This case report describes a patient initially diagnosed with Gaucher disease (GD) with type I with homozygous mutation c.1448T > C p. (Leu483Pro) at age of 2, presenting with hepatosplenomegaly and cytopenia. Imiglucerase replacement therapy was initiated. At age 17, bilateral hearing loss developed, with subsequent Cranial MRI revealing thalamic damage, leading to a reclassification as type 3 GD. By age of 20, the patient presented with a range of symptoms, including abdominal pain, diarrhea, hypoproteinemia, multiple lymphadenopathy, edema, and Gaucher cell infiltration in the lymph nodes. Comprehensive diagnosis identifies Gaucher tumor and protein-losing enteropathy. Imiglucerase therapy at 90‐120 U/kg every 2 weeks significantly improved clinical symptoms, emphasizing the importance of tailored interventions for managing GD manifestations.

1. INTRODUCTION CD7 is an ideal chimeric antigen receptor (CAR) target for T-cell acute lymphocytic leukemia (T-ALL). Donor-derived CAR-T-cell therapy, as an emerging treatment strategy, shows excellent efficacy in refractory/relapsed (r/r) T-ALL, with over 90% of complete remission (CR), brings new promise to improve prognosis and survival quality, and provides more opportunities for following bridging transplantation.1 However, CD7-CAR-T-cell recipients are always immunocompromised for a number of reasons: depletion of healthy T and NK cells; the need for drugs, which are lymphodepleting, prior to CAR-T-cell therapy; a history of hematological malignancies; multiple-lines chemotherapy; and hematopoietic stem-cell transplantation (HSCT). Meanwhile, patients post donor-derived CAR-T-cell therapy are at high risk of graft-versus-host disease (GVHD) considering infusion of allogeneic cell and increase incidence of infection.2–5 Since the beginning of coronavirus disease 2019 (COVID-19) pandemic in 2020, the increasing transmissibility of the SARS-Cov2 virus and probable cytokines release syndromes (CRS), undoubtedly pose a huge challenge to safety of immunotherapy, especially in patients who received donor-derived CAR-T-cell therapy.6 For those who have been infected with the SARS-Cov-2, CAR-T-cell treatment should be put off until 2 weeks after the relief of COVID-19 and reverse of negative in RNA test.7,8 However, for patients already undergoing CAR-T-cell treatment, it is not yet known whether the development of a COVID-19 infection will increase the risk of CRS or GVHD or their severity, or whether the immunodeficiency caused by CD7-CAR-T-cell therapy would worsen the COVID symptoms. We report here, at first time that a T-ALL child who relapsed after allogenic-HSCT was treated with donor-derived CD7-CAR-T-cell therapy, accompanied by Omicron variant infection and subsequently soon severe intestinal acute GVHD (aGVHD). The case provided aims to serve as a reference for the clinical application and safety evaluation of donor-derived CD7-CAR-T-cell therapy in r/r T-ALL associated with COVID-19 diseases. 2. CASE REPORTS An 11-year-old girl was diagnosed with T-ALL with gene mutations including PTEN, EED, FAT1 and CUX1 in July 2020 and had undergone induction chemotherapy to achieved remission followed with multiple-lines consolidation therapy. On November 16, 2021, the patient received haploidentical HSCT (father, 6/12 HLA match). In October 2022, morphological evaluation of bone marrow showed 68.5% lymphoblasts and prolymphocytes, and short tandem repeat (STR) polymerase chain reaction analysis demonstrated 36.4% of donor chimerism, indicating the relapse of ALL. With a conditioning regimen of fludarabine (30 mg/m2, 3 days) and cyclophosphamide (300 mg/m2, 3 days), donor-derived CD7-CAR-T-cell (5 × 105 cells/kg) was infused on November 11, 2022 (d0). Nine days later, grade 1 CRS occurred but was immediately controlled with methylprednisolone (1 mg/kg, day 10 and 12 post CAR-T-cell infusion) (Fig. 1A, Supplemental table 1, https://links.lww.com/BS/A74).Figure 1.: Summary of clinical courses, treatment and laboratory results for the patient after donor-derived CD7-CAR-T-cell therapy. (A) Clinical timeline of disease course and key clinical information