Racial Differences in Accepting Pegfilgrastim Onpro Kit (On-Body Injector) Use Among Cancer Patients.

Background: 1.1.Neulasta Onpro kit eliminates need for additional clinic visit after chemotherapy. Given the racially diverse population in our institution, we investigated acceptance of Onpro kit among patients on chemotherapy. Research Design and Methods: 1.2.Single-institution, retrospective review conducted in patients with GI tumors who received Onpro kit within 1 hour of completion of systemic chemotherapy from Jan 2014 through Jan 2018. Clinic/nursing notes and pharmacy records were reviewed to identify patients who refused Onpro kit and to discern reasons for refusal, including racial reason. Results: 1.3.Total 238 orders for kit were voided amongst 68 patients (Caucasian 41; African American 7; Spanish 3; Asian 17). Overall, 15/68 patients refused kit (22%) of these 87% were Asian. The reasons for refusal included dislike of bulky attachment to skin, request to place kit on stomach instead of arm, trepidation over unwitnessed administration of drug, fear of reaction, disposal at home, fear of pain, lack of confirmation of proper dose administration, and need for MRI. Conclusions: 1.4.While Onpro kit is an attractive alternative, 22% of patients with voided orders, mainly of Asian race, declined its application. We believe the current study represents the first look at important racial differences in accepting Onpro kit. Consideration of patients' cultural heritage, race, ethnicity and education may facilitate communication between physicians and patients to achieve optimal cancer care.

Incidence and implications of chemotherapy related hand-foot syndrome.

INTRODUCTION: Hand-foot syndrome (HFS) is a well-established cutaneous adverse event of certain chemotherapeutic agents, mainly capecitabine, continuously infused 5-fluorouracil, docetaxel and pegylated liposomal doxorubicin. Erythema, dysesthesia, pain, cracking and desquamation located on palms and soles are the most characteristic manifestations. Although HFS is a reversible and non-life-threatening clinical condition, it can often affect patient's quality of life significantly, hence necessitating therapeutic modifications or even treatment discontinuation. Areas covered: This is review article on current data regarding the clinical characteristics, grading and management of HFS. Special focus has been given to recent literature studying novel therapeutic strategies. Expert opinion: Early recognition, patient education and supportive measures are considered as the key elements in the management of HFS. Up to date, treatment interruption and dose intensity reduction are the mainstay of HFS management. Many topical formulations and systemic treatment regimens have been proposed, with COX-2 inhibitors being the most promising agents. Nevertheless, large prospective randomized controlled trials are needed in order to agree on solid, evidence-based treatment algorithms.

Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: a pooled analysis of individual patient data from four randomized, controlled trials.

BACKGROUND: Adjuvant oxaliplatin plus capecitabine or leucovorin/5-fluorouracil (LV/5-FU) (XELOX/FOLFOX) is the standard of care for stage III colon cancer (CC); however, there is disagreement regarding oxaliplatin benefit in patients aged >70. In most analyses, the impact of medical comorbidity (MC) has not been assessed. Efficacy and safety of adjuvant XELOX/FOLFOX versus LV/5-FU were compared with respect to age and MC using pooled data from four randomized, controlled trials, selected for access to patient-level MC data and including commonly endorsed and utilized regimens. PATIENTS AND METHODS: Individual data from patients with stage III CC in NSABP C-08, XELOXA, X-ACT, and AVANT were pooled, excluding bevacizumab-treated patients. Patients were grouped by treatment, MC (low versus high), or age (<70 versus ≥70), and compared for disease-free survival (DFS), overall survival (OS), and adverse events (AEs). Multivariable Cox proportional hazards regression controlled for gender, T stage, and N stage. RESULTS: DFS benefits were shown for XELOX/FOLFOX versus LV/5-FU regardless of age or MC, although benefits were modestly attenuated for patients aged ≥70. Hazard ratios were 0.68 (P < 0.0001) and 0.77 (P < 0.014) for <70 and ≥70 age groups; 0.69 (P < 0.0001) and 0.59 (P < 0.0001) for Charlson Comorbidity Index ≤1 and >1 groups; and 0.70 (P < 0.0001) and 0.58 (P < 0.0001) for National Cancer Institute Combined Index ≤1 and >1 groups. OS was also significantly improved in all groups. Grade 3/4 serious AE rates were comparable across cohorts and MC scores and higher in patients aged ≥70. Oxaliplatin-relevant grade 3/4 AEs, including neuropathy, were comparable across ages and MC scores. CONCLUSIONS: Results further support consideration of XELOX or FOLFOX as standard treatment options for the adjuvant management of stage III CC in all age groups and in patients with comorbidities, consistent with those who were eligible for these clinical trials.

