[Diagnosis and treatment understanding of Waldenström macroglobulinemia in China: a cross-sectional study].

Objective: To conduct a nationwide physician survey to better understand clinicians' disease awareness, treatment patterns, and experience of Waldenström macroglobulinemia (WM) in China. Methods: This cross-sectional study was conducted from February 2022 to July 2022 by recruiting clinicians with WM treatment experience from hematology, hematology-oncology, and oncology departments throughout China. Quantitative surveys were designed based on the qualitative interviews. Results: The study included 415 clinicians from 219 hospitals spread across thirty-three cities and twenty-two provinces. As for diagnosis, the laboratory tests prescribed by physicians for suspected WM patients were relatively consistent (92% -99% recommendation for laboratory, 79% -95% recommendation for pathology, 96% recommendation for gene testing, and 63% -83% recommendation for imaging examination). However, from a physician's perspective, there was 22% misdiagnosis occurred in clinical practice. The rate of misdiagnosis was higher in lower-level hospitals than in tertiary grade A hospitals (29% vs 21%, P<0.001). The main reasons for misdiagnosis were that WM was easily confused with other diseases, and physicians lacked the necessary knowledge to make an accurate diagnosis. In terms of gene testing in clinical practice, 96% of participating physicians believed that WM patients would require gene testing for MYD88 and CXCR4 mutations because the results of gene testing would aid in confirming diagnosis and treatment options. In terms of treatment, 55% of physicians thought that the most important goal was to achieve remission, while 54% and 51% of physicians wanted to improve laboratory and/or examination results and extend overall survival time, respectively. Among patients with treatment indications, physicians estimated that approximately 21% of them refused to receive treatment, mainly owing to a lack of affordable care and disease awareness. When selecting the most appropriate treatment regimens, physicians would consider patient affordability (63% ), comorbidity (61% ), and risk level (54% ). Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% ). For those patients who received treatment, physicians reported that approximately 23% of patients did not comply with the treatment regimen due to a lack of affordability and disease awareness. Furthermore, 66% of physicians believe that in the future, increasing disease awareness and improving diagnosis rates is critical. Conclusions: This study is the first national physician survey of WM conducted in China. It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.

[Clinical efficacy of posterior femoral muscle flaps combined with posterior femoral cutaneous nerve nutrient vessel flap and closed lavage in the treatment of stage â £ ischial tuberosity pressure ulcers].

Objective: To explore the clinical efficacy of posterior femoral muscle flaps combined with posterior femoral cutaneous nerve nutrient vessel flap and closed lavage in the treatment of stage Ⅳ ischial tuberosity pressure ulcers. Methods: This study was a retrospective observational study. From March 2021 to March 2022, 15 patients with stage Ⅳ ischial tuberosity pressure ulcers who met the inclusion criteria were admitted to Dezhou Dongcheng Hospital, including 11 males and 4 females, aged 31 to 72 years. The pressure ulcer wound size ranged from 6.0 cm×4.5 cm to 10.0 cm×6.0 cm, with cavity diameters of 10-14 cm. Five cases were complicated with ischial tuberosity bone infection. After clearing the lesion, the biceps femoris long head muscle flap with an area of 10.0 cm×4.0 cm-18.0 cm×5.0 cm and the semitendinosus muscle flap with an area of 8.0 cm×4.0 cm-15.0 cm×5.0 cm combined with the posterior femoral cutaneous nerve nutrient vessel flap with an area of 6.5 cm×5.5 cm-10.5 cm×6.5 cm was transplanted to repair the pressure ulcer wound. The flap donor area was directly sutured, and the closed lavage with tubes inserted into the wound cavity was performed for 2-3 weeks. The postoperative survival of the muscle flaps and skin flaps, the wound healing of the donor and recipient areas were observed. The recurrence of pressure ulcers, the appearance and texture of flaps, and scar conditions of the donor and recipient areas were followed up. Results: All the muscle flaps and skin flaps in the 15 patients successfully survived after surgery. Two patients experienced incisional dehiscence at one week after surgery due to improper turning over, during which the incision in the recipient area was pressed on, and the wounds healed after dressing changes of 3 to 4 weeks; the wounds in the donor and recipient areas healed well in the other patients. All patients received follow-up after surgery. During the follow-up period of 6 to 12 months, none of the patients experienced pressure ulcer recurrence, and the texture, color, and thickness of the skin flaps closely resembled those of the surrounding skin at the recipient site, with only linear scar left in the donor and recipient areas. Conclusions: When using the posterior femoral muscle flaps combined with the posterior femoral cutaneous nerve nutrient vessel flap and closed lavage to treat stage Ⅳ ischial tuberosity pressure ulcers, the tissue flap can be used to fully fill in the dead space of the pressure ulcers. After treatment, the wound heals well, the appearance of the donor and recipient areas is better, and the pressure ulcers are less prone to reoccur.

