[Pathogenesis and Targeted Treatment Progress of Splenomegaly in Primary Myelofibrosis--Review].

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm with splenomegaly as the major clinical manifestation, which is commonly considered to be linked to splenic extramedullary hematopoiesis. Alteration of CXCL12/CXCR4 pathway can lead to the migration of hematopoietic stem cells and hematopoietic progenitor cells from bone marrow to spleen which results in splenic extramedullary hematopoiesis. In addition, low GATA1 expression and the abnormal secretion of cytokines were found to be significantly associated with splenomegaly. With the application of JAK1/2 inhibitors in clinical, the symptoms of splenomegaly have been significantly improved in PMF patients. This article will review the pathogenesis and targeted treatment progress of splenomegaly in PMF.

Spleen size greater than 9.76 cm may impact the treatment strategy for blunt splenic injury in adults - A retrospective analysis of experience at a tertiary trauma center in Taiwan.

BACKGROUND/OBJECTIVE: The present study investigated the impact of splenomegaly on the treatment outcomes of blunt splenic injury patients. METHODS: All blunt splenic injury patients were enrolled between 2010 and 2018. The exclusion criteria were age less than 18 years, missing data, and splenectomy performed at another hospital. The patients were divided into two groups based on the presence of splenomegaly, defined as a spleen length over 9.76 cm on axial computed tomography. The primary outcome was the need for hemostatic interventions. RESULTS: A total of 535 patients were included. Patients with splenomegaly had more high-grade splenic injuries (p = 0.007). Hemostatic treatments (p < 0.001) and transarterial embolization (p = 0.003) were more frequently required for patients with splenomegaly. Multivariate analysis showed that male sex (p = 0.023), more packed red blood cell transfusions (p = 0.001), splenomegaly (p = 0.019) and grade 3-5 splenic injury (p < 0.001) were predictors of hemostatic treatment. The failure rate of transarterial embolization was not significantly different between the two groups (p = 0.180). The sensitivity and specificity for splenomegaly in predicting hemostatic procedures were 48.8% and 66.5%, respectively. The positive and negative predictive values were 62.8% and 52.9%, respectively. The overall mortality rate was 3.7%. CONCLUSION: Splenomegaly is an independent predictor for the requirement of hemostatic treatments in blunt splenic injury patients, especially transarterial embolization. Transarterial embolization is as effective for blunt splenic injury patients with splenomegaly as it is for those with a normal spleen.

Successful haploidentical hematopoietic stem cell transplantation (HSCT) and durable engraftment by repeated donor lymphocyte infusions for a Chinese patient with transfusion-dependent hemoglobin (Hb) Hammersmith and massive splenomegaly.

BACKGROUND: Hemoglobin (Hb) Hammersmith is a rare form of unstable ß-chain hemoglobinopathy causing hemolytic anemia. This rare event led to a more serious transfusion-dependent phenotype in a patient. It was successfully cured by haploidentical hematopoietic stem cell transplantation (HSCT). METHODS AND RESULTS: A 9-year-old mainland Chinese male with a history of neonatal unconjugated hyperbilirubinemia was diagnosed to have hemoglobin (Hb) Hammersmith. He required regular blood transfusion but was unable to be transfused to desired parameters for 8 years prior to transplant due to social and geographical reasons. He subsequently developed marrow hyperplasia and progressive splenomegaly (down to umbilicus level), suggestive of extramedullary hematopoiesis. Eventually, the family came to Hong Kong and complied to a more intensive transfusion regimen and preconditioning chemotherapy 3 months prior to transplant. He underwent haploidentical HSCT using paternal TCRαß/CD45RA-depleted graft but suffered from graft rejection, despite splenic irradiation for massive splenomegaly. It was successfully salvaged with second HSCT with unmanipulated graft from the same donor with additional serotherapy and donor lymphocyte infusions. CONCLUSION: Allogenic haploidentical HSCT for hemoglobin Hammersmith is feasible but adequate immunosuppression during conditioning is crucial. Precise adoptive cell therapy can promote durable engraftment.