A phase II, open-label, multicenter study to evaluate the antitumor efficacy of CO-1.01 as second-line therapy for gemcitabine-refractory patients with stage IV pancreatic adenocarcinoma and negative tumor hENT1 expression.

BACKGROUND: Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5'-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. METHODS: Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). RESULTS: Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1-8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. CONCLUSION: This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma.

Epidemiology and natural history of central venous access device use and infusion pump function in the NO16966 trial.

BACKGROUND: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer. METHODS: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump performance in the NO16966 trial. RESULTS: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6-4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction. CONCLUSIONS: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings.

Therapeutic human monoclonal antibodies against cancer.

There are over 30 monoclonal antibodies that are FDA approved for a variety of diseases ranging from malignancies to autoimmune diseases to macular degeneration. These antibodies include murine, fully humanized, and chimeric antibodies. There are a number of monoclonal antibodies used in the treatment of malignancies; in fact, three of the top five grossing antibodies (bevacizumab, trastuzumab, and rituximab) are used in oncology Scolnik (mAbs 1:179-184, 2009).

Open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of intravenously administered CNF1010 (17-(allylamino)-17-demethoxygeldanamycin [17-AAG]) in patients with solid tumors.

BACKGROUND: 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. METHODS: Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m(2)/day) and three-to-six-patient (≥25 mg/m(2)/day) cohorts according to a modified Fibonacci's schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed. RESULTS: Thirty-five patients were treated at doses ranging from 6 to 225 mg/m(2). A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m(2); shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m(2); extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m(2)) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m(2), with a dose-proportional increase in C max and AUC0-inf. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses >83 mg/m(2). CONCLUSION: The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.

Is there a role of targeted agents in the management of adrenocortical cancers?

Background. Adrenocortical carcinoma (ACC) is a rare and aggressive tumor arising from the adrenal cortex with an incidence of one to two cases per million within the general US population. Recent developments in the understanding of the pathogenesis of ACC have led to multiple clinical trials involving targeted agents in the management of ACC. Patients and Methods. We report two cases of refractory adrenocortical cancer (cisplatin, adriamycin, etoposide, and mitotane) who were treated with targeted agents such as erlotinib and sutent, respectively. A total of 2 women with adrenocortical cancer were reviewed and followed for a median time of 6 months. Radiological response, duration of response and toxicities were evaluated. Results. In both cases, the targeted agents were able to control the disease for a short duration, but due to the deterioration in performance status and fatigue the agents were discontinued. Conclusion. The current observations emphasize the need for better targeted treatment modalities and strategies for the management of this fatal disease.

Desmoplasia in pancreatic cancer. Can we fight it?

The hallmark of pancreatic tumours, the desmoplastic reaction, provides a unique microenvironment that affects pancreatic tumour behaviour, its ability to grow and metastasize as well as resist the effects of chemotherapy. Complex molecular interactions and pathways give rise to the desmoplastic reaction. Breakdown or penetration of the desmoplastic reaction may hold the key to overcoming the limits of delivery of efficacious chemotherapy or the development of new targeted treatments. Herein we discuss such new developments to fight the desmoplastic reaction, including inhibitors of the epidermal growth factor, fibroblast growth factor, the hedgehog pathway, as well as new molecular targets like CD40 agonist and its effects on T cells, extracellular matrix modifying enzymes such as LOXL2 inhibitor and novel tumour penetrating peptides for delivery of drugs.

A phase I study evaluating the effect of CDHP as a component of S-1 on the pharmacokinetics of 5-fluorouracil.

