Familial 46, XY Disorder of Sexual Development identified in a Ph+BCR::ABL1P210+ Acute Lymphoblastic Leukemia septuagenarian female with RCBTB2::LPAR6 fusion gene: a case report.

Background: Familial 46, XY Disorder of Sexual Development (DSD) was discovered in a Ph+, BCR::ABL1P210+ Acute Lymphoblastic Leukemia (ALL) female with RCBTB2::LPAR6 fusion gene. Siblings developing 46, XY DSD are extremely rare. Patients with 46, XY DSD have much higher rates of gonadal cancers. Nevertheless, the incidence of hematologic malignancies in patients with DSDs has received little attention. RCBTB2::LPAR6 is a rarely reported fusion gene in ALL. Case presentation: Herein, we report a rare case of a newly diagnosed Ph+, BCR::ABL1P210+ ALL patient who was 77 years old and female by social sex. Whole Exome Sequencing (WES) and RNA sequencing revealed TET2 and NF1 mutations in addition to a rarely reported RCBTB2::LPAR6 fusion gene and 17 other genes with uncertain clinical significance. The patient was surprisingly found to have a male karyotype. On ultrasound, neither the uterus nor the ovaries were discernible. A detailed family and marital history revealed that the patient had undergone surgery at an early age for an unexplained inguinal mass. She had slow pubertal development, scanty menstruation, and few overtly feminine characteristics. She had three marriages, but none succeeded in getting pregnant. The patient had never sought therapy for infertility due to the inaccessibility of medical treatment and a lack of medical knowledge. Her sister, 73 years old and female by social sex, who had amenorrhea in adolescence and was unable to conceive, had the same experience. To our surprise, she also had a male karyotype. Conclusions: Due to the absence of long-term social attention and follow-up, studies on the incidence of hematologic malignancies in patients with 46, XY DSD are incredibly uncommon. Siblings developing 46, XY DSD is extremely rare. We report the oldest patient diagnosed with 46, XY DSD. There have not yet been any reports of familial 46, XY DSD with a concurrent diagnosis of Ph+BCR::ABL1P210+ ALL with a rarely reported RCBTB2::LPAR6 fusion gene.

TP53 and KMT2D mutations associated with worse prognosis in peripheral T-cell lymphomas.

There are limited studies on mutation profiling for Peripheral T-cell lymphomas (PTCL) in the Chinese population. We retrospectively analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients. Targeted next-generation sequencing (NGS) was performed for tissues from these patients. At least one mutation was detected in 60 (90.9%) patients, with a median number of 3 (0-7) mutations, and 32 (48.5%) cases detected with more than 4 mutations. The genes with higher mutation frequencies were TET2, RHOA, DNMT3A, IDH2, TP53, STAT3, and KMT2D respectively. When mutant genes are classified by functional group, the most prevalent mutations are related to epigenetics and signal transduction. IPI ≥2, PIT ≥2, and failure to achieve partial remission (PR) were factors for inferior progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed TP53 was an adverse factor for PFS (HR, 3.523; 95% CI, 1.262-9.835; p = 0.016), and KMT2D was an adverse factor for OS (HR, 10.097; 95% CI, 1.000-101.953; p = 0.048). Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses.

Hematologic secondary malignancies among 102 Chinese patients with Waldenstrom's macroglobulinemia: a single-center case experience and literature review.

Waldenstrom's macroglobulinemia (WM) is a rare and indolent B-cell lymphoma. To investigate the type and survival of hematologic secondary malignancies (SMs) in Chinese patients with WM, we retrospectively reviewed the characteristics of 102 patients with WM from February 2002 to May 2023 in our center. Four men and two women were diagnosed with hematologic SMs. Of the six patients with hematologic SMs, one was diagnosed with acute myeloid leukemia (AML), one with multiple myeloma (MM), one with myelodysplastic syndrome (MDS), one with B-cell acute lymphoblastic leukemia (B-ALL), and two with diffuse large B-cell lymphoma (DLBCL). The median age was 65.5 years (56-74 years). The median interval time between diagnosis of WM and hematologic SMs was 39.5 months (10-117 months). Among those with WM with hematologic SMs, five died and one survived. Overall survival (OS) was just 33 months (12-119 months) on median. A total of 32 patients died and 64 survived in the group of WM without hematologic SMs, and the median OS was 82 months (3-250 months). This is the first study in the Chinese population on hematologic SMs in WM. The purpose of this study was to investigate the prognosis of hematologic SMs in WM in the Chinese population, as well as to compare the population's characteristics to those of other centers. We investigated the underlying causes further and presented a research strategy for our forthcoming investigation. We intend to investigate risk factors for SMs as well as more accessible screening methods.

