Long-term outcomes of neuroendoscopic cyst partial resection combined with stereotactic radiotherapy for craniopharyngioma.

PURPOSE: The aim of this study was to evaluate the treatment outcomes of neuroendoscopic cyst partial resection (ECPR) combined with stereotactic radiotherapy (SRT) for cystic craniopharyngiomas. METHODS: In this retrospective study, 22 craniopharyngioma patients undergoing ECPR combined with SRT were included. This combination therapy was indicated for suprasellar cystic craniopharyngiomas in patients whose pituitary function was preserved but would be difficult to preserve in direct surgery. The outcomes of combination therapy, including tumor control and postoperative visual and pituitary functions, were investigated. RESULTS: ECPR was safely performed, and cyst shrinkage was accomplished in all cases. After ECPR, visual function improved in 12 of 13 patients (92%) with visual field disturbance and did not deteriorate in any patients. Pituitary function was preserved in 14 patients (64%) and deteriorated in eight patients (36%) after ECPR. As a complication of ECPR, meningitis occurred because of a wound infection in one patient. In 18 of 22 patients (82%), the tumor was controlled without further treatment 19 - 87 months (median, 33 months) after SRT. Hypopituitarism was an adverse event after SRT in two of the 18 patients who achieved tumor control. Four patients (18%) had enlarged cysts after SRT. Postoperative pituitary function was significantly more likely to deteriorate in cases of extensive detachment from the ventricular wall, and retreatment was significantly more common in cases with hypothalamic extension. CONCLUSION: Although limited to some cases, ECPR combined with SRT is a less invasive and useful therapeutic option for suprasellar cystic craniopharyngiomas. However, its long-term prognosis requires further evaluation.

Effects of the Cortisol Milieu on Tumor-Infiltrating Immune Cells in Corticotroph Tumors.

CONTEXT: Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors. OBJECTIVE: We aimed to clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy. METHODS: Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas were compared with other pituitary tumors, and further divided into 3 different cortisol-exposed milieus: Naïve (ACTHomas without preoperative treatment), Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A 3-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors. RESULTS: The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph and gonadotroph tumors (both P < .01). Then we compared the differences in TILs among Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163+ and CD204+ cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204+ cells. CONCLUSION: We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4+ cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu.

FSH-producing pituitary neuroendocrine tumor as a cause of ovarian hyperstimulation syndrome.

Summary: Functioning gonadotroph tumors are rare neoplasms that can cause ovarian hyperstimulation syndrome (OHSS) in women of reproductive age. Here, we present a case of a follicle-stimulating hormone (FSH)-producing pituitary neuroendocrine tumor (PitNET) with irregular menstrual cycles and OHSS in a Japanese woman. A 34-year-old woman with bilateral multi-cystic ovarian mass was referred to our hospital for ovarian surgery. The imaging feature of magnetic resonance imaging (MRI) of the ovary and elevated estradiol levels with normal FSH and low luteinizing hormone (LH) levels led us to suspect the presence of a functioning gonadotroph PitNET. MRI revealed a 19-mm pituitary tumor, and increased tracer uptake was observed in the pituitary lesion on 111In-pentetreotide scintigraphy. Transsphenoidal tumor resection resulted in the resolution of the ovarian enlargement, normalization of her menstrual cycles, and spontaneous pregnancy. Immunohistochemistry (IHC) of the resected tumor for pituitary transcription factors, including steroidogenesis factor 1 (SF1) and estrogen receptor alpha, demonstrated positive immunoreactivity, whereas IHC for pituitary-specific positive transcription factor 1 was negative, suggesting that the tumor belonged to the SF1 lineage of PitNETs (gonadotroph tumor). The tumor cells showed positive expression of FSHß, while LHß was mostly negative. Consistent with the high pituitary tumor uptake observed on 111In-pentetreotide scintigraphy, the pituitary tumor showed positive expression of somatostatin receptor 2A. Detailed clinical and histological evaluations will provide useful information to understand these rare functioning gonadotroph tumors better. Learning points: Functioning gonadotroph tumors are very rare neuroendocrine tumors of pituitary origin. Women of reproductive age presenting with bilateral multi-cystic ovarian enlargement, irregular menstrual cycles, and hyperestrogenemia under unsuppressed follicle-stimulating hormone (FSH) levels should be evaluated for FSH-producing tumor. Raising awareness of OHSS due to functioning gonadotroph tumors is crucial to prevent unnecessary ovarian surgery. Comprehensive histological analysis may provide useful information to better understand the characteristics of functioning gonadotroph tumors.

