The frequency of mutations in advanced thyroid cancer in Japan: a single-center study.

We analyzed the outcomes of genetic testing to study the frequency of mutations in advanced thyroid cancer in Japan. Patients (n = 96) with unresectable or metastatic thyroid carcinoma were included for retrospective chart review. Results of gene panel testing, which was performed between May 2020 and April 2023, were analyzed. The median age of the patients was 73.5 years (range, 17-88); 59 were women, and 39 were men. Overall, 17 patients had anaplastic thyroid carcinoma (ATC), 68 had papillary thyroid carcinoma (PTC), 7 had follicular thyroid carcinoma, and 6 had poorly differentiated thyroid carcinoma (PDTC). Of the 81 patients with differentiated thyroid carcinoma (DTC) and PDTC, 88.9% were radioactive iodine-refractory, and 32.7% of all cases had previously been treated with multiple kinase inhibitors. Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion. Of PTC cases, 83.1% had BRAF mutations, 9.2% had RET fusion, and 1.5% had NTRK fusion. One case each of ATC and PTC had a tumor mutation burden of ≥10. ATC cases had a significantly higher prevalence of TP53 alterations than the other cases (82.3% vs. 11.8%), whereas the frequencies of TERT promoter mutations were 88.2% in ATC cases and 64.7% in the other cases, albeit without a significant difference. In conclusion, 58.8% of ATC, 93.8% of PTC, and 42.9% of PDTC had genetic alterations linked to therapeutic agents. Active gene panel testing is required to increase treatment options.

Histological findings of thyroid cancer after lenvatinib therapy.

AIMS: Lenvatinib is a multikinase inhibitor used for treating unresectable or metastatic cancers, including thyroid cancer. As total thyroidectomy followed by radioactive iodine therapy is a commonly recommended initial treatment for thyroid cancer, histological findings of the thyroid after lenvatinib therapy remain unclear. Therefore, the aim of this study was to analyse in-vivo changes in patients who underwent thyroidectomy after lenvatinib therapy. METHODS AND RESULTS: We screened 167 patients with thyroid cancer [papillary thyroid cancer (PTC), n = 102; follicular thyroid cancer (FTC), n = 26; anaplastic thyroid cancer (ATC), n = 39] who underwent lenvatinib therapy. Among these patients, six underwent thyroidectomy (lenvatinib-treated group: PTC, n = 3; FTC, n = 1; ATC, n = 2), and the specimens were examined. Five patients with PTC who did not receive lenvatinib therapy were included for comparison (untreated group). Microvessel density (MVD) was evaluated in both groups. The PTC and FTC specimens showed relatively more ischaemic changes than ATC specimens. Coagulative necrosis and ischaemic changes in cancer cells were frequently observed. ATC specimens showed fibrosis and mild cell damage. As hypothyroidism is a common side effect of lenvatinib therapy, non-cancerous thyroid tissues were also examined. Histological findings included mild lymphocytic infiltration, lymphoid follicular formation, histiocytic reaction and follicular epithelial destruction. The MVD in lenvatinib-treated tissues was significantly lower than that in untreated tissues. CONCLUSIONS: Lenvatinib therapy probably induces relatively specific ischaemic changes in thyroid cancer cells. Moreover, inflammatory cell infiltration and decreased MVD occur to varying degrees in non-cancerous thyroid tissue and may be related to hypothyroidism, a side effect of lenvatinib.

Lenvatinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: Treatment Optimization for Maximum Clinical Benefit.

