Harris V. Naina

Splanchnic vein thrombosis in acute pancreatitis: a single-center experience.

Objectives This study aimed to estimate outcomes of splanchnic vein thrombosis (SVT) in hospitalized patients with acute pancreatitis (AP). Methods This was a retrospective study (January 1996 to December 2006) via chart review. Results Over 10 years, 1.8% (45/2454) of patients with AP with a mean (SD) age of 58 (15) years were diagnosed with SVT. Splenic vein thrombosis was the most common form of SVT (30/45 patients, 67%). Seventeen patients were anticoagulated with heparin, when the SVT was diagnosed in the acute stage followed by oral anticoagulation (AC). The thrombosis that was most commonly anticoagulated was portal vein thrombosis in 11 (65%) of 17 patients. Of 17 patients in the AC group, 2 (12%) showed recanalization as compared with 3 (11%) of 28 patients in the non-AC group (P > 0.05). The mortality was 3 (7%) of 45 (2 from the AC group versus 1 in the non-AC group, P > 0.05). Two of these died of multiorgan failure, and the other, from septic shock. None of the deaths were due to bleeding complications. Conclusions Splanchnic vein thrombosis occurred in 1.8% patients of AP. The use of AC was reasonably safe with no fatal bleeding complications. However, there was no significant difference in the recanalization rates in those with and without AC.

Long-term follow-up of patients with monoclonal gammopathy of undetermined significance after kidney transplantation.

Introduction: Long-term data regarding kidney transplantation (KTx) patients with monoclonal gammopathy of undetermined significance (MGUS) are scarce. We evaluated the long-term outcomes of these patients in a single-center retrospective study from the Mayo Clinic, Rochester, Minn., USA. Methods: Patients who had an MGUS before transplant or developed one after KTx were selected. Monoclonal protein was screened as part of the KTx evaluation by serum protein electrophoresis. Screening for posttransplant lymphoproliferative disorder (PTLD) or MGUS after transplant was not required by protocol. Patients with multiple myeloma, dysproteinemia-related kidney disease or no pretransplant serum protein electrophoresis were excluded. Results: Between 1963 and 2006, 3,518 patients underwent KTx. MGUS was identified in 42 patients, with 23 before transplant and 19 after transplant. Median follow-up for these patients was 8.5 years (range 0.3–37). Four (17.4%) pretransplant MGUS patients developed a hematologic malignancy: 2 smoldering multiple myeloma and 2 PTLD – an Epstein-Barr virus-positive diffuse large cell lymphoma and a Hodgkin lymphoma. None of the 19 patients who developed an MGUS after transplant progressed to multiple myeloma, but 2 (10.5%) developed Epstein-Barr virus-negative T cell lymphoproliferative disorders at 16 and 26 years after transplant. Median survival was 26.1 and 28.0 years for the pretransplant and posttransplant MGUS groups, respectively. Conclusion: Progression from true MGUS to multiple myeloma is rare after KTx. KTx appears safe in true MGUS patients if the monoclonal gammopathy was not the cause of the kidney disease. None of the patients progressed to multiple myeloma, but 2 developed smoldering multiple myeloma and several developed PTLD. Further studies are needed to explain the relationship between MGUS and PTLD.

Successful Treatment of Relapsed and Refractory Extramedullary Acute Promyelocytic Leukemia With Tamibarotene

