Xin-xin Cao

Pulmonary hypertension in POEMS syndrome

POEMS syndrome is a rare clonal plasma cell disease. Patients with POEMS syndrome are at risk of developing pulmonary hypertension, but the data on its incidence and impact on outcome are limited. We reviewed records of 154 POEMS syndrome patients with complete duplex echocardiography data for estimation of pulmonary artery systolic pressure (sPAP) at the time of diagnosis. Forty-two (27%) of 154 patients with pulmonary hypertension (estimated sPAP ≥50mmHg) were identified. Median age was 46 years (range 31–71 years). Patients with pulmonary hypertension were more likely to have peripheral edema (P=0.04), ascites (P=0.02), pleural effusion (P=0.005), and have longer time from onset to diagnosis (P=0.004) when compared with those without pulmonary hypertension. Restrictive abnormalities and decreased diffusion capacity of carbon monoxide were observed in 83% and 96% patients with pulmonary hypertension, compared with 50% and 72% in patients without pulmonary hypertension, respectively. Reversibility of pulmonary hypertension was observed after treatment of POEMS syndrome. After median follow of 32 months, survival of patients with pulmonary hypertension was worse than those without (median overall survival 54 months vs. median not reached, P=0.021). In conclusion, pulmonary hypertension is a common feature of POEMS syndrome, and is associated with signs of extravascular volume overload. Although active treatment of POEMS syndrome can reverse pulmonary hypertension, survival of these patients is worse than those without pulmonary hypertension.

Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome

Although autologous stem cell transplantation or melphalan‐based chemotherapy has significantly improved the prognosis of POEMS syndrome, a few patients will relapse or be refractory to primary therapy, and there is a lack of studies regarding these patients. In this study, we used low‐dose lenalidomide (10 mg daily) and dexamethasone (40 mg, once weekly) to treat twelve patients with relapsed (n = 8) or refractory (n = 4) POEMS syndrome. After a median follow‐up time of 20 months, the overall hematologic response rate was 77% with 44% having a complete response. Eight (67%) patients had neurological response, and the median overall neuropathy limitation scale score was reduced from 3 (range, 1–9) to 2 (range, 0–6). Serum vascular endothelial growth factor response rate was 91% and 46% of patients had normal serum VEGF levels. One patient had progression of the disease 3 months after the end of treatment and subsequently died from the disease. Therefore, the estimated 2 year overall survival and progression‐free survival were 92%. The low‐dose lenalidomide and dexamethasone regimen was well tolerated, with no treatment‐related death or any grade 3 or 4 toxicity. In conclusion, low‐dose lenalidomide plus dexamethasone therapy is an effective and safe regimen for patients with relapsed or refractory POEMS syndrome.

Markedly elevated serum total N-terminal propeptide of type I collagen is a novel marker for the diagnosis and follow up of patients with POEMS syndrome

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a rare plasma-cell dyscrasia.[1][1],[2][2] Its diagnosis relies on both clinical and laboratory features, and osteosclerosis is a major diagnostic criterion.[3][3] Although conventional imaging

The clinical spectrum of IgM monoclonal gammopathy: A single center retrospective study of 377 patients.

OBJECTIVES We retrospectively evaluated the clinical features, serum levels of IgM, and prevalence of IgM related diseases in patients with serum immunofixation electrophoresis (sIFE) confirmed IgM monoclonal gammopathy at our center. METHODS We included patients with sIFE confirmed IgM monoclonal gammopathy between January 2008 and December 2014 in this retrospective study. We evaluated clinical data, sIFE, serum IgM levels, and diagnosis. RESULTS In total, 7107 patients had sIFE confirmed monoclonal gammopathy, with 377 (5.3%) patients having the IgM type. The median age was 62 years (range, 19-105 years). The median level of serum IgM is 8.3g/L (range, 0.24-150g/L). The diagnosis included monoclonal gammopathy of undetermined significance (MGUS, 157 patients, 41.6%), Waldenstrom macroglobulinemia (WM, 105 patients, 27.9%), B cell non-Hodgkins lymphoma (69 patients, 18.3%), primary cold agglutinin disease (pCAD, 16 patients, 4.2%), primary amyloidosis (14 patients, 3.7%), cryoglobulinaemia (six patients, 1.6%), IgM MGUS associated neuropathy (five patients, 1.3%), multiple myeloma (three patients, 0.8%), and POEMS syndrome (two patients, 0.5%). Levels of serum IgM>15.5g/L were 80.6% sensitive and 89.2% specific for the diagnosis of WM. Kappa type light chain indicated the diagnosis of WM, pCAD, IgM MGUS associated neuropathy and cryoglobulinaemia, while lambda type light chain indicated POEMS and amyloidosis. There were 41/157 (26.1%) MGUS patients diagnosed with complications due to IgM-unrelated autoimmune diseases. CONCLUSION IgM monoclonal gammopathy contains a broad spectrum of diseases. Levels of serum IgM and the type of light chain can be used to help with differential diagnosis. The association between MGUS and some autoimmune diseases requires further investigation.