Global warming may significantly increase childhood anemia burden in sub-Saharan Africa.

Childhood anemia constitutes a global public health problem, especially in low- and middle-income countries (LMICs). However, it remains unknown whether global warming has an impact on childhood anemia. Here, we examined the association between annual temperatures and childhood anemia prevalence in sub-Saharan Africa and then projected childhood anemia burden attributable to climate change. Each 1°C increment in annual temperature was associated with increased odds of childhood anemia (odd ratio = 1.138, 95% confidence interval: 1.134-1.142). Compared with the baseline period (1985-2014), the attributable childhood anemia cases would increase by 7,597 per 100,000 person-years under a high-emission scenario in the 2090s, which would be almost 2-fold and over 3-fold more than those projected in moderate- and low-emission scenarios. Our results reveal the vulnerabilities and inequalities of children for the excess burden of anemia due to climate warming and highlight the importance of climate mitigation and adaptation strategies in LMICs.

Case report: A rare case of coexisting Waldenstrom Macroglobulinemia and B-cell acute lymphoblastic leukemia with KMT2D and MECOM mutations.

Background: Waldenstrom Macroglobulinemia (WM) is a rare and indolent lymphoma of B-cell origin characterized by elevated monoclonal IgM, with MYD88L265P mutation and CXCR4 mutation as common molecular alterations. B-cell Acute Lymphoblastic Leukemia (B-ALL) is clinically heterogeneous, characterized by abnormal proliferation and aggregation of immature lymphocytes in the bone marrow and lymphoid tissue. WM and ALL are hematologic malignancies of B-cell origin with completely different clinical manifestations and biological features. KMT2D and MECOM mutations are very rare in ALL and usually indicate poor disease prognosis. The coexistence of WM and ALL with KMT2D and MECOM mutations have not been reported. Case presentation: A 74-year-old female patient was diagnosed with WM in July 2018 and received four cycles of chemotherapy of bortezomib and dexamethasone. In November 2018, she received immunomodulator thalidomide as maintenance therapy. In November 2020, Bruton's Tyrosine Kinase inhibitors (BTKi) has been introduced into the Chinese market and she took zanubrutinib orally at a dose of 80 mg per day. The disease remained in remission. In December 2021, she presented with multiple enlarged lymph nodes throughout the body. Bone marrow and next-generation sequencing (NGS) suggested the coexistence of WM and B-ALL with KMT2D and MECOM mutations. The patient was treated with zanubrutinib in combination with vincristine and dexamethasone, after which she developed severe myelosuppression and septicemia. The patient finally got remission. Due to the patient's age and poor status, she refused intravenous chemotherapy and is currently treated with zanubrutinib. Conclusions: The coexistence of WM and B-ALL is very rare and has not been reported. The presence of both KMT2D and MECOM mutations predicts a poor prognosis and the possibility of insensitivity to conventional treatment options. BTKi achieves its anti-tumor effects by inhibiting BTK activation and blocking a series of malignant transformations in B-cell tumors. In addition, it also acts on T-cell immunity and tumor microenvironment. Combination therapy based on BTKi may improve the prognosis of this patient.

Atypical nontraumatic chylothorax in a monoclonal IgM elevated nodal marginal zone lymphoma: A case report and review of the literature.

Nodal Marginal Zone Lymphoma(NMZL) is an indolent lymphoma with a very low clinical incidence and is sometimes difficult to differentiate diagnostically from Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM). NMZL with elevated monoclonal immunoglobulin M (IgM) is even rarer. Nontraumatic chylothorax can be seen in aggressive lymphoma, which often happens with chest tightness and dyspnea as the primary clinical manifestation. We reported the first case of monoclonal IgM elevated NMZL complicated by atypical nontraumatic chylothorax. A 64-year-old male patient was first admitted to the Department of Respiratory Medicine with symptoms of chest tightness and shortness of breath. He was given several times thoracentesis to drain pleural effusion to improve pulmonary compression symptoms. The patient had a combination of elevated monoclonal IgM and atypical lymph node biopsy pathology. After two times lymph node biopsies and genetic testing, the patient was finally diagnosed with NMZL. Within a short time, he was admitted to the Department of Hematology due to the reappearance of massive pleural effusion, which indicated chylothorax. The patient repeatedly presented with left-sided pleural effusion, and the color went from red to yellow, and finally white. Only about half of the chylothorax cases present with typical clinical manifestations. We report this case intending to draw the attention of clinicians to hematologic malignancies with atypical nontraumatic chylothorax.