Gilteritinib Monotherapy as a Transplant Bridging Option for a Patient with FLT3-Mutated Acute Promyelocytic Leukemia Who Developed a Second Relapse after All-Trans Retinoic Acid + Chemotherapy, Arsenic Trioxide, and High-Dose Cytarabine Therapy.

We report a case of FLT3-mutated APL who developed disease relapse despite all-trans retinoic acid (ATRA) + chemotherapy, and re-induction chemotherapy with arsenic trioxide (ATO) and high-dose (HD) cytarabine (Ara-C) therapy failed to yield complete remission. Because the leukemic cells were resistant to all the aforementioned therapies, we started the patient on monotherapy with gilteritinib, a selective FLT3-inhibitor, as an alternative re-induction treatment option rather than further intensive chemotherapy. The patient showed complete hematologic remission in response to this therapy. This case serves as supporting evidence for the use of single-agent therapy with gilteritinib as a bridge to transplantation in patients with refractory FLT3-mutated APL.

The prevalence of lynch syndrome (DNA mismatch repair protein deficiency) in patients with primary localized prostate cancer using immunohistochemistry screening.

BACKGROUND: Prostate cancer is one of the most heritable human cancers. Lynch syndrome is an autosomal dominant inheritance caused by germline mutations in DNA mismatch repair (MMR) genes, which are also associated with an increased incidence of prostate cancer. However, prostate cancer has not been defined as a Lynch syndrome-associated cancer. The proportion of Lynch syndrome patients in primary prostate cancers is unclear. In this study, we investigated MMR protein loss using universal immunohistochemical screening to determine the prevalence of Lynch syndrome in patients with localized prostate cancer who underwent radical prostatectomy. METHODS: One hundred twenty-nine surgical specimens from radical prostatectomy performed at Toranomon Hospital between 2012 and 2015 were retrospectively tested using universal screening with immunohistochemistry staining for expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6. For all suspected MMR-deficient patients, germline genetic tests focusing on MMR genes were performed. RESULTS: MMR protein loss was found in only one patient (0.8%) who showed dual MSH2/MSH6 loss. This patient showed a single nucleotide pathogenic germline mutation from c.1129 C to T (p.Gln377*) at exon 7 in the MSH2 gene. He was diagnosed with a primary prostate cancer at 66 years of age. He had a documented history of Lynch syndrome (Muir-Torre syndrome) with previous colon cancer, sebaceous tumor, and keratoacanthoma as well as subsequent bladder cancer, all of which also showed dual MSH2/MSH6 loss. He also had a strong family history of colorectal and other Lynch syndrome-associated cancers. The pathological stage was pT3aN0M0, and the pathological grade was Gleason 7(4 + 3) with tertiary pattern 5. CONCLUSIONS: In this study, immunohistochemical screening of MMR proteins for Lynch syndrome was performed in a series of prostate cancer cases. The prevalence of Lynch syndrome in localized prostate cancer was 0.8%, which is low compared with other Lynch syndrome-associated cancers.

Touch imprint cytology is useful for the intraoperative pathological diagnosis of PitNETs' surgical margins.

Touch imprint cytology (TIC) and frozen section (FS) procedures are essential for intraoperative pathological diagnosis (IPD). They are invaluable tools for therapeutic decision-making, helping surgeons avoid under or overtreatment of patients. Pituitary neuroendocrine tumors (PitNETs) are generally small, slow-growing tumors with low-grade malignancy located at the base of the skull where it is impossible to maintain a wide tumor margin. Therefore, transsphenoidal surgery (TSS) should be performed with necessary caution, and with sufficient and minimal resection. Thus, this study aimed to evaluate the diagnostic accuracy of TIC for the diagnosis of PitNET and determine its ability to accurately evaluate the surgical margin compared to the FS procedure. A total of 104 fresh specimens from 28 patients who underwent TSS for PitNETs were examined using TIC and FS. TIC specimens were categorized according to the cell imprinting pattern. All specimens with a large number of neuroendocrine cells diffusely attached to the glass surfaces had PitNET components. Contrarily, no rich or diffuse cell attachments were observed in any non-tumoral endocrine cells. In conclusion, recognizing a pattern of endocrine cell adherence to glass is highly effective in IPD to certify the existence of a PitNET component.