Case Report A 25-year-old man presented in 2004 with extensive ecchymosis and lower extremity compartment syndrome requiring emergency surgery. At this time he was diagnosed with acute promyelocytic leukemia (APL). Conventional cytogenetic analysis of the bone marrow showed additional material on chromosome 7p, whereas molecular studies revealed promyelocytic leukemia gene-retinoic acid receptor alpha (PML-RARA) rearrangement (details of the patient’s cytogenetic and molecular analysis have been previously published). He was treated with all trans retinoic acid (ATRA) and idarubicin followed by two cycles of consolidation chemotherapy with doxorubicin and ATRA. In 2006, while he was on maintenance chemotherapy with methotrexate, 6 mercaptopurine, and ATRA, he developed pain in his shoulder. Diagnostic studies showed promyelocytic sarcoma (PS) of the scapula. A bone marrow biopsy showed relapse in the bone marrow. He was treated with a combination of ATRA, gemtuzumab ozogamicin, and arsenic trioxide (ATO) and achieved a complete molecular remission. In January 2007, he presented with back pain and was diagnosed with PS of the thoracic vertebra, confirmed by both fluorescent in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction, with no evidence of relapse in the bone marrow. He was treated with ATO and idarubicin and local radiation to the affected spine. This resulted in a complete remission and he then underwent matched unrelated allogenic stem-cell transplantation in February 2007, using high-dose cyclophosphamide and busulfan as the preparative regimen. He developed mild chronic graft versus host disease which was controlled with prednisone 10 mg every other day. He did well until January 2009 when he developed cough and shortness of breath. A CT scan of his chest showed a mass, measuring 8.5 2.5 cm in the superior vena cava extending into the right atrium. He underwent surgical resection of this mass revealing PS. His CSF analysis was negative for leukemic cells. He received ATO and ATRA and intensity modulated radiotherapy to the atrium and superior vena cava at a dose of 25.20 Gy in 14 treatments. After the radiation, he was treated with one cycle of high-dose cytarabine. After recovering from the chemotherapy, he was put on maintenance therapy with ATRA and ATO. In September 2009, he developed a mass in the left supraclavicular fossa measuring 2.5 2.2 cm. A biopsy confirmed recurrence of PS and a positron emission tomography (PET) scan showed multiple [F]fluorodeoxyglucose (FDG) avid masses in the soft tissue and bone, in the chest and pelvis. A bone marrow biopsy done at this time did not show any evidence of bone marrow involvement. He did not have any neurological symptoms and he declined a lumbar puncture for CSF analysis. He was treated with gemtuzumab ozogamicin and ATRA, but a repeat PET scan done in December 2009 showed only a mixed response. At this time there were more than 20 FDG avid nodules in the abdomen, chest, and deep muscles and subcutaneous tissues. These nodules ranged from 3 3 mm to 2 2 cm in diameter and standard uptake values in these nodules ranged from 2.2 to 13.6. An FDG avid PS involving the rectum is shown in (Fig 1). At this time he was started on tamibarotene on a compassionate basis at a dose of 6 mg/m/d orally divided into two daily doses for 56 days. He then had a 14-day rest period from medication, followed by resumption of tamibarotene for 28 days, followed again by a 14-day rest period. At this time he began a maintenance schedule, in which tamibarotene was administered in cycles for 28 days in a row followed by 28 days off. No other concomitant chemotherapy was administered. Four weeks after the initiation of tamibarotene, a PET scan showed tumor shrinkage (Fig 2) and 16 weeks after the initiation of the drug a PET scan showed complete resolution of his FDG avid PS sites (Fig 3). Eight months after the initiation of tamibarotene, his PET scan remained negative for FDG avid sites. The drug was well tolerated with only mild headache, nausea, and loss of appetite during the first cycle, with the symptoms improved over subsequent cycles. He is now 12 months out from initiation of tamibarotene with no evidence of disease and we plan to continue therapy indefinitely.

