

Statins work synergistically with androgen receptor blockers and androgen biosynthesis inhibitors, improving survival in patients with metastatic castration resistant prostate cancers (mCRPCs). Survival improvement is more pronounced for patients receiving androgen biosynthesis inhibitors compared with patients receiving androgen receptor blockers. A rare adverse interaction between simvastatin and abiraterone (Zytiga), an androgen biosynthesis inhibitor, was observed in a patient with mCRPC due to pharmacokinetic changes resulting from obstructive jaundice.

Capillary Leak Syndrome From Rituximab Therapy of Lymphoma.

Capillary leak syndrome (CLS) is characterized by plasma extravasation into the interstitium with resultant hypotension, anasarca, hemoconcentration, and hypoalbuminemia in the absence of albuminuria. Initially reported in Clarkson's disease (systemic capillary leak syndrome), CLS has been observed in multiple disease settings, the most common being sepsis. In oncology, CLS has been reported more often as a complication from therapy, and less often from malignancy. In this case study, we documented clinical manifestation, laboratory features, and radiological findings of CLS from rituximab therapy when employed in combination with a multi-agent chemotherapy regimen (EPOCH-R). Differentiating drug-induced CLS from sepsis, which presents with the same clinical features, is important in avoiding further exposure to rituximab, which could be fatal to the patient.

Delayed acute pancreatitis induced by nilotinib in a patient with chronic myeloid leukemia attaining sustained complete molecular response.

Advent of tyrosine kinase inhibitors (TKI) have revolutionized therapy of chronic myeloid leukemia. Imatinib was the first agent utilized in the therapy of CML. Nilotinib, a second generation TKI, results in an increase in number of patients achieving major molecular response at an earlier time point. Asymptomatic elevations in pancreatic enzyme is common and acute pancreatitis within weeks to months from start of therapy has been observed. Delayed onset pancreatitis has not been reported. We report a case of delayed onset pancreatitis in a patient with sustained complete molecular response. On account of the deep response, we were able to avoid starting alternate tyrosine kinase inhibitors that could also result in pancreatitis as a class effect.

Vitamin A and Hydrochlorothiazide Causing Severe Hypercalcemia in a Patient With Primary Hyperparathyroidism.

OBJECTIVE: To report a case of severe hypercalcemia, exacerbated by vitamin A supplementation and hydrochlorothiazide, in a patient with primary hyperparathyroidism. METHODS: Clinical and laboratory findings are presented along with response to therapy. RESULTS: A 68-year-old white female presented to the emergency department complaining of nausea, vomiting, and altered mental status. Laboratory findings revealed calcium 15.8 mg/dL (8.4-10.2), albumin 4.1 g/dL (3.8-4.8), and parathyroid hormone 62 pg/mL (14-64). Serum calcium improved after intravenous hydration with normal saline. Prior to this hospitalization, over-the-counter medications were significant for calcium (600 mg daily), vitamin A (11 000 IU daily), and vitamin D (800 IU daily).The patient's prescription medications were significant for hydrochlorothiazide (12.5 mg daily). Twenty-four-hour urine calcium was subsequently found to be 146 mg (35-250). Myeloma, lymphoma, and sarcoidosis were ruled out as the etiology for hypercalcemia. The diagnosis of primary hyperparathyroidism was confirmed. She was treated surgically for primary hyperparathyroidism. The right and left superior parathyroid showed hypercellular parathyroid on pathology. The patient was normocalcemic after surgery. CONCLUSION: Previous reports suggest that very high doses of vitamin A is required to cause hypercalcemia. This case suggests that in a setting of primary hyperparathyroidism and hydrochlorothiazide therapy, vitamin A may contribute to the development of severe hypercalcemia in patients who are on calcium and vitamin D supplements. Given their biologic effects, public awareness needs to be created regarding the injudicious use of vitamins.

Long-term outcome results of the first tandem autotransplant trial for multiple myeloma.