Preoperative detection of functional somatostatin receptors in a patient with an insulinoma.

Octreotide is used in patients with insulinomas to treat hypoglycemia, and somatostatin receptor (SSTR) 2 expression is important for its efficacy. We report a case of insulinoma in a 50-year-old woman that responded to an octreotide test, showed accumulation in somatostatin scintigraphy, and was positive for SSTR2A on immunostaining.

Clinical decision-making based on 11C-methionine PET in recurrent Cushing's disease with equivocal MRI findings.

OBJECTIVE: Diagnosis and accurate localization of recurrent tumors in Cushing's disease (CD) are challenging, especially after multiple transsphenoidal surgeries (TSSs) or radiosurgery. Even experts face difficulties in detecting these recurrent tumors, and a favorable surgical outcome is not guaranteed. In this report, the authors aimed to determine the usefulness of 11C-methionine positron emission tomography (MET-PET) for evaluating patients with recurrent CD with inconclusive magnetic resonance imaging (MRI) lesions and to develop a treatment protocol for these cases. METHODS: In this retrospective study of patients with recurrent CD in the period between April 2018 and December 2022, the authors assessed the usefulness of MET-PET in determining whether equivocal MRI findings were recurrent tumors or postsurgical cavities and deciding further treatment options. All patients had undergone at least one TSS, and most had undergone multiple TSSs and had pathologically confirmed corticotroph tumors with hypercortisolemia. RESULTS: Overall, 15 patients with recurrent CD (10 females and 5 males) were included, all of whom had undergone MET-PET. All patients had been subjected to multiple treatments, including TSSs or radiosurgeries. Their MRI scans demonstrated less-enhanced lesions that were not confirmed as recurrences even with cutting-edge MRI because they could not be distinguished from postsurgical changes with confidence. MET uptake was positive in 8 patients (9 examinations) and negative in 7. Following MET-PET, repeat TSS was performed in 5 patients. Corticotroph tumors were identified in all 5 patients, even though one of them had negative MET uptake. The MET uptake precisely identified a tumor location on the opposite side of the MRI-suspected lesion in 2 patients. Meanwhile, patients with negative uptake and mild hypercortisolism were only observed. Nonsurgical options were also used in other patients: temozolomide (TMZ) was administered in 2 patients owing to a prior history of multiple TSSs and radiosurgery and the drug-resistant nature of the disease. TMZ was highly effective in these patients; their Cushing's symptoms ameliorated, and their adrenocorticotropic hormone and cortisol levels continued to decline. Interestingly, MET uptake disappeared following TMZ treatment. CONCLUSIONS: MET-PET is extremely useful for confirming equivocal lesions on MRI in patients with recurrent CD and for deciding further treatment options. The authors propose a novel protocol based on MET-PET results for treating patients with relapsing CD in whom the recurrent tumors cannot be confirmed with MRI.

Generation and purification of ACTH-secreting hPSC-derived pituitary cells for effective transplantation.

Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-ß signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.

Functional calcium-responsive parathyroid glands generated using single-step blastocyst complementation.

Patients with permanent hypoparathyroidism require lifelong replacement therapy to avoid life-threatening complications, The benefits of conventional treatment are limited, however. Transplanting a functional parathyroid gland (PTG) would yield better results. Parathyroid gland cells generated from pluripotent stem cells in vitro to date cannot mimic the physiological responses to extracellular calcium that are essential for calcium homeostasis. We thus hypothesized that blastocyst complementation (BC) could be a better strategy for generating functional PTG cells and compensating loss of parathyroid function. We here describe generation of fully functional PTGs from mouse embryonic stem cells (mESCs) with single-step BC. Using CRISPR-Cas9 knockout of Glial cells missing2 (Gcm2), we efficiently produced aparathyroid embryos for BC. In these embryos, mESCs differentiated into endocrinologically mature PTGs that rescued Gcm2-/- mice from neonatal death. The mESC-derived PTGs responded to extracellular calcium, restoring calcium homeostasis on transplantation into mice surgically rendered hypoparathyroid. We also successfully generated functional interspecies PTGs in Gcm2-/- rat neonates, an accomplishment with potential for future human PTG therapy using xenogeneic animal BC. Our results demonstrate that BC can produce functional endocrine organs and constitute a concept in treatment of hypoparathyroidism.

Combined tubular adenocarcinoma, neuroendocrine carcinoma and adenocarcinoma with enteroblastic differentiation arising in Barrett esophagus.