BACKGROUND: Lenvatinib is a multitargeted tyrosine kinase inhibitor approved for treating patients with locally recurrent or metastatic progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC). In this review, we discuss recent developments in the optimization of RR-DTC treatment with lenvatinib. SUMMARY: Initiation of lenvatinib treatment before a worsening of Eastern Cooperative Oncology Group performance status and elevated neutrophil-to-lymphocyte ratio could benefit patients with progressive RR-DTC. The median duration of response with lenvatinib was inversely correlated with a smaller tumor burden, and prognosis was significantly worse in patients with a high tumor burden. An 18 mg/day starting dose of lenvatinib was not noninferior to 24 mg/day and had a comparable safety profile. Timely management of adverse events is crucial, as patients with shorter dose interruptions benefitted more from lenvatinib treatment. Caution should be exercised when initiating lenvatinib in patients who have tumor infiltration into the trachea or other organs, or certain histological subtypes of DTC, as these are risk factors for fistula formation or organ perforation. The Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) eligibility criteria should be considered prior to initiating lenvatinib treatment. CONCLUSIONS: Current evidence indicates that patients benefit most from lenvatinib treatment that is initiated earlier in advanced disease when the disease burden is low. A starting dose of lenvatinib 24 mg/day, with dose modifications as required, yields better outcomes as compared to 18 mg/day. Appropriate supportive care, including timely identification of adverse events, is essential to manage toxicities associated with lenvatinib, avoid longer dose interruptions, and maximize efficacy.

A New Electric Field Mill Network to Estimate Temporal Variation of Simplified Charge Model in an Isolated Thundercloud.

The gross charge distribution in an electrified cloud has already been estimated by polarity distribution of the electrostatic field on the ground surface. While either a dipole or a tripole charge structure is commonly accepted, the increase-decrease and motion of each point charge in those models are both still unclear. This paper presents a new network of electric field mills for multipoint electrostatic measurement to evaluate the temporal variations of a simple cloud charge model with second-scale resolution. Details of our newly developed equipment are described, with an emphasis on its advantages. This network was deployed in the north Kanto area of Japan and operated during the summer season in 2020. In order to simplify the relationship between cloud charge positions and the horizontal distribution of the measured electrostatic field, an isolated thundercloud is focused on. As an initial analysis, a negative point charge model is applied to an isolated cloud observed on 27 August 2020. The quantity and height of the point charge were estimated as being approximately -20 C and 7 km, respectively. The calculated charge location is generally coincident with the C-band radar echo regions. Significant correspondence is demonstrated between the intensity distribution of the electrostatic fields measured at seven sites and that calculated with estimated point charge. This result indicates the possibility to determine the amounts and positions of cloud charges inside the dipole charge structure based on multipoint measurement of the electrostatic field.

Membrane type 1 matrix metalloproteinase regulates anaplastic thyroid carcinoma cell growth and invasion into the collagen matrix.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancer types; however, the molecular mechanism contributing to the aggressive characteristics remain unclear. Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an important role in cancer invasion and has been associated with a poor prognosis in various malignant neoplasms. In this study, we investigated the relationship between MT1-MMP expression and the proliferation and invasion of ATC cells, along with the association with clinicopathologic factors in patients with ATC. Suppression of MT1-MMP reduced the proliferation and invasion of ATC cells, and suppressed ERK activity, indicating a role in cancer cell proliferation in collagen matrix culture conditions. The expression of MT1-MMP was detected in 29 of 34 (85.3%) surgical specimens from ATC patients. In addition, the expression of MT1-MMP in the tumor lesion was higher than that of normal and stromal tissues. Collectively, these results suggest that elevated MT1-MMP expression plays a role in the pathogenesis of ATC, which may promote its aggressive characteristics such as proliferation and invasion, highlighting a potential new therapeutic target.

Expression of fibroblast growth factor receptor 4 and clinical response to lenvatinib in patients with anaplastic thyroid carcinoma: a pilot study.

PURPOSE: Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC). METHODS: We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated. RESULTS: The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1-not estimable [NE]), and 4.6 (95% CI 1.1-NE) months, respectively (p = 0.003). CONCLUSIONS: Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated.

[Efficacy and Safety of Lenvatinib for Unresectable Anaplastic Thyroid Cancer].