Case report: Zanubrutinib-induced dermatological toxicities: A single-center experience and review.

Zanubrutinib, a next-generation non-covalent Bruton's tyrosine kinase (BTK) inhibitor, shows great efficacy in the treatment of B cell malignancies. Some patients may experience a series of side effects after the treatment of zanubrutinib. Grade 4 dermatological toxicities are rare, which present as severe rash and skin infection. Herein, we retrospectively reported the grade 4 dermatological toxicities of zanubrutinib in three consecutive patients. They were treated with zanubrutinib 160 mg twice daily orally. One patient was diagnosed with Primary Breast Diffuse Large B-cell Lymphoma(PB-DLBCL) and two patients were diagnosed with Chronic Lymphocytic Leukemia(CLL). Within one month after zanubrutinib treatment, all three patients developed grade 4 dermatological toxicities, including bruising, maculopapular rash, petechiae, ecchymosis, hemorrhagic blister, acne-Like rash, papulopustular rash, and skin infections. Zanubrutinib was discontinued in two patients due to unacceptable dermatological toxicities. Safety data from pre-licensing clinical trials showed that zanubrutinib-related side effects were frequent but well tolerated. To date, no severe dermatological toxicities were reported. The majority of patients can be relieved with symptomatic treatment, but a very small percentage of patients may face discontinuation of the drug.

Whole-genome sequencing as an alternative to analyze copy number abnormalities in acute myeloid leukemia and myelodysplastic syndrome.

Copy number aberrations (CNA) are the core determinants for diagnosis, risk stratification and prognosis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In this study, a shallow whole-genome sequencing-based assay, LeukoPrint, was utilized to depict genomic CNA profiles from the bone marrow of 137 newly diagnosed AML/MDS patients. It demonstrated 98.1% concordance of CNA profiles with cytogenetics and/or fluorescence in situ hybridization (FISH). It is advantageous in detecting CNAs of short segments (1 Mb) and from samples with low leukemic cell content, more accurate for describing complex karyotypes and less confounded by subjective bias. LeukoPrint improved the overall diagnostic yield by redefining the risk categories for 16 patients by presenting new information. In summary, LeukoPrint provided an automated, convenient, and cost-effective approach to describe genomic CNA profiles. It brought greater diagnostic yield and risk stratification information by incorporating into the routine cytogenetics based on the CNA-related criteria of standard ELN/IPSS-R guidelines.

Screening and identification of a novel FHL2 mutation by whole exome sequencing in twins with familial Waldenström macroglobulinemia.

BACKGROUND: Waldenström macroglobulinemia (WM) is a rare chronic B-cell lymphoma. Familial clustering of WM has been observed over the years. However, little is known about the contribution of inherited genetic variants to familial WM cases. METHODS: The authors performed whole exome sequencing (WES) of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Bioinformatics analysis of public biological databases was used to identify the most relevant familial WM candidate from WES. Transcript expression and protein levels of the familial WM candidate were evaluated in the WM patient and 2 unaffected members of the kindred. RESULTS: Among the 10 shared candidate mutations in the twins, the authors identified a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) as a familial WM-associated mutation. FHL2 appeared to be connected with reported signaling pathways and disease-driving genes such as IL6 and HCK in WM. In addition, the authors found reduced FHL2 messenger RNA and protein expression in peripheral blood samples from the patient with WM in comparison with the healthy siblings. CONCLUSIONS: Taken together, these findings indicate that an FHL2g226a mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases. LAY SUMMARY: Familial clustering in Waldenström macroglobulinemia (WM) has been observed over the years. The authors performed whole exome sequencing of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Among the 10 shared candidate mutations in the twins, a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) was identified as the most relevant familial WM candidate through bioinformatics analysis of a public database. Also, messenger RNA and protein expression of FHL2 was significantly lower in peripheral blood mononuclear cells of the WM patient in comparison with the healthy siblings, and this suggested that the function of FHL2 was impaired when mutated.

Short-term exposure to coarse particulate matter and outpatient visits for cardiopulmonary disease in a Chinese city.