UNLABELLED: The purpose of this study was to investigate the effect of gimeracil (CDHP), a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor, on the pharmacokinetics of 5-fluorouracil (5-FU) and other related metabolites by comparing the pharmacokinetic (PK) profile of S-1 (tegafur [FT] + CDHP + oteracil potassium [Oxo]) to that of FT alone. PATIENTS AND METHODS: Patients with advanced solid tumors received single oral doses of S-1 (50 mg) and FT (800 mg) on days 1 and 8 in a randomized crossover fashion. Plasma samples were collected on days 1, 2, 3, 8, 9 and 10. Single-dose PK parameters were determined for FT, 5-FU and α-fluoro-ß-alanine (FBAL). Following the single-dose crossover period, patients entered an extension phase and received treatment with S-1 b.i.d. for 14 days followed by a 7-day rest, repeated every 3 weeks. RESULTS: A total of 12 patients were enrolled; median age was 59 years and mean body surface area was 1.94 m(2). Following S-1 administration, 5-FU exposure was significantly greater (approximately 3-fold) compared to FT alone (p ≤ 0.0007 for AUC0-inf, AUC0-last, and C(max) of 5-FU) despite the 16-fold higher dose of FT administered alone compared to S-1, while plasma concentrations of FT and FBAL were significantly lower with S-1 (p < 0.0001 for all comparisons). Following both single- and multiple-dose administration of S-1, the average maximum DPD inhibition was observed at 4 h post-dose. The extent of inhibition was similar following single and multiple dosing. Following single- and multiple-dose administration of S-1, plasma concentrations of uracil returned to baseline levels within approximately 48 h of dosing, indicating reversibility of DPD inhibition by CDHP. CONCLUSION: Despite the differences in the FT dose administered, exposure to 5-FU was significantly greater following S-1 administration compared to FT administration. Conversely, exposure to FT and FBAL were significantly less following S-1 administration compared to FT administration. Thus, the DPD inhibitory action of CDHP contributes to a decrease in 5-FU catabolism and to significantly higher blood levels of 5-FU compared to FT alone.

Review. Colon cancer vaccines: an update.

Despite advances in research and treatment modalities, colorectal cancer still accounts for around half a million deaths yearly worldwide. Traditional and even newer pharmaceutical therapeutic regimens are limited in terms of tolerance, efficacy and cross-resistance. Additional non-cross resistant therapies with non-overlapping toxicities are needed to improve the outcome for patients with colorectal cancer. Cancer vaccines, designed to activate immune effectors (T-cells and antibodies) to prevent recurrence or treat advanced cancers, have now demonstrated clinical benefit in prostate cancer and lymphoma. Because immune effector infiltration into colon tumours is associated with improved clinical outcome, vaccines intended to activate immune responses against colon cancer have generated significant interest. This review discusses data supportive of the immune responsiveness of colorectal cancer, as well as the current status of colon cancer vaccines under development including those based on whole tumour cells or lysates, peptide or protein antigens, anti-idiotype antibodies, viral vectors, and dendritic cells. We also discuss challenges to colon cancer vaccine development, such as tumour associated mechanisms for immune evasion, and how future strategies may address these challenges.

Gastric cancer in the elderly: an overview.

AIMS: Gastric cancer in the elderly represents a distinct entity with specific clinicopathological characteristics and the majority of affected patients belong to this age group. Subtotal or total gastrectomy with radical lymph node dissection, adjuvant chemoradiotherapy or perioperative chemotherapy represent the only potentially curative treatment options and seem to be performed with acceptable morbidity and mortality rates in selected elderly patients. Published research is very limited due to the strict selection and under-representation of elderly patients in clinical trials. A review of current recommendations and practice was performed. METHODS: A comprehensive literature review was performed searching Medline for articles published since 1974, using "gastric cancer", "elderly" and "treatment" as keywords. OBSERVATIONS: The data suggest that elderly patients that fulfill the inclusion criteria of clinical trials experience the same advantages and toxicities from chemotherapy as younger patients. Fit elderly patients with operable gastric cancer should be candidates for the standard surgical resection provided that preoperative comorbidities are taken into account. Perioperative chemotherapy or postoperative chemoradiotherapy should be added in case of locally advanced disease. Palliative systemic chemotherapy seems to prolong survival in recurrent and metastatic disease. CONCLUSIONS: Chronological age alone is not sufficient reason to withhold curative or palliative treatment from an elderly gastric cancer patient. Performance status does not suffice in order to estimate the general condition of elderly patients and cofactors regarding their functional, social and mental status have to be considered.

Pharmacogenetics and biomarkers in colorectal cancer.

The prognosis of patients with colorectal cancer (CRC) is affected by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Predicting response and limiting drug-induced toxicity for patients with CRC are also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets and drug transport molecules are important contributing factors. At present, there is inconsistent and rather low use of pharmacogenetic testing in the clinical setting because of a lack of robust evidence or of resources. Patients' selection and tailored treatments by the introduction of genetic testing will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes in the most cost-effective way. Here, we review the main genetic alterations observed in familial and sporadic CRC and their associations with the metabolism, efficacy and toxicities of drugs used in this disease.

Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review.