The 208 trial showed that lenvatinib has a significant antitumor effect on unresectable anaplastic thyroid cancer(ATC). Herein, we present a retrospective review of data from 7 patients with unresectable ATC who received lenvatinib in our hospital between May 2015 and October 2016. Two patients were men and 5 were women. The median age was 78(range, 72-85)years, and 1 patient had Stage IV A disease, 1 had Stage IV B, and 5 had Stage IV C at diagnosis, respectively. Three patients experienced a partial response and 1 patient experienced stable disease. The response rate was 43%, and the disease control rate was 57%. The median progression-free survival(PFS)was 4.1(range, 1.1-12.2)months. Grade 3 and Grade 4 gastrointestinal hemorrhage were observed in 2patients and Grade 3 anorexia was observed in 1 patient. Further clinical research seems to be needed to establish a treatment strategy involving lenvatinib for ATC.

Absorption Kinetics of Subcutaneously Administered Ceftazidime in Hypoperfused Guinea Pigs.

BACKGROUND: Pneumonia is the most common cause of death in patients with severe motor and intellectual disabilities (SMID), and intravenous ceftazidime (CAZ) is a widely used treatment for such infections. However, intravenous administration in patients with SMID may be difficult because of insufficient vascular development. OBJECTIVES: The aim of our study was to determine the feasibility of subcutaneous drug administration by mentholated warm compresses (WMCs) as an alternative delivery method for ceftazidime in patients with SMID. METHODS: CAZ was subcutaneously administered to the abdominal region of naphazoline-treated hypoperfused guinea pigs, which were used as a hemodynamic model of patients with SMID. MWCs or warm compresses (WCs) were applied to the injection site to increase blood flow. We calculated the cumulative CAZ absorption over time by using the deconvolution method. RESULTS: Application of MWCs or WCs increased blood flow at the administration site and increased CAZ plasma levels. Application of MWCs or WCs after subcutaneous CAZ injection led to higher CAZ plasma levels than the mutant prevention concentration for a longer period than was observed for CAZ administration without the application of MWCs or WCs. CONCLUSIONS: The application of MWCs or WCs enhanced subcutaneous CAZ absorption by increasing blood flow. MWCs and WCs are considered to be safe and routine methods to induce defecation after surgery on the digestive system; thus, the combination of these methods and subcutaneous CAZ administration is a potential method for treating pneumonia in patients with SMID.

Initial clinical trial of a novel hemostat, TDM-621, in the endoscopic treatments of the gastric tumors.

BACKGROUND AND AIM: The feasibility of TDM-621, the synthetic infectious agent-free peptides, was tested in hemostasis of the bleeding after endoscopic treatments of the gastric tumors. METHODS: The patients who underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) were enrolled in the present study. The subject of hemostasis was the oozing after the EMR or ESD. The hemostatic effect, the secondary hemorrhage from one postoperative day to the day before discharge and operability were studied. RESULTS: The hemostatic effects were assessed in 12 patients. It was "remarkably effective" in 11 patients and "effective" in 1 patient. The operability was "very easy" in two patients, "easy" in eight patients and "acceptable" in two patients. No secondary hemorrhage was observed in all of 12 patients. No adverse effect considered to be related to TDM-621 was observed. CONCLUSION: It was shown that hemostasis using TDM-621 was feasible after endoscopic treatments of the gastric tumors without any technical trouble or adverse event.

Genomic landscape and clinical features of advanced thyroid carcinoma: a national database study in Japan.