Renal impairment in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome: incidence, treatment and outcome

BACKGROUND Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a multisystem disorder arising from underlying plasma cell dyscrasia. Renal impairment and related pathological changes have been reported, but data on its prevalence, response to therapy and impact on survival are still lacking. METHODS We retrospectively reviewed 299 patients diagnosed with POEMS syndrome in a tertiary-care university hospital from 2000 until 2014. The estimated glomerular filtration rate (eGFR) was used to define renal impairment and response, according to International Myeloma Working Group criteria. We examined the impact of renal impairment and response on patient survival. RESULTS Sixty-seven patients (22.4%) had renal impairment (eGFR < 60 mL/min/1.73 m(2)) at baseline. In a multivariate analysis, ascites was independently associated with renal impairment [odds ratio (OR) 12.366, P < 0.001]. Renal impairment was reversible in 66.0% of patients receiving therapy and was associated with a shorter time interval between symptom onset and treatment (OR 0.059, P = 0.043) and a vascular endothelial growth factor remission (OR 15.958, P = 0.050) in a multivariate analysis. In terms of therapy, patients with a renal response more commonly received a novel agent-based regimen (P = 0.037), which also led to a shorter response time (P = 0.001). With a median follow-up of 27.4 months, inferior survival was observed in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m(2)), but not in those with moderate dysfunction (eGFR 30-59 mL/min/1.73 m(2)), compared with patients without renal impairment. A renal response, if achieved, predicted improved survival. CONCLUSIONS Renal impairment is a common complication of POEMS syndrome, but can be reversed with effective therapy in most cases.

Prognostic study for overall survival in patients with newly diagnosed POEMS syndrome.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) is a multisystem disorder with a good long-term prognosis. In its dozens of clinical features, those with independent prognostic value are still not well characterized. We retrospectively included 362 patients with newly diagnosed POEMS syndrome at our institute from 2000 to 2015. On the basis of a randomized sample splitting, we first identified four baseline clinical variables, including age >50 years (hazards ratio (HR) 4.07, 95% confidence interval (CI) 1.41–11.76, P=0.009), pulmonary hypertension (HR 3.99, 95% CI 1.44–11.04, P=0.008), pleural effusion (HR 3.81, 95% CI 1.23–11.79, P=0.02) and estimated glomerular filtration rate <30 ml/min/1.73 m2 (HR 8.25, 95% CI 2.18–31.25, P=0.002), associated with inferior overall survival in the derivation cohort, with the use of multivariate Cox regression model. These factors were incorporated together to develop a prognostic nomogram. Concordance index calculation (0.727, 95% CI 0.601–0.853, P=0.018) and calibration curve plotting demonstrated its significant predictive and discriminatory capacity in the validation cohort. This nomogram could be a useful and convenient tool in clinical practice to evaluate individualized prognosis in patients with newly diagnosed POEMS syndrome.

Successful treatment of scleromyxedema with melphalan and dexamethasone followed by thalidomide maintenance therapy