Splenomegaly: Diagnosis and Management in Adults.

Splenomegaly can be due to several mechanisms but is almost always a sign of a systemic condition. Patient habits, travel, and medical conditions can increase risk of splenomegaly and suggest etiology. Symptoms can suggest infectious, malignant, hepatic, or hematologic causes. Physical examination will typically reveal splenomegaly, but abdominal ultrasonography is recommended for confirmation. Physical examination should also assess for signs of systemic illness, liver disease, and anemia or other hematologic issues. The most common causes of splenomegaly in the United States are liver disease, malignancy, and infection. Except for apparent causes such as infectious mononucleosis, basic laboratory analysis and ultrasonography are the first-line steps in determining etiology. Malaria and schistosomiasis are common in tropical regions, where as many as 80% of people may have splenomegaly. Management of splenomegaly involves treating the underlying disease process. Splenectomies and spleen reduction therapies are sometimes performed. Any patient with limited splenic function requires increased vaccination and prophylactic antibiotics for procedures involving the respiratory tract. Acute infections, anemia, and splenic rupture are the most common complications of splenomegaly, and people with splenomegaly should refrain from participating in contact sports to decrease risk of rupture.

Non-Pharmacologic Management of Splenomegaly for Patients with Myelofibrosis: Is There Any Role for Splenectomy or Splenic Radiation in 2020?

PURPOSE OF REVIEW: Myelofibrosis is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly. Currently approved medical therapies do not improve splenomegaly in all patients and effects are not sustained. Thus, spleen-directed therapies (i.e., splenectomy and splenic irradiation) have been used in some cases to palliate the signs and symptoms of the disease. Here, we critically review the literature regarding palliative splenectomy and splenic irradiation in myelofibrosis, and discuss their position in the current treatment landscape. RECENT FINDINGS: Retrospective studies have demonstrated that splenectomy improves symptoms of splenomegaly, decreases complications of portal hypertension, and decreases transfusion dependence. However, it carries a significant peri-operative and long-term morbidity and mortality rate. Splenic irradiation reduces splenic size but is limited by duration of response and myelosuppression. Spleen-directed therapies in myelofibrosis may be considered for refractory symptoms and complications of massive splenomegaly after carefully weighing the associated risks, though overall survival may not be impacted. Development of medical therapies that target and reverse the underlying disease pathophysiology is required in order to have a significant impact on the natural history of the disease process.

Left-sided portal hypertension after pancreatoduodenectomy with resection of the portal/superior mesenteric vein confluence. Results of a systematic review.

BACKGROUND: Pancreatoduodenectomy with synchronous resection of the portal vein/superior mesenteric vein confluence may result in the development of left-sided portal hypertension. Left-sided portal hypertension presents with splenomegaly and varices and may cause severe gastrointestinal bleeding. The aim of the study is to review the incidence, treatment, and preventive strategies of left-sided portal hypertension. METHODS: A systematic literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to identify all studies published up to September 30, 2019 reporting data on patients with left-sided portal hypertension after pancreatoduodenectomy with venous resection. RESULTS: Eight articles including 829 patients were retrieved. Left-sided portal hypertension occurred in 7.7% of patients who had splenic vein preservation and 29.4% of those having splenic vein ligation. Fourteen cases of gastrointestinal bleeding owing to left-sided portal hypertension were reported at a mean interval of 28 months from pancreatoduodenectomy. Related mortality at 1 month was 7.1%. Treatment of left-sided portal hypertension consisted of splenectomy in 3 cases (21%) and colectomy in 1 (7%) case, whereas radiologic, endoscopic procedures or conservative treatments were effective in the other cases (71%). CONCLUSION: Left-sided portal hypertension represents a potentially severe complication of pancreatoduodenectomy with venous resection occurring at greater incidence when the splenic vein is ligated and not reimplanted. Left-sided portal hypertension-related gastrointestinal bleeding although rare can be managed depending on the situation by endoscopic, radiologic procedures or operative intervention with low related mortality.