Platelet and red blood cell indices in Harris platelet syndrome

Inherited thrombocytopenias, including inherited giant platelet disorders (IGPD) or macro thrombocytopenias are relatively rare, but their prevalence is likely underestimated from complexities of diagnosis and a spectrum of subclinical phenotypes. Harris platelet syndrome (HPS) is the most common IGPD reported from the Indian subcontinent. Of note there are an increased number of hemoglobinopathies reported from the geographic location. We analysed red blood cell and platelet indices of blood donors with HPS from the north eastern part of India and compared them with blood indices of blood donors of south India. We found a statistically significant lower platelet count in blood donors with HPS (median, range) 132 (71–267) vs. 252 (160–478) as compared to donors from south India (P < 0.001). Mean platelet volume (MPV) was higher in donors with HPS 13.1, (range 12–21.9 fl) as compared to donors from south India 7.35 (range 6–9.2 fl) (P < 0.001). This study showed that blood donors with HPS had a low median platelet bio-mass 0.17 (0.10–0.38%) vs. 0.19 (0.13–0.28%) in donors from south India. The platelet distribution width (PDW) was 17.4 (14.9–19.6) in donors with HPS vs. 16.38 (15.2–18.5) in south Indian blood donors (P < 0.001). Thirty-three donors with HPS had a normal platelet count with MPV more than 12 fL. Only donors with HPS had giant platelets and thrombocytopenia on peripheral blood smear examination. None of these donors had Dohle body inclusion in their leukocytes. Compared to donors from south India, donors with HPS had a significantly lower hemoglobin 13.8 (12–16.3 gm/dL) vs. 14.8 (12–18) respectively (P < 0.001) while red distribution width (RDW) was higher in HPS 13.6 (11.5–16.7) vs. 12.8 (11.4–15.1). However we did not find any statistically significant difference in MCV, MCH, MCHC between the two groups. Peripheral blood smear did not show any obvious abnormal red blood cell morphology. In the blood donors with HPS we found a statistically higher MPV, RDW and a lower platelet count and platelet biomass. A population-based study will be helpful in determining the existence of any hemoglobinopathies among subjects with HPS.

Cullen's sign revisited.

tion odnt of ion ht be rs et the artmorateral ct in wall reons ack. The retroform lcove as i des panc h the o ) of 7 rie f th of e had C these p iton ith s vise t titis b ncrea rts in t f this s even r n was s cy, w evelo iagn des y R y has b still e ely u ctus s ior or i irect d ude a ), m d i a R a p eriumbilical discoloration was first described by Cullen 1 i 918 in association with a ruptured ectopic pregna ullen’s sign ( Figure 1), described as a subcutaneous ma festation of severe acute pancreatitis, is often discussed eldom observed. Although historically associated w ancreatitis, Cullen’s sign has been described in var linical scenarios, including rectus sheath hematoma (RS assive ovarian enlargement, amoebic liver absce plenic rupture, perforated duodenal ulcer, pancrea rauma, metastatic thyroid cancer, intra-abdominal no odgkin’s lymphoma, and as a complication of anticoa ation. The common thread among the reported cases ullen’s sign seems to be the presence of retroperito lood. In all likelihood, any condition that causes retro toneal hemorrhage is responsible for the appearance ullen’s sign. Through time, several theories ranging from direct ac o lymphatic transmission of pancreatic inflammatory pr cts have been advanced to account for the developme ubcutaneous ecchymosis in acute pancreatitis. The not hat the presence of blood in the abdominal wall mig esponsible for these signs was first explored by Meye l, who used computed tomography. They defined natomy of various retroperitoneal spaces and comp ents, revealing that there is direct extension of he hagic fluid from the posterior para renal space to the l dge of the quadratus lumborum muscle, where a defe he transversalis fascia permits access to the abdominal usculature. The intermuscular hemorrhagic fluid then p umably reaches the subcutaneous tissues via interrupti n muscular continuity. Cullen’s sign results from the tr ng of blood along the round ligament to the umbilicus ortal of entry to the round ligament complex from the eritoneum is via the gastrohepatic ligament to the falci igament at the inferior-posterior liver edge. 3 In turn, the fa iform ligament contributes to the connective tissue tube