CONTEXT: The relationship between genomic profile and prognosis of advanced thyroid carcinoma requiring drug therapy has not been reported. OBJECTIVE: To evaluate the treatment period and overall survival time for each genetic alteration in advanced thyroid carcinoma that requires drug therapy. METHODS: We conducted a retrospective observational study using a national database in Japan, which included 552 cases of thyroid carcinoma out of 53,543 patients in the database. RESULTS: The database included anaplastic thyroid carcinoma (23.6%), poorly differentiated thyroid carcinoma (10.0%), and differentiated thyroid carcinoma (66.4%). The most common genetic abnormalities were TERT promoter (66.3%), BRAF (56.7%), and TP53 (32.2%). The typical driver genes were BRAF V600E (55.0%), RAS (18.5%), RET fusion (4.7%), NTRK fusion (1.6%), and ALK fusion (0.4%). The most common regimen was lenvatinib, and the time to treatment failure was not different despite the presence of BRAF or RAS mutations. In differentiated thyroid carcinoma and poorly differentiated thyroid carcinoma, TP53 alterations independently predicted worse overall survival (hazard ratio = 2.205, 95% confidence interval: 1.135-4.283). In anaplastic thyroid carcinoma, no genetic alterations were associated with overall survival. CONCLUSION: Genetic abnormalities with treatment options were found in 62.7% of advanced thyroid carcinomas. TP53 abnormality was an independent poor prognostic factor for overall survival in differentiated thyroid carcinoma. The time to treatment failure for lenvatinib was not different based on genetic profile.

Case Report: Tuberous sclerosis complex-associated hemihypertrophy successfully treated with mTOR inhibitor sirolimus.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a mutation in either of the two tumor suppressor genes, TSC1 and TSC2. Due to dysregulated activity of the mammalian target of rapamycin (mTOR) pathway, hamartomas or benign tumors frequently occur in many organs and are often treated with mTOR inhibitors. Hemihypertrophy is a rare complication of TSC. Although not being a tumor, progressive overgrowth of the affected limb may cause cosmetic and functional problems, for which the efficacy of mTOR inhibitors has not been reported previously. We herein report a case of TSC-associated hemihypertrophy. In this case, genetic studies revealed TSC1 loss of heterozygosity as the cause of hemihypertrophy. Clinically, pharmacological treatment with an mTOR inhibitor sirolimus successfully ameliorated cosmetic and functional problems with no intolerable adverse effects.

Association of BRAF or TERT Promoter Mutations and Advanced Papillary Thyroid Carcinoma.

BACKGROUND/AIM: BRAF and TERT promoter mutations are associated with the poor prognosis of papillary thyroid carcinoma. This single-center retrospective study investigated the influence of these genes on advanced cases. PATIENTS AND METHODS: Advanced cases who underwent gene panel testing and cases who underwent complete resection were classified as groups A and C, respectively. The gene mutations were determined using gene panel testing or Sanger sequencing using tumor DNA. RESULTS: The study included 51 cases in group A and 44 cases in group C. In group A, all cases had unresectable lesions or distant metastasis; 82.4% of cases showed no accumulation of radioactive iodine in metastasis and 47.1% of cases were administered drug therapy. Meanwhile, all cases of group C did not have distant metastasis. The prevalence of TERT promoter mutations was significantly higher in group A compared to group C (70.6% vs. 18.2%, p<0.001). However, there was no significant difference in the prevalence of BRAF mutations between the two groups (86.3% vs. 90.9%). In Group C, disease-free survival was significantly shorter in patients harboring the TERT promoter mutations (p<0.001), despite no significant difference in that according to the BRAF mutation status. In addition, there was no significant difference in overall survival in group A according to the TERT promoter mutation status. CONCLUSION: Advanced papillary thyroid carcinoma was associated with the TERT promoter mutations, but not with BRAF mutation. Meanwhile, TERT promoter mutations did not affect overall survival among the advanced cases.

Clinicopathological analysis of thyroid carcinomas with the RET and NTRK fusion genes: characterization for genetic analysis.