post the CAR-T-cell infusion. (B) Tissue sections of the enteroscopic biopsy demonstrated that predominant chronic inflammation of mucosa and no infection of cytomegalovirus. (C) Changes in liver enzymes and cytokines reflected the hallmarks of aGVHD and CRS after CAR-T-cell therapy. aGVHD = acute graft-versus-host disease, ALT = alanine aminotransferase, AST = aspartate aminotransferase, CAR = chimeric antigen receptor, CMV = cytomegalovirus, COVID-19 = coronavirus disease 2019, CRS = cytokine release syndrome, DBIL = direct bilirubin, GGT = gamma-glutamyl transpeptidase, IFN = interferon, IL = interleukin, NP = nasopharyngeal swab, PCR = polymerase chain reaction, SARS-Cov2 = severe acute respiratory syndrome coronavirus 2, TBIL = total bilirubin, TNF = tumor necrosis factor.With the pandemic wave of Omicron variant in China in December 2022,9 the child was unvaccinated before and identified as being positive for SARS-COV2 virus at day 25 after CAR-T-cell therapy. Cycle thresholds were 28.05 and 27.29 for the OFR1ab and N genes, respectively. First, the patient felt febrile and muscular ache, with normal oxygen saturation on room air and clear lungs by computed tomography. Unfortunately, 3 days after infection, the child had intermittent abdominal pain, diarrhea, and rapidly developed into persistent bloody stool. Laboratory evaluation showed a significant increase in transaminase and bilirubin. The child was confirmed acute GVHD (aGVHD: gut, grade III; liver, grade III). Pathological findings at enteroscopic biopsy revealed chronic inflammation of mucosa and a decreasing number of crypts including some with atypical shapes, which were consistent with aGVHD. The specimen also showed that epithelial cells were of enlarged nuclei with evident nucleoli, indicating viral infection. However, immunochemical staining demonstrated that no cytomegalovirus, Epstein-Barr virus and polyomavirus were found (Fig. 1A–B). The specimens were further for metagenomic next-generation sequencing (mNGS), which supported a diagnosis of Enterococcus faecium, but no Omicron variant. With administration of methylprednisolone and cyclosporine (maintenance concentration, 150–250 μg/L), transaminase and bilirubin resolved rapidly but intestinal aGVHD failed to be controlled. The child was then treated with basiliximab (20 mg, twice a week for 2 weeks), mesenchymal stromal cells (once in 31 days after infusion, not continued due to the economic burden) and JAK inhibitor ruxolitinib (10mg twice daily). The methylprednisolone was administrated by 2 mg/kg/d for a week and reduced by 10 to 20 mg every 5 to 7 days as other medicines above added and the condition improved. In the meantime, Azvudine (FNC) was administered for reducing viral load of SARS-CoV-2. However, the virus test of nasopharyngeal swabs could not turn negative until 22 days later. We further conducted the RNA test on a lower respiratory tract lavage fluid later and luckily found no positive result (Fig. 2A). The GVHD was controlled with mushy stool of 150 to 300 mL once a day but no more bloody stool or abdominal pain.Figure 2.: The safety and efficacy of donor-derived CD7-CAR-T-cell therapy with SARS-CoV-2 infection. (A) Patients’ SARS-CoV-2 viral cycle threshold trend indicated the severely delayed virus clearance and again positive virus test later. (B) Dynamics analysis of CD7-CAR-T-cell revealed excellent amplification and DNA copies of CAR-T-cell transgenes increased up to about 5 × 104. (C) Donor chimerism rate of the patient showed that STR-PCR resolved to fully donor chimerism again after CAR-T-cell therapy. BM = bone marrow, N = nucleocapsid protein, OF = open-reading frame, PB = peripheral blood, STR-PCR = short tandem repeat polymerase chain reaction.Encouragingly, the dynamic analysis of CD7-CAR-T-cell therapy showed excellent amplification in both peripheral blood and bone marrow. Copies of CAR-T-cell transgenes increased up to about 5 × 104. Consequently, the child reversed to CR again. On 14, 43, and 72 days after CAR-T-cell therapy, bone marrow and flow cytometry indicated CR (Supplemental Figure 1, https://links.lww.com/BS/A74), and STR resolved to fully donor chimerism (Fig. 2B–C). So, the patient could be discharged home transiently for regular follow-up and following treatment. The neutrophil lasts to be greater than 0.5 × 109/L and the patient lives without blood transfusion. Nevertheless, 85 days post CAR-T-cell treatment at home, the child’s omicron nucleic acid showed positive again, accompanied by mild fever and diarrhea. The patient immediately began taking Paxlovid medication. Fortunately for this time the nucleic acid turned negative after 7 days due to regular monitoring and timely treatment. 