[Clinical characteristics and progression risk factors for patients with monoclonal gammopathy of undetermined significance].

Objective: To analyze the clinical presentation and progression risk factors of patients with monoclonal gammopathy of undetermined significance (MGUS) in China. Methods: We retrospectively assessed the clinical features and disease progression of 1 037 patients with monoclonal gammopathy of undetermined significance between January 2004 and January 2022 at Peking Union Medical College Hospital. Results: A total of 1 037 patients were recruited in the study, including 636 males (63.6%) , with a median age of 58 (18-94) years. The median concentration of serum monoclonal protein was 2.7 (0-29.4) g/L. The monoclonal immunoglobulin type was IgG in 380 patients (59.7%) , IgA in 143 patients (22.5%) , IgM in 103 patients (16.2%) , IgD in 4 patients (0.6%) , and light chain in 6 patients (0.9%) . 171 patients (31.9%) had an abnormal serum-free light chain ratio (sFLCr) . According to the Mayo Clinic model for risk of progression, the proportion of patients in the low-risk, medium-low-risk, medium-high risk, and high-risk groups were 254 (59.5%) , 126 (29.5%) , 43 (10.1%) , and 4 (0.9%) , respectively. With a median follow-up of 47 (1-204) months, 34 of 795 patients (4.3%) had disease progression, and 22 (2.8%) died. The overall progression rate was 1.06 (0.99-1.13) /100 person-years. Patients with non-IgM MGUS have a markedly higher disease progression rate per 100 person-years than IgM-MGUS (2.87/100 person-years vs 0.99/100 person-years, P=0.002) . The disease progression rate per 100 person-years in non-IgM-MGUS patients of Mayo classification low-risk, medium-low risk and medium-high risk groups were 0.32 (0.25-0.39) /100 person-years, 1.82 (1.55-2.09) /100 person-years, and2.71 (1.93-3.49) /100 person-years, which had statistically difference (P=0.005) . Conclusion: In comparison to non-IgM-MGUS, IgM-MGUS has a greater risk of disease progression. The Mayo Clinic progression risk model applies to non-IgM-MGUS patients in China.

[Prognostic value of translocation t(11;14) in primary light-chain amyloidosis treated with bortezomib-based regimen].

Objective: To investigate the prognostic value of translocation t(11;14) in newly-diagnosed primary light-chain (AL) amyloidosis patients treated with bortezomib-based regimen. Method: Clinical information of newly-diagnosed AL amyloidosis patients in Peking Union Medical College Hospital who had baseline t(11;14) data and accepted bortezomib-combined therapies from September, 2015 to September, 2021 was collected. The relationships between t(11;14) status and baseline characteristics, hematological response, organ response and prognosis were analyzed. Results: A total of 152 patients were included, aged (59.5±9.1) years and 93 cases were male (61.2%). Forty-six patients carried t(11;14) (30.3%). There was no statistical difference in the proportion of organ involved, distribution of Mayo 2004 and 2012 stages and laboratory indexes between patients with and without t(11;14) (all P>0.05). For hematological response, the difference in the rates of ≥very good partial response (VGPR) between those with t(11;14) and without after the first cycle [28.2%(11/39) vs 37.4%(34/91), P>0.05] was not statistically significant. After 3 cycles, the difference in the rates of ≥VGPR between two groups was not statistically significant [35.9%(14/39) vs 51.1%(46/90), P>0.05]. The difference in the ratio of the best hematological response reaching ≥VGPR between two groups during the first-line treatment was not statistically significant [52.2%(24/46) vs 64.2%(68/106), P>0.05]. But patients with t(11;14) had lower cardiac response rate at 3 months [15.2%(5/33) vs 34.6%(28/81), P=0.038] and 6 months [19.4%(6/31) vs 50.6%(42/83),P=0.003] than those without, but the difference in cardiac response rates at 12 months was not statistically significant [41.7%(10/24) vs 53.5%(38/71),P>0.05]. For survival, the differences in overall survival (not reached vs 50.1 months, P>0.05) and hematological event-free survival (36.2 months vs 39.9 months, P>0.05) between patients carrying t(11;14) and those without were not statistically significant. Conclusion: Patients with t(11;14) had lower cardiac response rate than those without, but their hematological response and survival are not significantly different from those free from t(11;14).