Limited studies have been conducted to evaluate the short-term relationships between exposure to coarse particulate matter (PM2.5-10) and outpatient visits in China. We designed this time-series analysis in a Chinese city Yancheng, to explore the relationship of PM2.5-10 with outpatient visits for cardiopulmonary diseases. The study period was from 2013 to 2015. A typical generalized additive model was used. We explored the lag patterns by building a series of lag of exposure. We also built two-pollutant models to ascertain the independence of PM2.5-10. Stratified analyses were applied to compare the season-specific associations. Finally, we pooled the concentration-response (C-R) curves for PM2.5-10 and outpatient visits. We recorded a daily average of 85 and 43 outpatient visits for cardiovascular and respiratory causes, respectively. PM2.5-10 exposures of lag 05 day yielded the best estimates for both outcomes. Per 10-µg/m3 increase in PM2.5-10, there was a 1.69% (95% confidence interval [CI]: 0.68%-2.72%) increase in outpatient visits for respiratory causes, and a 0.85% (95% CI: 0.13%-1.57%) increase for cardiovascular causes. The association kept robust after adjusting for PM2.5 and O3, and there were larger associations in warm seasons. The C-R curves had a larger slope for respiratory diseases in relatively lower concentrations (<30 µg/m3), and PM2.5-10 was positively associated with cardiovascular diseases in higher concentrations (>30 µg/m3). This study indicated significant associations of PM2.5-10 with cardiopulmonary outpatient visit. Such results may be used for health risk assessment and policy making for particulate air pollution control.

Association between ambient temperature and daily emergency hospitalizations for acute coronary syndrome in Yancheng, China.

Acute coronary syndrome (ACS) is a major public health concern worldwide. Few studies have directly evaluated the associations between ambient temperature and ACS incidence. To explore the association between ambient temperature and ACS emergency hospitalizations in the area of subtropical monsoon climate, data on ACS emergency hospitalizations were collected from two highest-ranking hospitals in the central urban area of Yancheng, China, from January 1, 2013, to December 31, 2018. We applied the time-series method to investigate the potentially lagged and non-linear effects of ambient temperature on ACS using the generalized linear model combined with the distributed lag non-linear model after adjusting for time trend, day of the week, holiday, and relative humidity. We identified a total of 5303 cases of ACS emergency hospitalizations during the study period. The exposure-response curves between ambient temperature and ACS hospitalizations were inverse "J-shaped." The effects of extreme low temperature on ACS hospitalizations occurred on the present day and lasted for 3 days, followed by the harvesting effect. The effects of extreme high temperature occurred on the present day and lasted for 5 days. The cumulative relative risks of ACS were 2.14 [95% confident interval (CI): 1.32 to 3.47] for extremely low temperature and 1.66 (95% CI: 1.33 to 2.06) for extremely high temperature over the lag of 0-5 days, compared with the reference temperature (25.0 °C). Both low and high temperatures were significantly associated with higher risks of emergency hospital admissions for ACS in Yancheng, China.

Association between ambient particulate matter air pollution and ST-elevation myocardial infarction: A case-crossover study in a Chinese city.

BACKGROUND: Abundant epidemiological studies have revealed that short-term exposure to ambient air pollution increased the incidence of ischemic heart diseases. However, few investigations have explored the association between air pollution and ST-elevation myocardial infarction (STEMI), one major subtype of such events. METHODS: We conducted a time-stratified case-crossover study in two major hospitals of Yancheng, a city in East China, from January 2015 to February 2018. We used conditional logistic regression models to explore the association between hourly concentrations of air pollutants and STEMI hospitalizations. We explored potential effect modification in susceptible subgroups by age, gender, smoking status, and comorbidities. Two-pollutant models were fitted to test the robustness of the association. RESULTS: We identified a total of 347 STEMI patients. In single-pollutant models, each 10 µg/m3 increase in concentrations of fine and inhalable particulate matter (PM) (lag 13-24 h) was associated with increments of 5.27% [95% confidence interval (CI): 1.09%, 9.46%] and 3.86% (95%CI: 0.83%, 6.88%) in STEMI hospitalizations, respectively. We observed slightly larger associations of STEMI hospitalization with PM in patients who were older than 65, female, non-smoker, and with comorbidities (hypertension, diabetes or hyperlipidemia). The associations were generally robust to adjustment of criteria gaseous pollutants except for carbon monoxide. CONCLUSION: This is the first study in China that suggested acute exposure to elevated PM concentrations may trigger STEMI. Patients with cardiometabolic comorbidities were slightly more susceptible to air pollution.

Effect of the interaction between outdoor air pollution and extreme temperature on daily mortality in Shanghai, China.