3. DISCUSSION Despite lower lethal risks in former healthy persons, Omicron with its faster spread and stronger ability to escape vaccine-induced immunity, still brought enormous threats for patients with immunodeficiency. The recent study about hematologic patients infected with omicron showed 8.2% of critical illness which were admitted to an intensive care unit occurred. For adult hematological tumor with CAR-T-cell therapy or HSCT, mortality from SARS-CoV-2 infections has been reported as 33% to 40%; An international study of CAR-T-cell recipients between 0 and 30 years with SARS-CoV-2 infections showed a 28.6% hospitalization rate and 4.3% death rate.9–13 However, the impact of Omicron infection on patients with CD7-donor-derived CAR-T-cell treatment is not well understood. Donor-derived CD7-CAR-T-cell therapy has great potential in r/r T-ALL.CD7 is expressed on the surface of normal and over 95% of T-ALL T cells, respectively. Furthermore, donor-derived CD7-CAR-T-cell solves the problems of fratricide and malignant contamination by autologous CD7-CAR-T-cell.14,15 In a clinical study of 20 patients with r/r T-ALL, donor-derived CD7-CAR-T-cell has achieved 90% of CR with manageable safety profile. Another research of 20 patients with r/r T-ALL and lymphoblastic lymphoma showed the similar results after CD7-CAR-T-cell therapy, with about 94.12% CR and no serious adverse events.2,3 It could not inevitably ignore the high risk of aGVHD in CD7-CAR-T-cell therapy since the donor nature of CAR-T-cell. Li et al reported a study of 12 patients of r/r T-ALL or T-cell lymphoblastic lymphoma who underwent donor CD7-CAR-T-cell therapy then bridging to allo-HSCT, most of whom had active GVHD after CAR-T-cell therapy and 3 developed aGVHD following allo-HSCT. In some other studies about donor-derived CD7-CAR-T-cell, the incidence of GVHD was over 50%.2–4 Omicron may further exacerbate the risk of gut GVHD. GVHD is the immune-mediated tissue damage by the activation of donor immune-competent T cells with antigens normally expressed by the recipient. Host exposure to gut microbiota due to gut barrier disruption is one of the important initiating events for GVHD.16 Several studies have found that a considerable number of COVID-19 patients presented with gastrointestinal symptoms; and SARS-CoV-2 virus was found in the fecal specimens of more than half patients. Research studies show that the gastrointestinal changes might be the secondary effect of respiratory changes, finally resulting in the imbalance of intestinal ecological. Intestinal cells highly express angiotensin-converting enzyme 2 and transmembrane protease serine 2 receptors, which are targets of SARS-CoV-2 and play a vital role in entry for viral infection of gastrointestinal cells.17–20 On the other hand, previous studies have shown that the SARS-CoV-2 vaccine may be a potential trigger of GVHD after transplantation. In a study of 113 allo-HSCT patients, 13% developed new or exacerbated GVHD symptoms after vaccination. In another study of 298 patients with allo-HSCT, the overall incidence of new chronic GvHD and exacerbated chronic GvHD after receiving the SARS-CoV2 vaccine was 14%, and the median time from vaccination to GVHD was about 3 to 4 weeks. In multivariate analysis, previous chronic GVHD and recent transplantation are associated with a higher incidence of GVHD after COVID-19 vaccination.21,22 In this case, the child experienced COVID-19 pandemic during CD7-donor-derived CAR-T-cell treatment. The child contracted Omicron and developed severe intestinal GVHD in 