Modern management of splenomegaly in patients with myelofibrosis.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly secondary to extramedullary hematopoiesis. Patients frequently exhibit debilitating symptoms including pain and early satiety, in addition to cellular sequestration causing severe cytopenias. JAK 1/2 inhibitors, such as ruxolitinib and fedratinib, are the mainstay of therapy and produce significant and durable reductions in spleen volume. However, many patients are not eligible for JAK 2 inhibitor therapy or become refractory to treatment over time. Novel therapies are in development that can reduce the degree of splenomegaly for some of these patients. However, splenectomy, splenic irradiation, and partial splenic artery embolization remain valuable therapeutic options in select patients. In this review, we will discuss currently available pharmacologic therapies and describe promising drugs currently in development. We will also delve into the efficacy and safety concerns of splenectomy, splenic irradiation, and partial splenic artery embolization. Finally, we will propose a treatment algorithm to help guide clinicians in the management of symptomatic splenomegaly in patients with MF.

Partial Splenic Artery Embolization in 35 Cancer Patients: Results of a Single Institution Retrospective Study.

PURPOSE: To evaluate the safety and efficacy of partial splenic embolization (PSE) in cancer patients with different etiologies of splenomegaly/hypersplenism. MATERIALS AND METHODS: The medical records of 35 cancer patients who underwent 39 PSE procedures were analyzed. The splenomegaly/hypersplenism was due to chemotherapy (n = 17), portal hypertension (n = 10), or hematologic malignancy (n = 8). After the first 11 PSEs, celiac plexus neurolysis, corticosteroids, and non-steroid anti-inflammatory drugs (NSAIDs) were included in the post-procedural management. RESULTS: PSE led to 59 ± 16% (mean ± standard deviation) splenic infarcts. The infarct volume per 1 mL 300-500 µm tris-acryl gelatin microspheres was not significantly different between the chemotherapy-induced group (264 ± 89 cm3) and the portal hypertension group (285 ± 139 cm3) but was significantly higher in the hematology group (582 ± 345 cm3). Platelet count increased from 65.7 ± 19.7 k/µl to a peak platelet count of 221 ± 83 k/µl at 2 weeks after PSE. Patients with a follow-up period of more than 1 year had the most recent platelet count of 174 ± 113 k/µl. Platelet count increase was significantly higher in the chemotherapy-induced group than the portal hypertension group. Adding celiac plexus neurolysis, corticosteroids, and NSAIDs to the post-procedural management resulted in a decreased rate of major complications from 73% to 46% and a decrease in the rate of moderate or severe pain from 92% to 20%. CONCLUSIONS: PSE improved platelet counts in cancer patients despite different etiologies of splenomegaly. The addition of celiac plexus neurolysis, corticosteroids, and NSAIDS to the post-PSE treatment protocol reduced complications. Data from this study could help to predict the amount of 300-500 µm tris-acryl gelatin microspheres required to achieve a planned infarct size.

Clinical features of idiopathic portal hypertension in China: A retrospective study of 338 patients and literature review.