[Efficacy and safety of daratumumab in the treatment of advanced light chain amyloidosis].

Objective: The study investigated the efficacy and safety of daratumumab in the treatment of cardiac light chain (AL) amyloidosis. Methods: We retrospectively analyzed the clinical characteristics, hematologic response, organ response, long-term survival, and adverse events of 20 patients with newly diagnosed or relapsed/refractory cardiac AL amyloidosis treated with daratumumab in Peking Union Medical College Hospitalo from January 2017 to March 2021. Results: The overall median age of 20 patients was 62 (range, 45-73) yeas, with a male to female ratio of 2.3:1. Nine patients were newly diagnosed, while 11 patients had relapsed or refractory disease. Based on Mayo 2004 cardiac AL staging system, stages Ⅱ and Ⅲ diseases were present in 20 patients respectively. Four patients died during the first cycle of daratumumab, and the remaining 16 patients completed a median of 3 (range, 1-10) cycles of treatment. Overall hematologic response rates were 80% each at 1, 3, and 6 months after treatment initiation, and 45% , 60% , and 60% of the patients achieved at least a very good partial response at 1, 3, and 6 months respectively. The median duration to hematologic response was 13 (range, 6-28) days. At 3, 6, and 12 months, 20% , 30% , and 40% of the patients respectively achieved a cardiac response, and the median days to response was 91 (range, 30-216) days. As of the last follow-up, 9 (45% ) patients died. The 1-month mortality rate of all the patients and stage IIIb patients was 25% and 40% , respectively. The 1-year overall survival rate was 48.4% . Lymphocytopenia was the most common hematological adverse event (above grade 3) . Non-hematological adverse events were mainly infusion-related reactions and infections. Conclusion: Daratumumab could induce deep and rapid hematologic response in newly diagnosed and previously treated cardiac AL amyloidosis patients. However, daratumumab was not effective in preventing the high and early mortality rate in stage Ⅲb patients.

[Efficacy and safety of vemurafenib in the treatment of BRAF(V600E)-mutated Erdheim-Chester disease].

Objective: To evaluate the safety and efficacy of vemurafenib in the treatment of BRAF(V600E)-mutated Erdheim-Chester disease (ECD) . Methods: We retrospectively analyzed the clinical data, response rate, adverse events and survival of 12 patients with ECD treated with vemurafenib from March 2015 to October 2020 in Peking Union Medical College Hospital. Results: Of 12 patients [7 males and 5 females, median age = 51.5 (range, 32-66) years old], the median number of organs involved was 6 (range, 4-8) , and the median treatment duration of vemurafenib was 11 (3-60) months. All patients had improvement of clinical symptoms, of which 2 cases were completely relieved, and 10 cases were partially relieved. Seven patients evaluated by (18)F-FDG-positron emission tomography/computed tomography achieved a metabolic response, including 2 patients with a complete metabolic response and 5 patients with a partial metabolic response. The common adverse events in the overall cohort were grade 1 to 2 (Common Terminology Criteria for Adverse Events 5.0) , including skin rash (58.3%) , arthralgia (25.0%) , and digestive tract reactions (16.7%) . The median follow-up time was 13.5 (3-60) months. One patient with central nervous system involvement died due to a cerebrovascular event, and one patient relapsed 10 months after drug withdrawal. The estimated 2-year overall survival rate and 2-year progression free survival rate were 88.89% and 66.67%, respectively. Conclusions: Vemurafenib is safe and effective in the treatment of BRAF(V600E)-mutated ECD.