3 days. Because it was less than 1 month after CAR-T-cell treatment at that time, the child was well cared from both the hospital and the parents without unclean diet, dietary change, or other special cases. What is more, the intestinal biopsy confirmed the existence of GVHD, and more importantly the highly suspicious virus infection by altered epithelium with its thickened capsule, enlarged nuclei, and prominent nucleoli. Further immunohistochemistry revealed that this viral infection was not cytomegalovirus, Epstein-Barr virus, or polyomavirus. We also sent intestinal specimens for mNGS but did not find definitive evidence of SARS-CoV-2 maybe due to some omissions in unstable RNA virus for sample storage and transportation problems. Since the virus is ubiquitous and will continue for a long time, considering its significant impact on the severe GVHD and prognosis of patients after CAR-T-cell especially CD7-CAR-T-cell therapy, the subtle relationship between COVID-19 and GVHD should be given sufficient attention and further research. For patients with severe immunodeficiency after CAR-T-cell therapy, it was not easy to eliminate COVID-19, and combination of severe GVHD undoubtedly further aggravated the difficulty. We quickly implemented intensive antiviral treatment and anti-GVHD treatment. Considering the interaction between plaxivoid and other drugs including cyclosporine, we chose the available treatment Azivudine for anti-virus.23 The COVID-19 might result in more severe intestinal rejection, whereas the treatment of anti-GVHD may also avoid the serious CRS reaction of the lungs and even the whole body that COVID-19 may induce. Luckily, the covid-19 diseases was relieved and the intestinal GVHD was also well controlled. So, regular SARS-CoV-2 RNA testing and timely and effective antiviral treatment are urgent, which may help to change the extremely dangerous phenomenon into a manageable and benefit outcome for patients. In conclusion, this is the first time to depict the course of donor-derived CD7-CAR-T-cell patients after infection with omicron, which has considerable clinical implications for how to treat these patients more safely in the future. Patients after CD7-CAR-T-cell treatment who are infected with Omicron may experience severe delayed virus clearance and multiple relapses, exacerbating the risk of GVHD and pneumonia. Therefore, during the prevalence of COVID-19 diseases in local areas, donor-derived CD7-CAR-T-cell should be performed cautiously or even postponed if conditions permit. Although omicron no longer poses a threat in the normal population, more data and further exploration are needed on how to manage patients receiving CD7-CAR-T-cell treatment during local COVID-19 outbreaks. ACKNOWLEDGMENT This study was supported by a grant from the National Natural Science Foundation of China (No 82070217). The authors acknowledge the team of staff and researchers at the department of hematology and clinical laboratory center of Shanxi Bethune Hospital for their assistance. AUTHOR CONTRIBUTIONS J.W. and Z.G. conceived of the study. Y.L. and J.T. collected and analyzed the clinical data. L.M. and Z.Y. contributed to data collection, diagnosis, and treatment of the diseases. Y.L., Z.G., and J.W. wrote the manuscript with the help of all the authors.

BACKGROUND:Minimal change disease (MCD), a pathological type of nephrotic syndrome (NS), can occur in patients with tumors. We report two adult cases of MCD associated with papillary thyroid carcinoma (PTC), known to be extremely rare in adults.CASE PRESENTATION:A 35-year-old female patient was simultaneously diagnosed with MCD and PTC. The MCD was effectively treated with thyroidectomy and prednisone.In addition, a 50-year-old male patient, who had been diagnosed with PTC three years prior, had MCD confirmed by renal biopsy. The patient achieved complete remission following treatment with tacrolimus and rituximab.CONCLUSIONS:The present case report describes and discusses the diagnostic and treatment processes employed in these two patients. Clinicians need to be aware of the renal effects of treating patients with solid tumors.