Thyroid carcinomas exhibit various genetic alterations, including the RET and NTRK fusion genes that are targets for molecular therapies. Thus, detecting fusion genes is crucial for devising effective treatment plans. This study characterized the pathological findings associated with these genes to identify the specimens suitable for genetic analysis. Thyroid carcinoma cases positive for the fusion genes were analyzed using the Oncomine Dx Target Test. Clinicopathological data were collected and assessed. Among the 74 patients tested, 8 had RET and 1 had NTRK3 fusion gene. Specifically, of the RET fusion gene cases, 6 exhibited "BRAF-like" atypia and 2 showed "RAS-like" atypia, while the single case with an NTRK3 fusion gene presented "RAS-like" atypia. Apart from one poorly differentiated thyroid carcinoma, most cases involved papillary thyroid carcinomas (PTCs). Primary tumors showed varied structural patterns and exhibited a high proportion of non-papillary structures. Dysmorphic clear cells were frequently observed. BRAF V600E immunoreactivity was negative in all cases. Interestingly, some cases exhibited similarities to diffuse sclerosing variant of PTC characteristics. While calcification in lymph node metastases was mild, primary tumors typically required hydrochloric acid-based decalcification for tissue preparation. This study highlights the benefits of combining morphological and immunohistochemical analyses for gene detection and posits that lymph node metastases are more suitable for genetic analysis owing to their mild calcification. Our results emphasize the importance of accurate sample processing in diagnosing and treating thyroid carcinomas.

[Three patients with local recurrence of ER-positive breast cancer for whom anastrozole was clinically effective].

We treated three postmenopausal female patients with unresectable local recurrence from breast cancer. All pathological diagnoses of the local recurrence lesions were ER-positive breast cancer. For treatment, we administered anastrozole to these three patients. One has been stable disease for 25 months after taking anastrozole. Another has also showed stable disease for 18 months, and the last patient has been a partial response. We performed a biopsy from a recurring lesion on these three patients, and made a diagnosis of ER-positive breast cancer. This strategy of unresectable local recurrence revealed that these three patients could have had a stable condition for a long duration by taking anastrozole.

Outcome of initial lenvatinib treatment in patients with unresectable anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is a very rare disease with a poor prognosis and with no established effective drug therapy. The present study aimed to report the outcomes of lenvatinib single-agent therapy as an initial drug treatment in ATC, and to investigate its safety and efficacy. This retrospective cohort study included 56 patients with unresectable primary ATC, of whom 36 were treated with lenvatinib and 12 with weekly paclitaxel, and 8 patients who refused any drug treatment who received palliative care. The average survival in the lenvatinib group was 5.8 months, which was significantly longer than 2.0 months in the paclitaxel group (P=0.005). The efficacy of lenvatinib in the 36 patients with ATC, whose primary tumors were unresectable, was evaluated. The response rate was 33% and the median overall survival time was 5.0 months. A safety review indicated that lenvatinib should be used under the careful observation of local findings. Two patients, who showed a reduction with lenvatinib, underwent conversion surgery, which prolonged the prognosis in terms of avoiding events, such as asphyxia, fistula and hemorrhage due to tumor growth; however, the surgical margins were positive, indicating that complete remission was impossible even if surgical resection was performed. Therefore, starting with lenvatinib treatment and identifying a therapeutic drug based on genomic analysis is an acceptable treatment strategy for ATC while halting the disease progression.

Ovarian goiter detected during post-operative follow-up of papillary thyroid cancer: a case report.

A 70-year-old female without any past medical history underwent total thyroidectomy and central neck dissection for papillary thyroid cancer (PTC) (pT3bN1aM0 pStage II). Her post-operative thyroglobulin (Tg) level remained high (around 100 ng/mL), which increased to 366 ng/mL 5 years after surgery. Computed tomography revealed metastasis to the left III and right Vb and VI lymph nodes and an incidental ovarian tumor. Transvaginal ultrasonography and magnetic resonance imaging suspected malignancy, resulting in total hysterectomy and bilateral adnexal resection. A pathological diagnosis of ovarian goiter with no malignancy was then established. For lymph node metastasis of PTC, right neck dissection and left III lymph node resection were performed. Post-operative blood examination showed a significant decrease in the Tg level (5.9 ng/mL). In conclusion, systemic imaging or I-131 remnant ablation should be performed after total thyroidectomy, as evident in the present case in which Tg levels did not decrease after total thyroidectomy.

Lenvatinib and selpercatinib successfully treated RET fusion gene-positive papillary thyroid carcinoma cardiac metastases: a case report.