Scleromyxedema (SM), the generalized papular and sclerodermoid form of lichen myxedematosus, is a fairly uncommon disease associated with monoclonal gammopathy and systemic manifestations.[1] It usually appears in middle and older age and affects men and women equally.[2,3] There are limited data regarding its pathogenesis, clinical course, and prognosis. Because of its rarity, there is no widely accepted consensus on the treatment of this disease. We have studied the clinical features and treatment outcomes of SM cases diagnosed at the Peking Union Medical College Hospital between January 2010 and December 2015. Diagnostic criteria were (i) generalized papular and sclerodermoid eruption; (ii) microscopic evidence of mucin deposition, fibroblast proliferation, and fibrosis; (iii) detection of monoclonal gammopathy; and (iv) absence of a concomitant thyroid disorder.[1] Clinical responses were evaluated according to the following parameters: (i) flattening of the papules; (ii) softening of skin induration; (iii) reduction of skin thickness; and (iv) improvement of systemic symptoms. Complete response (CR) was defined as the disappearance of symptoms and no detectable skin findings on examination. Partial response (PR) was defined as a decrease in skin changes and improvement in systemic symptoms.[4] Hematology response: CR was defined as negative immunofixation electrophoresis (IFE) of serum and urine. A very good partial response (VGPR) was defined as the serum and urine M components being detectable by IFE but not on electrophoresis or a 90% reduction in serum M component. PR was defined as 50% reduction of serum M-protein. Stable disease (SD) was defined as not meeting criteria for CR, VGPR, PR, or progressive disease. Progressive disease (PD) was defined as an increase of 25% from lowest response value in the serum M component. Five patients met the criteria for SM between January 2010 and December 2015, including three males and two females. The median age at diagnosis was 49 years (range 37–67 years). General characteristics of patients and treatments are outlined in Table 1. Median disease duration (from the first symptom to diagnosis) was 26 months (range 18–48 months). All five patients had the characteristic skin findings, which were generalized scleradermoid eruption studded with multiple, firm papules 1 to 3 mm in diameter involving the face, posterior ear, trunk, and limbs. All the patients had skin thickening and hyperpigmentation. Skin biopsy revealed dermal fibrosis with increased dermal mucin deposition. Only one patient (No. 2) had extracutaneous manifestations, namely, carpal tunnel syndrome that was demonstrated by electromyogram. None of the other four patients had any extracutaneous complaint, and the chest X-ray, transthoracic echocardiography, and pulmonary function tests were normal. The serum IFE showed IgGk monoclonal gammopathy in all five patients. The M protein of patient 1 could not be found by serum protein electrophoresis (SPE). The median M protein level determined by SPE of the other four patients was 2.9 g/L (range 1.3–6.5 g/L). One patient was excluded because no information about her treatment or follow-up was available. The other four patients were treated with 6 to 8 courses of a combination of melphalan and dexamethasone (MD) as induction therapy. MD was administered orally as

14q32 translocations and 13q14 deletions are common cytogenetic abnormalities in POEMS syndrome.

POEMS syndrome is a paraneoplastic syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell (PC) proliferative disease, and skin changes. Although chromosomal aberrations have been found and extensively described for other PC disorders, whether POEMS syndrome shares similar cytogenetic profiles has been rarely reported. In this study, we aimed to clarify the cytogenetic abnormalities of patients with POEMS syndrome in our center.

Long-term follow-up study of porcine anti-human thymocyte immunoglobulin therapy combined with cyclosporine for severe aplastic anemia.

Immunosuppressive therapy with antithymocyte immunoglobulin (ATG) and cyclosporine A is the first treatment option for severe aplastic anemia (SAA) patients without transplantation. Horse ATG is not marketed in China. Because the price of porcine ATG (pATG) is only about one‐third of the price of rabbit ATG (rATG), long‐term follow‐up studies of pATGs efficacy will help provide valuable insights into the treatment of SAA. Retrospective studies were performed to analyze the clinical information of 102 SAA patients treated with pATG and cyclosporine A from 1999 to 2014 in Peking Union Medical College Hospital. The median age was 29 years old (range 12–72). Median follow‐up time was 59.6 months (0.2–176.8). The overall response rate was 74.5% (CR 42.1%, PR 32.4%). The recurrence rate was 9.9%. The mortality rate was 16.7%. The median survival time has not been reached, and the 5‐year survival rate was 81.8%. Other hematologic abnormalities were observed in 7.8% of patients, including symptomatic PNH, MDS, and AML. Multivariate analysis revealed there was no significant effect on survival by factors such as gender, age, severity of disease, treatment time, and PNH clone (P > 0.05). These data have indicated pATG therapy combined with cyclosporine A has significant long‐term efficacy and high overall survival in SAA.

Comparison of Different Buffers for Protein Extraction from Formalin-Fixed and Paraffin-Embedded Tissue Specimens.

We determined the best extraction buffer for proteomic investigation using formalin-fixation and paraffin-embedded (FFPE) specimens. A Zwittergent 3–16 based buffer, sodium dodecyl sulfate (SDS)-containing buffer with/without polyethylene glycol 20000 (PEG20000), urea-containing buffer, and FFPE-FASP protein preparation kit were compared for protein extraction from different types of rat FFPE tissues, including the heart, brain, liver, lung, and kidney. All of the samples were divided into two groups of laser microdissected (LMD) and non-LMD specimens. For both kinds of specimens, Zwittergent was the most efficient buffer for identifying peptides and proteins, was broadly applicable to different tissues without impairing the enzymatic digestion, and was well compatible with mass spectrometry analysis. As a high molecular weight carrier substance, PEG20000 improved the identification of peptides and proteins; however, such an advantage is limited to tissues containing submicrograms to micrograms of protein. Considering its low lytic strength, urea-containing buffer would not be the first alternative for protein recovery. In conclusion, Zwittergent 3–16 is an effective buffer for extracting proteins from FFPE specimens for downstream proteomics analysis.