BACKGROUND: Both outdoor air pollution and extreme temperature have been associated with daily mortality; however, the effect of their interaction is not known. METHODS: This time-series analysis examined the effect of the interaction between outdoor air pollutants and extreme temperature on daily mortality in Shanghai, China. A generalized additive model (GAM) with penalized splines was used to analyze mortality, air pollution, temperature, and covariate data. The effects of air pollutants were stratified by temperature stratum to examine the interaction effect of air pollutants and extreme temperature. RESULTS: We found a statistically significant interaction between PM10/O3 and extreme low temperatures for both total nonaccidental and cause-specific mortality. On days with "normal" temperatures (15th-85th percentile), a 10-µg/m³ increment in PM10 corresponded to a 0.17% (95% CI: 0.03%, 0.32%) increase in total mortality, a 0.23% (0.02%, 0.44%) increase in cardiovascular mortality, and a 0.26% (-0.07%, 0.60%) increase in respiratory mortality. On low-temperature days (<15th percentile), the estimates changed to 0.40% (0.21%, 0.58%) for total mortality, 0.49% (0.13%, 0.86%) for cardiovascular mortality, and 0.24% (-0.33%, 0.82%) for respiratory mortality. The interaction pattern of O3 with lower temperature was similar. The interaction between PM10/O3 and lower temperature remained robust when alternative cut-points were used for temperature strata. CONCLUSIONS: The acute health effects of air pollution might vary by temperature level.

Diurnal temperature range is a risk factor for coronary heart disease death.

BACKGROUND: Although the relation between day-to-day temperature change and coronary heart disease (CHD) mortality is well established, it is unknown whether temperature variation within 1 day, ie, diurnal temperature range (DTR), is an independent risk factor for acute CHD death. METHODS: We used time-series and case-crossover approaches to assess the relation between DTR and daily CHD mortality between 2001 and 2004 in Shanghai, China. Specifically, we used exposures averaged over periods varying from 1 to 5 days to assess the effects of DTR on CHD mortality. We estimated the percent increase in the number of daily deaths related to CHD that were associated with DTR, after adjustment for daily meteorologic conditions (temperature and relative humidity) and levels of outdoor air pollutants. RESULTS: Both time-series and case-crossover analyses showed that DTR was significantly associated with the number of daily deaths related to CHD. A 1 degrees C increase in 2-day lagged DTR corresponded to a 2.46% (95% CI, 1.76% to 3.16%) increase in CHD mortality on time-series analysis, a 3.21% (95% CI, 2.23% to 4.19%) increase on unidirectional case-crossover analysis, and a 2.13% (95% CI, 1.04% to 3.22%) increase on bidirectional case-crossover analysis. CONCLUSIONS: Our findings suggest that DTR is an independent risk factor for acute CHD death.

[A case report of misdiagnosed mantle cell lymphoma].

Mantle cell lymphoma (MCL) is a rare group of non-Hodgkin's lymphoma (NHL), which is difficult to discriminate from other subtype of small lymphocytic lymphoma in morphologic appearance. In order to enhance the understanding of MCL, a case of MCL first diagnosed as follicular lymphoma (FL) was reported. The clinical and laboratory characteristics of MCL were analyzed and summarized. The results showed that the findings of flow cytometry (FCM) and immunohistochemical staining technique were compatible with the diagnosis of MCL. Cytogenetic analysis can detect multiple types of chromosomal abnormalities, including t (11; 14). In conclusion, MCL is a disease which diagnosis is difficulty confirmed. Interphase fluorescence in situ hybridization, multiplex fluorescence in situ hybridization, FCM and immunohistochemical staining technique play important roles in the diagnosis of MCL.

[Detection of 13q14 deletion in chronic lymphocytic leukemia by using probes D13S319 and D13S25].

To investigate the incidence of 13q14 deletion [del (13q14)] in chronic lymphocytic leukemia (CLL), Spectrum Orange labeled sequence-specific DNA probes D13S319 and D13S25 for 13q14 and interphase fluorescence in situ hybridization (I-FISH) were applied to detect del (13q14) in 24 patients with B-CLL. The results showed that among 24 patients, 10 patients (41.7%) had del (13q14) with D13S319, 11 patients (45.8%) had del (13q14) with D13S25, and 9 patients (37.5%) had del (13q14) with both D13S319 and D13S25. The incidence of del (13q14) in Binet stage A, B, C was 4/7 (57.1%), 3/7 (42.9%) and 5/10 (50.0%) respectively by D13S319 probe detection, and there was no significant difference between three Binet stages (P>0.05). It is concluded that the region of loss at 13q14 locates between D13S319 and D13S25 in CLL, and the I-FISH is a rapid and sensitive technique for analysis of del (13q14) in CLL.