[Clinical characteristics and outcome of patients with type â ¡ cryoglobulinemia].

Objective: To explore the clinical characteristics and outcome of patients with type Ⅱ cryoglobulinemia in our center. Methods: Clinical data of 61 patients diagnosed with type Ⅱ cryoglobulinemia in Peking Union Medical College hospital from May 2015 to January 2020 were retrospectively analyzed. Results: A total of 61 patients were enrolled in the study, including 26 (42.6%) males, with a median age of 53 (range 28-79) years. The primary diseases identified were hepatitis C virus infection (21.3%) , hepatitis B virus infection (21.3%) , autoimmune diseases (14.8%) , and hematological tumors (11.5%) . Idiopathic cryoglobulinemia patients accounted for 19 cases (31.1%) . The major symptoms presented were purpura, proteinuria, hematuria, renal failure, fever and arthralgia. The median concentration of cryoglobulin level was 215.9 (22.0-17 075.8) g/L, and the IgM-monoclonal component of cryoglobulin was identified in 54 patients (88.5%) . Rheumatoid factor increased in 93.2% of patients. C3 decreased in 57.6% of patients. C4 decreased in 61.0% of patients. Treatment was initiated in 49 patients (80.3%) , and the total clinical remission rate was 75.5%. The expected 3-year overall survival was 89.3%. Conclusion: Type Ⅱ cryoglobulinemia was a systemic disease with multi-organ involvement. Most type Ⅱ CGs were secondary to hepatitis virus infection. Early diagnosis and proper treatment could bring better outcome.

[Clinical presentation and prognosis in patients with light-chain amyloidosis with an ultra-high level of serum free light-chain].

Objective: To investigate the clinical features and outcomes of patients with light-chain (AL) amyloidosis with an ultra-high level of serum free light-chain (FLC) . Methods: Five hundred and ninety-five patients with AL amyloidosis were retrospectively reviewed between January 2009 and January 2020 at Peking Union Medical College Hospital. We analyzed the clinical features and prognosis of patients with ultra-high FLC levels [difference between involved and uninvolved light chains (dFLC) >500 mg/L; n=124] and those without ultra-high FLC levels (dFLC≤500 mg/L; n=471) . Results: Patients with ultra-high FLC presented with more frequent cardiac involvement (82.3% vs 70.1%, P=0.007) , and a higher percentage of patients with 2004 Mayo Ⅲ stage (41.8% vs 33.8%, P=0.029) , but less frequent renal involvement than patients without an ultra-high FLC (59.7% vs 71.8%, P=0.009) . Patients with an ultra-high FLC achieved a lower proportion of hematologic (72.4% vs 82.3%, P=0.048) and cardiac response (37.3% vs 54.7%, P=0.016) and had shorter overall survival (13.0 months vs not reached, P<0.001) and a higher early death rate within 3 months (28.2% vs 11.3%, P<0.001) than those without an ultra-high FLC. Ultra-high FLC independently predicted worse prognosis in patients with AL amyloidosis (HR=2.279, 95%CI 1.685-3.083, P<0.001) . Conclusions: Patients with an initially ultra-high FLC represented a subgroup with more common cardiac involvement, more advanced cardiac stages, and extremely poor prognosis.

[The 487th case: prominent eyes, headache, blurred vision].

One 51 years old man was admitted to the rheumatology department with a history of prominent eyes, headache and blurred vision for half year. The main manifestations included retrobulbar inflammatory pseudotumor and retroperitoneal fibrosis. He was initially diagnosed as granulomatosis with polyangiitis. Prednisone and cyclophosphamide were administrated and effective. New mass of dura mater and osteosclerosis presented during follow up. Finally Erdheim Chester disease(ECD) was diagnosed by biopsy and pathological examination. Vemurafenib, a v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) inhibitor, 480 mg was given twice a day. The patient's condition is stable and still in follow-up. Although ECD is a rare histiocytosis, clinicians should pay attention to its manifestations and differential diagnoses.

[A pediatric-inspired regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: results from a single center].