Background: Cardiac metastasis from thyroid cancer is rare and has an extremely poor prognosis. Although some patients who undergo heart surgery survive, the therapeutic effectiveness of systemic therapy is limited. Case Description: A 53-year-old woman with a history of papillary thyroid carcinoma (PTC) presented with cough and right chest discomfort. She underwent total thyroidectomy, followed by three rounds of radioactive iodine therapy, to treat pulmonary metastasis. Metastases to the lung, chest wall, liver, heart, and lymph nodes were observed on computed tomography. Core needle biopsy of the tumor in the right chest wall revealed the recurrence of PTC. Cardiac metastasis was discovered by echocardiography and cardiac magnetic resonance imaging, and blood test indicated a thyroglobulin level of 851 ng/mL. Based on the presence of cardiac metastasis and strong clinical symptoms, the condition was assumed to be fatal, and lenvatinib was started right away. Three weeks after starting lenvatinib, every metastatic lesion shrank. Once the ERC1-RET fusion gene was identified, we switched to selpercatinib therapy. Ten weeks after starting selpercatinib, every tumor shrank and blood thyroglobulin dropped to 68.1 ng/mL. Initial symptoms such as cough and right chest pain improved. Lenvatinib- and selpercatinib-related adverse effects can be managed with supportive care. Conclusions: To the best of our knowledge, this is the first case of successful systemic therapy for cardiac metastasis from PTC. Conventionally, cardiac surgery is the main treatment for cardiac metastasis, but now systemic therapy is also an important alternative.

Validation of EZH2 Inhibitor Efficiency in Anaplastic Thyroid Carcinoma Cell Lines.

BACKGROUND/AIM: The prognosis of anaplastic thyroid carcinoma (ATC) is poor, and there is currently no established treatment to improve its outcome. We previously reported that enhancer of zeste homolog 2 (EZH2) was highly expressed in ATC, and may be a therapeutic target; however, the effects of EZH2 on ATC growth currently remain unknown. MATERIALS AND METHODS: We investigated the effects of an EZH2 inhibitor (DZNep) on four ATC cell lines (8305C, KTA1, TTA1 and TTA2). We performed a gene panel analysis of all ATC cell lines to identify differences in DZNep sensitivity between the cell lines. To investigate the effects of DZNep on the recovery of differentiation, we assessed changes in thyroid differentiation markers (TDMs) before and after the DZNep treatment using PCR. RESULTS: EZH2 was expressed in all ATC cell lines. The cell-reducing effects of DZNep were detected in all ATC cell lines, and were the strongest in KTA1 cells followed by TTA2 cells. The TTA1 and 8305C cell lines, which showed weak cell-reducing effects, had TP53 mutations. No changes in TDMs were observed in any ATC cell line. CONCLUSION: DZNep, an EZH2 inhibitor, exerted suppressive effects on the growth of ATC cell lines and has potential as a therapeutic strategy; however, its effects may be attenuated in ATC with TP53 mutations.

Estimability study on the age of toddlers' gait development based on gait parameters.

In the first few years of toddlers' locomotion, various gait parameters improve gradually and dynamically with gait development. Therefore, in this study, we hypothesized that the age of gait development, or the level of gait development with age as its indicator, can be estimated from several gait parameters related to gait development, and investigated its estimability. In total, 97 healthy toddlers aged about 1-3 years participated in the study. All five selected gait parameters showed a moderate or higher correlation with age, but the duration with a large change and the strength of the association with gait development varied for each gait parameter. Multiple regression analysis was performed using age as the objective variable and five selected gait parameters as explanatory variables, and an estimation model (R2 = 0.683, adjusted R2 = 0.665) was created. The estimation model was verified using a test dataset separate from the training dataset (R2 = 0.82, p < 0.001). It was suggested that the age of gait development could be estimated from gait alone. Gait analysis based on empirical observations may reduce the need for skilled observers and their potential variability.

Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including ßII-spectrin. Most patients with IgAN also have serum anti-ßII-spectrin IgA. As in patients with IgAN, IgA+ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to ßII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous ßII-spectrin exposed on the surface of embryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.