BACKGROUND AND AIM: Idiopathic portal hypertension (IPH) refers to a relatively rare condition characterized by intrahepatic portal hypertension in the absence of underlying disease such as liver cirrhosis. METHODS: We retrospectively reviewed 338 patients with IPH that were diagnosed at the pathological consultation center of our hospital. RESULTS: The ratio of male to female patients was 1:1. Mean age at onset was 35.1 ± 16.5 years; male patients on average were 12 years younger than female patients at onset. The median duration from onset to IPH diagnosis was 12 months. In 50 patients, medication use may have been an etiological factor. The most common clinical manifestations were splenomegaly (91.3%) and hypersplenism (68.9%); 57.0% patients presented varicosis, while 25.1% patients had a history of variceal bleeding. Nodular regenerative hyperplasia was found in 22.2% liver biopsies. Among patients for whom laboratory data were available, 65.0%, 50.3%, and 71.4% patients presented leukopenia, anemia, and thrombocytopenia due to hypersplenism. Liver function was mostly in the compensated stage. Female patients showed worse leukopenia and anemia, while male patients were more likely to have abnormal serum transaminase and bilirubin levels. Sixty-seven patients received surgical or interventional treatment. CONCLUSIONS: High-quality liver biopsy, detailed clinical information, and expert pathologist are necessary for diagnosis of IPH. IPH can occur concurrently with other liver disease such as hepatitis and drug-induced liver injury. Medication appears to be an important etiological factor for IPH in China. Management approach was largely focused on treatment of portal hypertension and its complications.

Idiopathic Portal Hypertension.

Idiopathic portal hypertension (IPH) is a rare disorder characterized by clinical portal hypertension in the absence of a recognizable cause such as cirrhosis. Laboratory tests often reveal a preserved liver function with anemia, leukopenia, and thrombocytopenia due to splenomegaly. Imaging studies reveal signs of portal hypertension, whereas liver stiffness and portal pressure values are usually normal or slightly elevated. Liver biopsy is considered mandatory in order to rule out other causes of portal hypertension, mainly cirrhosis. Liver histology may only show subtle or mild changes, and the definite diagnosis of IPH often requires an expert pathologist and a high-quality specimen. The most frequent clinical presentation is variceal bleeding. Ascites is rarely observed initially, although it may occasionally appear during follow-up. Typical histological findings associated with IPH have been described in patients without portal hypertension, probably representing early stages of the disease. Although the pathophysiology of this entity remains largely unknown, it is frequently associated with underlying immunological disorders, bacterial infections, trace metal poisoning, medications, liver circulatory disturbances, and thrombotic events. The long-term prognosis of patients with IPH, where ascites and the underlying condition are important prognostic factors, is better than in patients with cirrhosis. Treatments that modify the natural history of the disease remain an unmet need, and management of IPH is frequently restricted to control of portal hypertension-related complications.

Idiopathic portal hypertension and extrahepatic portal venous obstruction.

BACKGROUND: Idiopathic portal hypertension (IPH) and extrahepatic portal venous obstruction (EHPVO) are non-cirrhotic vascular causes of portal hypertension (PHT). Variceal bleed and splenomegaly are the commonest presentations. AIM: The present review is intended to provide the existing literature on etiopathogenesis, clinical profile, diagnosis, natural history and management of IPH and EHPVO. RESULTS: IPH and EHPVO are both characterized by normal hepatic venous pressure gradient, moderate to massive splenomegaly with preserved liver synthetic functions. While the level of block in IPH is presinusoidal, in EHPVO it is at prehepatic level. Infections, autoimmunity, drugs, immunodeficiency and prothrombotic states are possible etiological agents in IPH. Contrastingly in EHPVO, prothrombotic disorders and local factors around the portal vein are the incriminating factors. Diagnosis is often clinical, supported by simple radiological tools. Natural history is defined by episodes of variceal bleed and symptoms related to enlarged spleen. Growth failure, portal biliopathy and minimal hepatic encephalopathy are additional concerns in EHPVO. Long-term survival is reasonably good with endoscopic surveillance; however, parenchymal extinction leading to decompensation is seen in a minority of patients in both the disorders. Surgical shunts revert the complications secondary to PHT. Meso-Rex shunt has become the standard surgery in children with EHPVO. CONCLUSION: This review gives a detailed summary of these two vascular conditions of liver-IPH and EHPVO. Further research is needed to understand the pathogenesis and natural history of these disorders.

Should rituximab replace splenectomy in the management of splenic marginal zone lymphoma?