干燥综合征肾损害以肾小管间质损害为主，累及肾小球较少见。本文报告1例经唇腺和肾活检证实的原发性干燥综合征合并膜增生性肾小球肾炎病例。患者以大量蛋白尿起病，经激素联合羟氯喹、环孢素等药物治疗后病情好转。

Objective:To investigate the clinicopathological characteristics of renal leukocyte chemotactic factor 2 amyloidosis (ALECT2).Methods:The patients with renal ALECT2 diagnosed by renal biopsy in Peking University First Hospital, Shanxi Medical University Second Hospital and Shanxi Bethune Hospital from January 2001 to October 2021 were retrospectively enrolled. According to whether the patients had concurrent glomerular diseases, they were classified into two groups: isolated ALECT2 group and ALECT2 with concurrent renal diseases group. Clinicopathological data of the two groups were compared. Light microscopy, immunofluorescence and immunoelectron microscopy were applied to investigate pathological characteristics of renal tissues. Mass spectrometry was used to analyze the composition of renal amyloid deposits. Gene sequencing was employed to detect the leukocyte chemotactic factor 2 ( LECT2) gene sequence in peripheral blood of the patients. Results:Sixteen patients with ALECT2 were enrolled in this study and nine of them had concurrent renal diseases. The age of 16 patients was (65.00±8.45) years old. The sex ratio of males to females was 7 to 9. Most of patients were Han ethnicity (15/16). Eight patients came from Shanxi province. Fifteen patients presented with varying degree of proteinuria [2.16(1.07, 4.72) g/24 h]; 5 patients had nephrotic syndrome; 11 patients had renal insufficiency; 12 patients had microscopic hematuria. Part of patients also had hypertension (12/16) and diabetics (6/16). Compared with isolated ALECT2, the ALECT2 group with concurrent renal diseases had a higher proportion of nephrotic syndrome (5/9 vs 0/7, P=0.034). Renal biopsy results showed that all patients (16/16) had amyloid deposits in the interstitium of renal cortex with varying degree of inflammatory cell infiltration and fibrosis, and glomeruli (12/16) and arterioles (14/16) were involved by amyloid deposits. The amyloid deposits were strongly congophilic and immunohistochemistry for LECT2 was positive. By semi-quantitative analysis, the proportions of glomerular and overall amyloid loads in ALECT2 with concurrent renal diseases group were lower than those in isolated ALECT2 group (both P<0.05). Electron microscopy revealed randomly oriented and non-branching fibrils with a diameter of 8-12 nm. The LECT2 peptides were detected by mass spectrometry in renal amyloid deposits of 8 patients, and homozygous G allele of LECT2 was found in 7 patients by gene sequencing. Complete follow-up data of 13 patients showed that 2 patients died, 1 patient developed end-stage renal disease at the time of renal biopsy, and most of the rest patients had stable renal function (8/10). Conclusions:Patients with renal ALECT2 mainly present with proteinuria, along with a high incidence of renal insufficiency, microscopic hematuria, and concurrent renal diseases. The pathologic feature is the preferential deposition of amyloid in renal cortical interstitium.

Primary mucinous tumors of the testis and paratestis are very rare, with only 29 reported cases detected in a PubMed search. The histopathological characteristics of primary testicular mucinous tumors are similar to their ovarian counterparts, and the diagnosis and naming criteria refer to the criteria for female ovarian mucinous tumors. However, the clinical and imaging features of primary testicular mucinous tumors are poorly understood, and they are thus frequently undiagnosed or misdiagnosed. We present the case of a patient with a primary testicular mucinous tumor. A 52-year-old man presented with a 1-year history of painless enlargement of the left scrotum. Ultrasound examination revealed a cystic mass in the left testis, with viscous fluid areas and calcified spots, irregular solid bulges on the cyst wall, and a small blood supply. Serum alpha-fetoprotein, β-human chorionic gonadotropin, lactate dehydrogenase, renal function, inflammatory markers, and routine urine and blood examinations were all normal. The patient underwent radical resection of the left testis. Postoperative pathology showed a multilocular cystic mass, with the inner wall of the sac lined with mucous columnar epithelial cells, some with mild nuclear atypia, and no interstitial infiltration. The pathological diagnosis was testicular mucinous tumor. Postoperative abdominal and pelvic computed tomography, colonoscopy, and gastroscopy showed no suspicious lesions. The final diagnosis was primary testicular borderline mucinous tumor. The patient underwent postoperative follow-up examinations once a year for 4 years. Serum tumor markers, scrotal ultrasound, abdominal and pelvic computed tomography scans, and colonoscopy and gastroscopy revealed no evidence of metastases or other primary adenocarcinoma. This case highlights the clinical and imaging characteristics of primary testicular mucinous tumors, which might aid their differential diagnosis.