Harris syndrome - a geographic perspective

Congenital thrombocytopenias, once considered rare and obscure, are now recognized with increasing frequency, because of the quantification of platelet number as a part of routine blood testing. Among class II non-muscle myosin heavy chains, II-A is the only gene found to be responsible for a human disease, called MYH9-related disease [1]. It includes four autosomal dominant syndromes previously known as May– Hegglin anomaly, Sebastian, Fechtner and Epstein syndromes. Naina et al. [2] described a new syndrome, asymptomatic constitutional macro thrombocytopenia (ACMT) characterized by mild to severe thrombocytopenia, giant platelets [Mean platelet volume (MPV) >10 fL] with normal platelet functions without any bleeding symptoms in blood donors from West Bengal [2]. In order to avoid confusion between ACMT and congenital amegakaryocytic thrombocytopenia (CAMT) this entity is henceforth referred to as Harris syndrome. A prospective study was conducted over 8 months at the Christian Medical College and Hospital, Vellore, to determine the geographic distribution of Harris syndrome in India and neighboring countries. Of the 10 200 blood donors screened over a period of 8 months; 1002 were randomly screened for Harris syndrome. Nine hundred and thirty-one blood donors were residents of India, and remaining 71 were from Nepal, Bhutan and Bangladesh. All donors were questioned about history of abnormal bleeding episodes. Blood samples were collected in ethylenediaminetetraaccetic acid (EDTA). Automated platelet counts were performed using a Coulter STKS (Coulter, Hialeah, Florida) within 2 h of collection. Peripheral blood smears were examined to confirm the thrombocytopenia and presence of giant platelets. A total of 10 random affected samples (five moderate thrombocytopenia and five mild thrombocytopenia) were screened for mutations in the MYH9A gene (May Hegglin gene) with denaturing high-performance liquid chromatography (dHPLC). All exons and flanking intronic regions were assayed and all abnormal dHPLC profiles were sequenced. There was no history of any abnormal bleeding episode in any of the donors. A peripheral blood smear confirmed the diagnosis of thrombocytopenia and giant platelets. There were no abnormal inclusion bodies in the leukocytes. Thrombocytopenia was graded as mild (100–150 · 10 9 L )1 ), moderate (50–100 · 10 9 L )1 )a nd severe (<50· 10 9 L )1 ). Results were divided into five groups based on the place of origin of each donor (southern India, northern India, western India, eastern India and neighboring countries; Table 1). The distribution of Harris syndrome is shown in Fig. 1. There was a statistically significant difference in platelet count (P <0 .000) and mean platelet volume P < 0.000) between eastern states and all other states. We detected six abnormal profiles, all of which were single-nucleotide polymorphisms (SNPs) represented in the control population. Preliminary family studies have shown possible autosomal dominant mode of inheritance. In conclusion, MYH9A was not mutated in these samples and another gene with a probable similar function is the likely causative factor. Further genetic and molecular studies should yield a new insight into the pathogenesis of the disease.

Treating childhood leukemia without cranial irradiation [2]

To the Editor: Pui and colleagues (June 25 issue)1 report a high likelihood of event-free and overall survival among children with acute lymphoblastic leukemia (ALL) treated with an intensive regimen of intrathecal chemotherapy and systemic drugs that penetrate the central nervous system (CNS). Their goal was to eliminate cranial irradiation and its late toxic effects. Most other trials of treatment for childhood ALL already treat the majority of patients (80% or more) without cranial irradiation, with similarly favorable results. Indeed, only 14% of patients in the study reported on by Pui et al. would have received cranial irradiation in previous trials. In these patients, survival did not appear to be adversely affected by the elimination of irradiation. Although the overall outcome of this trial was favorable, some subgroups of patients remained at high risk for relapse. Also, the acute systemic and CNS toxic effects of the treatment were not insubstantial, and the long-term neurocognitive outcomes are unknown. Before this investigational approach can be considered the standard of care, its consequences should be more thoroughly evaluated, ideally in randomized trials with larger numbers of patients and longer follow-up. Stephen E. Sallan, M.D.

Rituximab-based therapy and long-term control of autoimmune autonomic ganglionopathy

We present a patient with autoimmune autonomic ganglionopathy (AAG) who had persistently positive ganglionic nicotinic acetylcholine receptor antibody levels despite immunosuppressive therapy. Rituximab-based therapy for an incidental lymphoma was associated with prolonged symptomatic and serological control of AAG.

Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome

Background Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin. Methods Mice transplanted with 6 lines of renal cell carcinoma (RCC) were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin. Results Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis). From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC. Conclusion Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1.

Primary cutaneous follicle center lymphoma arising adjacent to silicone breast implant.

Primary cutaneous B-cell lymphomas are a rare clinical entity, comprising only about 3 cases per 1 million people per year. Even more scarce are breast implanteassociated lymphomas. This article presents a case of primary cutaneous follicle center lymphoma that developed adjacent to a silicone breast implant placed during reconstructive surgery. In addition to the case presentation, the article discusses the convoluted history behind breast implanterelated malignancies as well as the relatively new class of non-Hodgkin lymphomas called primary cutaneous B-cell lymphomas.