BACKGROUND: SMZL is a relatively rare low grade B-cell lymphoma, characterized usually by an indolent clinical behavior. Since there is no prospective randomized trials to establish the best treatment approach, decision on therapeutic management should be based on the available retrospective series. Based on these data, rituximab and splenectomy appear to be the most effective. Splenectomy represented the standard treatment modality until early 2000s. More than 90% of the patients present quick amelioration of splenomegaly related symptoms along with improvement of cytopenias related to hypersplenism. The median progression free survival was 8.25 years in the largest series of patients published so far, while the median 5- and 10- year OS were 84% and 67%, respectively. Responses to splenectomy are not complete since extrasplenic disease persists. Patients with heavy bone marrow infiltration, lymphadenopathy or other disease localization besides the spleen are not good candidates for splenectomy. Furthermore splenectomy is a major surgical procedure accompanied by acute perioperative complications as well as late toxicities mainly due to infections. For that reasons splenectomy is not appropriate for elderly patients or patients with comorbidities with a high surgical risk. On the other hand rituximab monotherapy displays high efficacy with minimal toxicity. Several published series have shown an ORR more than 90%, with high CR rates (∼50%). The 10-year PFS and OS were 63% and 85%, respectively in a series of 104 SMZL patients. The role of rituximab maintenance has been investigated by only one group. Based on these data, maintenance with rituximab further improved the quality of responses by increasing significantly the CR rates (from 42% at the end of induction to 71% at the end of maintenance treatment), as well as the duration of responses: 7-year PFS was 75% for those patients who received maintenance vs 39% for those who did not (p < 0.0004). However no difference in OS has been noticed between the two groups, so far. Summarizing the above data, it is obvious that Rituximab monotherapy is associated with high response rates, long response duration and favorable safety profile, rendering it as the treatment of choice in SMZL.

ß-Thalassemia intermedia: a comprehensive overview and novel approaches.

ß-Thalassemia intermedia is a clinical condition of intermediate gravity between ß-thalassemia minor, the asymptomatic carrier, and ß-thalassemia major, the transfusion-dependent severe anemia. It is characterized by a significant clinical polymorphism, which is attributable to its genetic heterogeneity. Ineffective erythropoiesis, chronic anemia, and iron overload contribute to the clinical complications of thalassemia intermedia through stepwise pathophysiological mechanisms. These complications, including splenomegaly, extramedullary erythropoiesis, iron accumulation, leg ulcers, thrombophilia, and bone abnormalities can be managed via fetal hemoglobin induction, occasional transfusions, chelation, and in some cases, stem cell transplantation. Given its clinical diversity, thalassemia intermedia patients require tailored approaches to therapy. Here we present an overview and novel approaches to the genetic basis, pathophysiological mechanisms, clinical complications, and optimal management of thalassemia intermedia.

[Hairy cell leukemia and pregnancy]. / Volosatokletochnyi leikoz i beremennost'.

The paper presents experience in following up and treating hairy cell leukemia (HCL) during pregnancy. The combination of HCL and pregnancy was observed in 5 patients. The patients' median age was 35 years (range, 28-42 years). The diagnosis of HCL was based on a conventional examination protocol: clinical blood analysis with the morphological assessment of lymphocytes, a myelogram and trepanobiopsy, immunophenotypic analysis of lymphocytes or bone marrow (in all the patients), cytochemical determination of tartrate-resistant acid phosphatase in 3 patients, and identification of BRAFV600E mutation in 3 patients. Three pregnant women were treated for HCL in the postpartum period. In one patient with HCL, pregnancy was seen in remission after treatment with cladribine. In one patient with HCL detected at 11 weeks' gestation, interferon-α therapy during the second trimester of pregnancy was performed for increased cytopenia, which was followed by cladribine therapy after delivery. Pregnancy and delivery were uncomplicated in all the patients; 3 patients had vaginal delivery and 2 patients underwent cesarean section. All infants were healthy, with no developmental abnormalities during a follow-up period of 6-140 months (median 30 months). All the patients with HCL are currently in remission: 4 patients in first remission at a follow-up of 10 to 48 months (median 15 months) and one patient in second remission at a follow-up of 88 months. Possible observational tactics is possible when HCL is detected during pregnancy. Treatment of HCL during pregnancy is necessary in cases of deep or progressive cytopenia and/or splenomegaly. The use of interferon-α or splenectomy is preferable.