Total Therapy 1, the first tandem autotransplant trial for newly diagnosed patients with multiple myeloma, was designed to increase the frequency of complete response (CR) and thereby extend survival. With a median follow-up of 12 years, 62 of 231 initially enrolled patients are alive (17% at 15 years); 31 remain event free (7% at 15 years) including 16 of 94 (41%) that initially achieved CR. Currently alive patients less frequently had cytogenetic abnormalities (CAs) at baseline (P = 0.002), postenrolment (P < 0.001) and at relapse (P = 0.004); elevations of serum C-reactive protein (CRP) (P = 0.003) and lactate dehydrogenase (P = 0.029), anaemia (P = 0.029) and they more often completed two transplants within 12 months (P = 0.019). Postenrolment overall survival (OS) and event-free survival (EFS) were superior in the absence of CA of the hypodiploidy or deletion 13 variety (P < 0.001 and 0.037 respectively) and in the presence of low CRP at baseline (P = 0.001 and 0.017 respectively). Postrelapse survival was longer in the absence of CA at relapse (P < 0.001), IgA isotype (P = 0.002), International Staging System stage 3 (P = 0.014), and when patients had two protocol transplants prior to relapse (P = 0.038). Ten-year EFS and OS could be accomplished in 15% and 33% of patients, respectively, when all agents available in 1989, especially high-dose melphalan, were applied together upfront for the management of myeloma.

Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity.

OBJECTIVES: To determine the progression-free survival at 12 weeks, to evaluate the toxic effects, and to analyze the biological activity of thalidomide in patients with relapsed multiple myeloma (MM) after high-dose chemotherapy and stem cell transplantation. PATIENTS AND METHODS: From 1999 to 2001, we performed a multicenter prospective phase 2 study in patients with MM that relapsed after high-dose chemotherapy and stem cell transplantation to evaluate the efficacy of oral thalidomide, with dose escalation from 200 to 600 mg/d over 12 weeks and a subsequent maintenance phase of 200 mg/d for up to 1 year. Outcome was correlated with serum and plasma levels of vascular endothelial growth factor and serum levels of tumor necrosis factor alpha, soluble intercellular adhesion molecule 1, interferon gamma, interleukin (IL) 2, and IL-6 during treatment. RESULTS: Thirty patients were treated (19 men and 11 women; median age, 58 years). The median number of prior therapies was 5, and the median duration from diagnosis of MM to study enrollment was 4.3 years. The 12-week progression-free survival rate was 67% (95% confidence interval [CI], 48%-86%). The observed response rate (partial response plus minor response) was 43% (95% CI, 28%-60%) with a median duration of 6 months. Attributable toxicities included constipation, fatigue, rash, and neuropathy, which was dose limiting in 8 patients (27%). Dose escalation from 200 to 600 mg/d was achieved in 50% of patients. Although responses were observed with lower doses, possibly eliminating the need to escalate the dose, responses were also seen in patients who completed the dose escalation. Some patients had disease progression while receiving the maintenance dose of 200 mg/d. Analysis of biomarker assays did not identify any biomarker associated with greater response, but a significant increase in levels of soluble intercellular adhesion molecule 1, IL-2, and interferon gamma was seen with thalidomide therapy. CONCLUSION: The optimal thalidomide dose varies, and adverse effects can be dose limiting. The dose of thalidomide therapy should be based on the individual patient to ensure that it is well tolerated and that a response is achieved.

Survival after relapse following tandem autotransplants in multiple myeloma patients: the University of Arkansas total therapy I experience.

Despite the superiority of high-dose (compared with standard) treatment in multiple myeloma, relapses still occur. We evaluated relapse patterns, salvage treatments employed and outcome in patients given tandem transplants on our total therapy I protocol. We focused on 146 patients (of 231 enrolled) who received tandem autotransplants < or =12 months apart and survived > or =2 months after the second transplant. With a median follow-up of 9 years after enrollment, 31 (21%) patients remain in complete or stable partial remission. Ninety-five (65%) patients received therapy for relapsing myeloma. The median time from the first transplant to relapse was 2.9 years. The median overall survival from relapse was 2.4 years. In one-quarter (23/95) of cases, the postrelapse interval exceeded the interval from the first transplant to relapse. On multivariate analysis, the presence of any cytogenetic abnormalities [P<0.001, Hazard Ratio (HR): 3.84] and beta-2 microglobulin levels >4 mg/l at relapse (P<0.001, HR: 2.87) were significant for poor survival after relapse. The median survival after relapse was 5.1, 1.3 and 0.7 years in patients with none (44%), one (46%) and two (10%) poor-risk factors, respectively. In conclusion, a sizeable fraction of myeloma patients relapsing after tandem autotransplants without poor-risk features enjoyed meaningful survival prolongation when appropriately treated.

Infection--an underappreciated cause of bone pain in multiple myeloma.