BACKGROUND: Standard therapy for locally advanced rectal cancer (LARC) is concurrent neo-adjuvant chemo-radiation using infusional 5-fluorouracil (CIV-5-FU). Capecitabine (CAP) offers a convenient oral replacement for CIV-5-FU. There is no randomized trial comparing infusional 5-FU to capecitabine. We retrospectively compared the safety and efficacy of CAP-based regimens with well-established CIV-5-FU-based regimens in LARC. MATERIALS AND METHODS: We collected published data on 542 patients treated on either CIV-5-FU (197) or CAP (345) with concurrent radiation (external radiation treatment, XRT) for LARC. This included Phase I or II studies published or available from Pubmed. Safety was assessed by determining proportion of patients who experienced grade III/IV adverse effects. Efficacy was assessed by determining pathological complete response (pCR). Chi-square tests were used to compare the two regimens. A P value less than 0.05 was considered statistically significant. Statistical tests were further corrected for multiplicity using the method of Benjamini and Yekutieli (Ann Stat, 29(4):1165-1188, 2001). RESULTS: pCR was significantly higher in patients getting CAP vs CIV-5-FU (25 vs 13%; P = 0.008,.P adj = 0.034). Both regimens were generally well tolerated. There was no grade IV toxicity reported. Grade III hand foot syndrome was more common in the CAP group, and grade III diarrhea was more common in the CIV group. CONCLUSIONS: CAP when compared to CIV seems to have superior efficacy with reasonable toxicities. It is reasonable to treat LARC with CAP + XRT.

DPYD*2A mutation: the most common mutation associated with DPD deficiency.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the elimination of approximately 80% of administered dose of 5-FU. DPD deficiency has been associated with severe 5-FU toxicity. Syndrome of DPD deficiency manifests as diarrhea, stomatitis, mucositis, and neurotoxicity and in some cases death. This is a true pharmacogenetic syndrome, with symptoms being unrecognizable until exposure to the drug. PATIENTS AND METHODS: A 75-year-old patient with metastatic pancreatic adenocarcinoma developed grade 4 thrombocytopenia, grade 3 coagulopathy, and grade 3 neurologic toxicity with a fatal outcome following administration of 5-FU. Due to pancytopenia, DPD activity could not be determined in peripheral blood mononuclear cells (PBMC) using a previously described radioassay. Therefore, screening and genotypic analysis of homozygous and heterozygous, known and unknown sequence variants, in the DPYD gene were performed using DHPLC as previously described. All DPYD sequence variants identified by DHPLC were confirmed by DNA sequencing using a dideoxynucleotide chain termination method and capillary electrophoresis on an ABI 310 Automated DNA Sequencer. RESULTS: Genotyping analysis of the DPYD gene revealed the presence of the heterozygous mutation, IVS14 + 1 G > A, DPYD*2A. CONCLUSION: Genotypic analysis using DHPLC can be employed to screen DPD deficiency in a patient with severe neutropenia. The mutation IVS14 + 1 G > A, DPYD*2A, is the most common mutation associated with DPD deficiency. A G > A base change at the splice recognition sequence of intron 14, leads to exon skipping and results in a 165-bp deletion in the DPD mRNA. We have previously demonstrated that a homozygote DPYD*2A genotype results in complete deficiency while the heterozygous DPYD*2A genotype results in partial deficiency of DPD.

DIC secondary to acute pancreatitis.

Various hematological abnormalities including fall in serial values of hemoglobin or hematocrit, coagulation factor abnormalities, leukocytosis, acute hemolytic anemia, thrombocytopenia, and thrombotic thrombocytopenic purpura or hemolytic uremic syndrome have been reported in patients with acute pancreatitis. Similarly, abnormalities of blood coagulation factors consistent with disseminated intravascular coagulopathy (DIC) have also been noticed in patients with pancreatitis. We report a case of a 33-year-old female with acute pancreatitis who presented with one episode of epistaxis and abnormal prothrombin time and partial prothrombin time. Coagulation work-up revealed thrombin time 24.3 s fibrinogen 110 mg/dl, D-dimers >1 and < 2, and fibrin degradation products >22. Pancultures did not show any evidence of infection. The patient maintained a normal renal and mental status during her illness. Her D-dimers continued to decrease with resolution of acute pancreatitis as evidenced by decreased abdominal pain, relief of nausea, control of vomiting, and decrease in serum amylase and lipase levels. This case report suggests that coagulation abnormalities are encountered in patients with acute pancreatitis. It is hypothesized that such hemostatic abnormalities may be related to early intravascular consumption of coagulation factors secondary to circulating pancreatic enzymes, particularly trypsin, or secondary to vascular injury. Recognition of these hematological complications including DIC is paramount. Physicians caring for these patients should be aware of such a complication of acute pancreatitis.

Thromboembolism following removal of femoral venous apheresis catheters in patients with breast cancer.