Objective: To investigate the efficacy of using a pediatric-inspired regimen for adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph(-)) acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) at a single center in China. Methods: Clinical data of 71 consecutive newly diagnosed AYA patients with Ph(-) ALL/LBL on a pediatric-inspired regimen in Peking Union Medical College Hospital from January 2012 to November 2018 were retrospectively analyzed. Results: Median age at diagnosis was 20 years (range: 15-38) , and 46 patients (64.8%) were male. Forty-nine (69.0%) had B-ALL/LBL. Among 62 ALL patients, 22 (35.5%) were high-risk. Complete remission rate was 93.0%. At follow-up with a median time of 44 months, the estimated 5-year disease-free survival (DFS) and overall survival (OS) was 56.3% and 64.3%, respectively. There was no significant difference in 5-year OS between allogeneic hematopoietic stem cell transplantation group and the continuous chemotherapy group after completion of 4 courses of chemotherapy. The 5-year DFS and OS for the non-high-risk group was 63.1% and 73.7%, respectively, which were significantly higher than 32.0% and 44.4% for the high-risk group, respectively (P<0.001) . Conclusions: The use of pediatric-inspired regimen for AYAs with Ph(-) ALL/LBL was feasible and effective.

[Anti-myelin-associated glycoprotein antibody positive IgM monoclonal gammopathy related peripheral neuropathy: 11 cases and literature review].

Objective: To improve the understanding of rare anti-myelin-associated glycoprotein (MAG) positive IgM monoclonal gammopathy related peripheral neuropathy (IgM-PN) . Methods: Eleven cases of IgM paraproteinemia and anti-MAG antibody positive neuropathy diagnosed since 2014 in Peking Medical Union College Hospital were summarized. The medical records including clinical manifestation, lab results, treatment and prognosis were analyzed. Results: Among the 11 patients (8 male and 3 female) , the median onset age is 63 years old (range from 52 to 77 years old) . The peripheral neuropathy of 9 patients were characterized by distal onset of numbness, 6 patients suffered from muscle weakness. The nerve conduction velocity study indicated that all 11 patients had demyelinating peripheral nerve damage, which was sensory predominant and more severe in lower limbs, 6 of them had secondary axonal damage. Monoclonal IgM gammopathy was identified in all 11 patients, among which 6 were IgM κ, 2 IgG κ and IgM κ bi-clonal, 3 IgM λ. Three patients were diagnosed with Waldenström's macroglobulinaemia. The anti-MAG-IgM antibody was positive in all 11 cases. After diagnosis, 9 patients received combination chemotherapy including rituximab or rituximab treatment alone. The monoclonal IgM level declined significantly in 7 patients. The neuropathy was stable or improved. Conclusions: Anti-MAG antibody positive IgM-PN is a rare M protein related disease. In peripheral neuropathy with undetermined etiology, we suggest to screen M protein and anti-MAG antibody. Chemotherapy including rituximab or rituximab alone is recommended as first-line therapy.

[Oral melphalan plus high-dose dexamethasone as first-line therapy for patients with primary light chain amyloidosis].

Objective: To evaluate the response of oral melphalan plus high-dose dexamethasone (MDex) for patients with primary light chain amyloidosis (pAL). Methods: Clinical data, hematological and organ responses, and survival of 76 patients with pAL who had received MDex from January 2009 to July 2017 were retrospectively analyzed. Results: Of 76 patients (47 males and 29 females with the median age of 56 [range, 20-74] years old), 19.70% patients were defined as Mayo 2004 stage 3, involvement of more than or two organs was presented in 65 (85.53%) patients. Among 60 response evaluable patients, overall hematological response was 48.33% with complete response of 20.00% and very good partial response of 20.00%, respectively. The median time to the hematological response was 5 (range, 1-15) months. 36.67% patients achieved organ response. After the median follow up of 23(range, 1-113) months for surviving patients, median progression-free survival (PFS) and overall survival (OS) were 34 and 43 months, respectively. In a three months landmark analysis, the median rates of PFS and OS were 46 and 65 months, respectively. The median OS rates of patients with Mayo 2004 stage 3 and non Mayo 2004 stage 3 were 5 and 65 months (P=0.001), respectively. Conclusions: MDex was an effective treatment for patients with early stage pAL, but was not suitable for those with severe cardiac involvement.