Bone pain, especially back pain, is a common presenting feature of myeloma patients. We report three multiple myeloma patients with exacerbations of back pain and referred shoulder pain resulting from vertebral infections. Two patients were treated with surgery, and one patient had computerized tomography-guided percutaneous needle aspiration for diagnostic purposes. All three patients received a prolonged course of antibiotics. Vertebral infection resolved with this treatment in all three patients without any recurrence. Previous dexamethasone therapy, together with an episode of bacteraemia, appears to be a predisposing factor for vertebral infection. Magnetic resonance imaging enabled the diagnosis in all three patients.

Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression.

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.

Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.

High-dose treatment (HDT) with autologous stem cell transplant (ASCT) is superior to conventional chemotherapy in multiple myeloma. However, relapses eventually occur, especially in the presence of unfavourable cytogenetic abnormalities, high beta-2 microglobulin levels prior to transplant and extensive prior treatment. Cytotoxic consolidation chemotherapy, following tandem transplants (TT), was given to 75 myeloma patients with at least one poor prognostic factor. When their outcome was compared with that of 75 matched controls who received dexamethasone +/- interferon post TT, no event-free or overall survival advantage was observed. Other approaches may be required to improve survival in multiple myeloma.

Nephrotic proteinuria associated with high-dose pamidronate in multiple myeloma.

Five patients receiving increased dose or frequency of pamidronate beyond the recommended dose (90 mg/monthly) exhibited nephrotic proteinuria (range 3.96-24 g/24 h). On dose reduction or discontinuation, three of these patients showed decreased proteinuria to normal levels (< 1 g/24 h), and proteinuria decreased to 4.5 g/24 h from a peak of 24 g/24 h in one patient. One patient on haemodialysis (hence not evaluable) had proteinuria of 2 g/24 h and elevated creatinine levels. One other patient continued to show elevated creatinine levels (272.8 micro mol/l). Renal biopsies obtained in two patients revealed focal segmental glomerulosclerosis.

Waldenström's macroglobulinaemia: current therapy and future approaches.

Waldenström's macroglobulinaemia is a rare B-cell malignancy. It is prevalent in the sixth and seventh decades, the median age at diagnosis being 63 years. Conventional treatment has involved alkylator therapy, especially chlorambucil given daily at a low dose or intermittently at a higher dose. Purine analogues, used initially as salvage therapy in refractory disease, are increasingly used for initial therapy. However, purine analogue therapy entails significant complications, including immunosuppression, pancytopenia and autoimmune haemolysis. Moreover, it is unclear whether purine analogues extend survival. All of these need to be considered before initiation of therapy. More recently, anti-CD20 monoclonal antibody and thalidomide have been used with a 30% response in treated patients. High-dose therapy with stem cell support achieves a partial response in a majority of patients receiving this modality of therapy. The median survival of 5 years has not improved considerably since the introduction of purine analogues. Complete response is still uncommon; using all available modalities of therapy may increase the complete response rate and improve survival. Great strides in understanding the malignant cell, the microenvironment and the potential interactions have identified potential targets for therapy in multiple myeloma. These agents may also be useful in Waldenström's macroglobulinaemia. Since this is a rare malignancy, all patients should be treated with well-designed clinical protocols to achieve improvement in outcome.

Optimizing dendritic cell-based immunotherapy in multiple myeloma.

Vaccination with idiotype protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. These studies used immature DCs, which are less potent at activating T cells and could differentiate to macrophages once the cytokines were withdrawn. After intravenous administration, DCs accumulate in the lungs and liver for up to 48 h, thus reducing their potential to migrate to lymphoid organs and interact with T cells. To improve the efficacy of DC vaccination in myeloma, we investigated the use of idiotype-pulsed mature DCs administered subcutaneously. Five patients (three IgG and two IgA myeloma) with stable partial remission following high-dose chemotherapy were enrolled. DC vaccines were administered three times at 2-week intervals at least 4 months post transplantation. Idiotype-specific T-cell responses, detected using enzyme-linked immunospot (ELISPOT) (four patients) and proliferation (two patients) assays, were elicited in four and anti-idiotypic B-cell responses in all five patients. The cytokine-secretion profile of activated T cells demonstrated a type-1 response. A 50% reduction in serum M-component was observed in one immunologically responding patient that persisted for 6 months and stable disease (for 6 months) resulted in the other three patients. The remaining patient without an immune response to the vaccination relapsed. No major side-effects were noted. Thus, subcutaneous administration of idiotype-pulsed mature DCs induced idiotype-specific T- and B-cell responses. Current efforts are geared towards optimizing the conditions of DC generation and administration, and the development of in vitro assays to monitor the cytotoxicity of the T cells.

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.