Allogeneic Stem Cell Transplantation in Myelofibrosis.

Myeloproliferative neoplasm (MPN) is a category in the World Health Organization classification of myeloid tumors. BCR-ABL1-negative MPN is a subcategory that includes primary myelofibrosis (MF), post-essential thrombocythemia MF, and post-polycythemia vera MF. These disorders are characterized by stem cell-derived clonal myeloproliferation. Clinically, these diseases present with anemia and splenomegaly and significant constitutional symptoms such as severe fatigue, symptoms associated with an enlarged spleen and liver, pruritus, fevers, night sweats, and bone pain. Multiple treatment options may provide symptom relief and improved survival; however, allogeneic stem cell transplantation (HCT) remains the only potentially curative option. The decision for a transplant is based on patient prognosis, age, comorbidities, and functional status. This review describes the recent data on various peritransplantation factors and their effect on outcomes of patients with MF and new therapeutic areas, such as the use and timing of Janus kinase inhibitors with HCT and gives overall conclusions from the available data in the published literature.

Selective Spleen Embolization of Splenomegaly to Improve Thrombocytopenia Facilitating Open Aortic Aneurysm Repair: A Staged Approach.

We present an 82-year-old man with a history of hairy cell leukemia, having an 11-cm abdominal aortic aneurysm, who also had severe thrombocytopenia (about 20 000 platelets/µL) and splenomegaly at presentation. The patient had unfavorable anatomy for endovascular aneurysm repair, and therefore, an open procedure was planned. To reduce risk for perioperative bleeding and optimize patient preoperative status, a staged approach was employed. Initially, several sessions of embolization of 2 splenic artery branches were performed with the intent to decrease spleen size and to increase platelet count thus decreasing the perioperative bleeding risk. Then, after successfully increasing platelet count (280 000 PLT/µL), open repair of the aneurysm was conducted. This case demonstrates that selective splenic embolization in patients with hypersplenism and subsequent thrombocytopenia who are in need for major surgery may achieve a significant rise in platelet count and optimize patient's preoperative status in order to avoid bleeding complications.

Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms.

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.

Big spleens and hypersplenism: fix it or forget it?

Hypersplenism is a common manifestation of portal hypertension in the cirrhotic. More than half of cirrhotics will have low platelet counts, but neutropenia is much less common. Despite being common in the cirrhotic population, the presence of hypersplenism is of little clinical consequence. The presence of hypersplenism suggests more advanced liver disease and an increase in risk of complications, but there is no data showing that correcting the hypersplenism improves patient survival. In most series, the most common indications for treating the hypersplenism is to increase platelet and white blood cell counts to allow for use of drugs that suppress the bone marrow such as interferon alpha and chemotherapeutic agents. There are several approaches used to treat hypersplenism. Portosystemic shunts are of questionable benefit. Splenectomy, either open or laparoscopically, is the most effective but is associated with a significant risk of portal vein thrombosis. Partial splenic artery embolization and radiofrequency ablation are effective methods for treating hypersplenism, but counts tend to fall back to baseline long-term. Pharmacological agents are also effective in increasing platelet counts. Development of direct acting antivirals against hepatitis C will eliminate the most common indication for treatment. We lack controlled trials designed to determine if treating the hypersplenism has benefits other than raising the platelet and white blood cell counts. In the absence of such studies, hypersplenism in most patients should be considered a laboratory abnormality and not treated, in other words forget it.