BACKGROUND: Apheresis catheters have simplified collection of peripheral blood stem cells (PBSC), but may be associated with thrombosis of the instrumented vessels. We performed a retrospective analysis to study the prevalence of thromboembolism associated with the use of femoral apheresis catheters in patients with breast cancer. PATIENTS AND METHODS: Patients were participants in clinical trials of high-dose chemotherapy with autologous PBSC rescue. They underwent mobilization with either high-dose cyclophosphamide (n = 21) or cyclophosphamide/paclitaxel (n = 64), followed by filgrastim. Double lumen catheters (12 or 13 Fr) were placed in the femoral vein and removed within 12 h of the last apheresis procedure. Apheresis was performed using a continuous flow cell separator and ACD-A anticoagulant. Thromboembolism was diagnosed by either venous ultrasonography or ventilation-perfusion scan. RESULTS: Nine of 85 patients (10.6%) undergoing large volume apheresis with use of a femoral catheter developed thromboembolic complications. Pulmonary embolus (PE) was diagnosed in five and femoral vein thrombosis in four patients. Four of the five patients who developed PE were symptomatic; one asymptomatic patient had a pleural-based, wedge-shaped lesion detected on a staging computed tomography scan. The mean number of apheresis procedures was 2.4 (range one to four) and the mean interval between removal of the apheresis catheter and diagnosis of thrombosis was 17.6 days. In contrast, none of 18 patients undergoing apheresis using jugular venous access and none of 54 healthy allogeneic donors undergoing concurrent filgrastim-mobilized PBSC donation (mean 1.7 procedures/donor) using femoral access experienced thromboembolic complications. CONCLUSIONS: Thromboembolism following femoral venous catheter placement for PBSC collection in patients with breast cancer may be more common than previously recognized. Healthy PBSC donors are not at the same risk. Onset of symptoms related to thrombosis tended to occur several weeks after catheter removal. This suggests that the physicians not only need to be vigilant during the period of apheresis, but also need to observe patients for thromboembolic complications after the catheter is removed. The long interval between the removal of apheresis catheter and the development of thromboembolism may have a potential impact on prophylactic strategies developed in future, such as the duration of prophylactic anticoagulation. Avoidance of the femoral site in breast cancer patients, and close prospective monitoring after catheter removal, are indicated.

Multiple myeloma and hairy cell leukemia: a rare association or coincidence?

Hairy cell leukemia (HCL) and multiple myeloma (MM) are well-defined entities with distinctive clinical and pathological features. Although most cases of HCL and MM fit their classic descriptions, more recent studies have revealed that their clinical and morphological boundaries may not only overlap but a transformation of HCL into MM could also occur. We report another case of HCL followed by the development of MM after 9 years. He also developed hemarthrosis of his right ankle at the time of diagnosis of MM. PCR analysis of DNA extracted from the bone marrow aspirate was negative for the presence of a monoclonally rearranged immunoglobulin heavy chain gene. Immunophenoytping revealed no evidence of HCL. There are several possible explanations for the development of MM in HCL patients, such as the coexistence of separate disease entities or different clinical and morphologic phases of a single disease entity. An accurate diagnosis of HCL or MM is critical because of differences in their treatment. Hemarthrosis in this patient may also have been the first manifestation of MM, a feature of MM which has rarely been reported.

Bleeding diathesis in multiple myeloma.

Patients with multiple myeloma having a higher titer of serum paraproteins can manifest hemostatic abnormalities. Most of these abnormalities predispose the patient to hemorrhage. Less commonly, thrombotic complications may occur in association with paraprotein disorders. We investigated a 56-year-old female diagnosed with multiple myeloma (type IgG kappa, 59 g/L) whose coagulation profile showed an increase in thrombin time and prothrombin time. To investigate the etiology of the abnormal coagulopathy, further diagnostic studies including coagulation factor assays, platelet aggregation studies, replitase time, mixing studies using pooled normal plasma, and protamine were performed. Mixing studies demonstrated correction of the prothrombin time. Thrombin time was near-corrected but the replitase-time was not corrected by these mixing studies. After chemotherapy, the paraprotein concentration decreased (12g/L) and the coagulation results returned to normal. Patients with multiple myeloma may develop bleeding diathesis secondary to a variety of mechanisms. One such mechanism is direct inhibition of fibrin monomer aggregation due to the paraprotein, resulting in prolongation of the thrombin time and the replitase time. The failure to correct the former by the addition of protamine further augments the direct role of FAB portion of the paraprotein molecule on inhibition of fibrin monomers.