Objective To discuss the BRAF V600E mutation rate in papillary thyroid carcinoma (PTC) and its relationship with the clinicopathological features. Methods Two hundred and sixty-five PTC patients(including 226 cases of classical type,29 cases of follicular type, 3 cases of high cell type, 2 cases of diffuse sclerosis type, 2 cases of eosinophilic type, 3 cases of cystic type) from August 2014 to October in Shanxi Provincial Cancer Hospital, were collected with completely clinical and pathological information. The BRAF V600E mutation was detected by real-time polymerase chain reaction (RT-PCR) method. Pearson χ 2 test and the exact probability method were used to analysis the relationship between gene mutations and clinicopathological data. Results BRAF V600E mutation rate in PTC patients was 73.21 %(194/265). There was no significant difference in the mutation rate of BRAF V600E among patients with different age, gender, tumor location,tumor number and extravaginal invasion(all P>0.05),but the mutation rates of BRAF V600E gene in patients with different tumor size, histopathological subtypes, lymph node metastasis and clinical stage were significantly different(all P<0.05).Conclusion The PTC patients with positive BRAF V600E mutation have poor clinicopathological features,and BRAF V600E mutation may be a predictor of advanced PTC.

Objective: To study the significance of microRNA-17, microRNA-19, c-myc, and E2F1 in T lymphoblastic lymphoma/leukemia (T-LBL/ALL) and their relationship to prognosis. Methods: Sixty cases of T-LBL/ALL with followup data were studied by using the immunohistochemical EnVision method for Ki-67, E2F1, and c-myc. Thirty cases of reactive lymph nodes were selected as the normal control group. Fluorescence in-situ hybridization (FISH) for the c-myc gene (located on chromosome 8q24) was performed to detect its breakage and gain/amplification. In addition, by way of the Quantitative real-time reverse transcription-polymerase chain reaction (PCR) method, we measured the microRNA-17 and microRNA-19 expression status in 60 cases of T-LBL/ALL. Results: Among the 60 cases of T-LBL/ALL, immunohistochemistry results showed that the percentages of tumor cell expression of E2F1 and c-myc were 51.7% and 66.7%. Ki-67 expression of ≤ 80% was found in 36 cases and > 80% was found in 24 cases. The positive rate of E2F1 protein was 51.7% (31/60) in 60 cases of T-LBL/ALL, but only 16.7% (5/30) in 30 cases of reactivated lymphoid tissue (χ2 = 15.72, P < 0.05). C-myc protein expression was correlated with mediastinal width and Ki-67 index (P < 0.05). FISH results showed that among the 60 cases, the c-myc gene with breakage of 8q24 was detected in six cases (10.0%) and gains in 11 cases (18.3%). Thirty cases of reactive lymph nodes did not incur breakage or gains of c-myc gene, which was not significant between the c-myc gene and protein expression (P > 0.05). The expression of miR-17, 19 in T-LBL/ALL was higher than in the reactivated lymphoid tissues (P < 0.05). The significance of miR-17, 19 was related to c-myc protein (P < 0.05), but the relationship of miR-17, 19, E2F1, and c-myc was not significant (P < 0.05). Log-rank analysis results: The prognosis of E2F1 and the c-myc protein positive group was worse than that of the negative group (P < 0.05). The expression of miR-17 and miR-19 (> M) was related to the prognosis (P < 0.05). Multivariable Cox regression analysis results: miR-17, 19 (> M) and c-myc protein are risk factors that affect the prognosis of T-LBL/ALL (P < 0.05). Positive E2F1 protein in the mediastinal width was higher than that in the normal mediastinum (P < 0.05). Conclusions: miR-17, 19, E2F1, and c-myc may play an important role on the development of T-LBL/ALL. There may be independent prognosis factors. Their links are very significant. Under the c-myc, molecular regulation between miR-17, 19 and E2F1 promotes excessive proliferation of T cells, playing a role in tumor formation and development.

胃癌是常见的消化道恶性肿瘤之一,在我国的发病率和病死率均居所有恶性肿瘤前列,由于多数胃癌患者在确诊时已为进展期,且中晚期胃癌患者无有效的治疗方案,即使采用围手术期化疗或辅助化疗,5年生存率仍不足7%[1].近年来随着靶向治疗的兴起,为晚期胃癌患者的治疗带来了新的希望,一项国际多中心随机对照三期临床研究(ToGA试验)的结果显示,化疗联合针对人类表皮生长因子受体2(human epidermal growth factor receptor-2,HER2)的曲妥珠单抗治疗可延长HER2阳性进展期胃癌患者的生存期[2],因此准确分析HER2状态是进展期胃癌HER2靶向治疗的关键.