Adenocarcinoma (AC) with neuroendocrine carcinoma (NEC) or enteroblastic (ENT) differentiation rarely develops in Barrett's esophagus (BE). A 76-year-old man was diagnosed with Barrett's AC (cT1bN0M0) and underwent thoracoscopic esophagectomy. A type 0-IIc + 0-Is lesion measuring 26 × 21 mm was macroscopically observed on a background of long segment BE (pT1bN0M0). The tumor comprised three different histological types of carcinoma (NEC, AC with ENT differentiation and moderately differentiated AC). NEC showed positivity for synaptophysin, chromogranin A and insulinoma-associated protein 1 with a Ki-67 index of 60.6%. ENT tumors were immunopositive for AFP and sal-like protein 4, and focally immunopositive for human chorionic gonadotrophin. The amounts of NEC, ENT and AC were 40%, 40% and 20%, respectively. p53 expression was positive throughout the tumor. Rb expression was negative at the NEC, but positive at the ENT and AC. CD4 and CD8 densities were lower in the NEC segment than in the AC and ENT segments, and PD-L1 expression was negative throughout the tumor. Early cancer arising in BE with a combination of tubular AC, ENT tumors and NEC is very rare. Our observations might contribute to understanding the carcinogenetic pathways and tumor microenvironment of NEC and ENT tumors.

Immunohistochemical and ultrastructural review of six cases previously diagnosed as null cell PitNETs.

Pituitary neuroendocrine tumors (PitNETs) lacking lineage affiliation are termed "null cell" PitNETs (NCTs). NCTs are characterized as being immunonegative for pituitary hormones as well as transcription factors. We analyzed the ultrastructure and immunohistochemistry of six hormone-negative and transcription factor (TPIT, PIT1, SF1)-negative PitNETs, with less than 1% immunoreactive cells. Histologically, three cases presented a perivascular pattern and pseudorosettes; the other three showed a solid pattern with oncocytic changes. Electron microscopic examination revealed poorly differentiated tumor cells with sparsely scattered secretory granules and intracellular organelles in all null cell tumors when compared with hormone-positive PitNETs. Two cases harbored a honeycomb Golgi (HG) structure, and three oncocytic tumors showed mitochondrial accumulation. The two HG cases were immunopositive for newly obtained TPIT (CL6251) and showed some adrenocorticotropic hormone-positive cells, while the remaining four were diffusely immunopositive for GATA3, with two SF1-positive cases identified in subsequent immunostaining. Thus, these six cases may be classified as two sparsely granulated corticotroph PitNETs, two gonadotroph PitNETs with SF1 re-staining, and two likely gonadotroph PitNETs with GATA3 immunostaining. No "true NCT" was detected among 1071 PitNETs, demonstrating the importance of precise diagnosis following the most recent criteria to improve therapeutic success.

Marked reduction of proteinuria after removal of a growth hormone-producing pituitary adenoma in a patient with focal segmental glomerulosclerosis: a case report and literature review.

Focal segmental glomerulosclerosis is a rare complication of acromegaly. A 74-year-old man was found to have acromegaly features such as enlargement of the forehead, nose, and hands. Laboratory tests showed a urine protein/creatinine ratio of 3.16 g/gCr and serum creatinine of 1.34 mg/dL. The levels of growth hormone and insulin-like growth factor I were markedly elevated, and the growth hormone level was not suppressed after 75 g oral glucose loading. Magnetic resonance imaging revealed a pituitary tumor with a diameter of 1.2 cm. Renal biopsy confirmed the diagnosis of focal segmental glomerulosclerosis. Transsphenoidal resection of the pituitary tumor led to remission of acromegaly and reduction in proteinuria highlighting the causal link between growth hormone overproduction and proteinuria. Treatment of acromegaly may be effective for acromegaly-associated focal segmental glomerulosclerosis.

Proteogenomic landscape and clinical characterization of GH-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors.

The clinical characteristics of growth hormone (GH)-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors (GHomas/somatotroph PitNETs) vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GHomas/somatotroph PitNETs to identify molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and nontargeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GHomas/somatotroph PitNETs. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by nontargeted proteomics and involved in G protein-coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing molecules associated with acromegaly that may affect medical treatment efficacy.

Resection of the Cavernous Sinus Medial Wall Improves Remission Rate in Functioning Pituitary Tumors: Retrospective Analysis of 248 Consecutive Cases.

BACKGROUND: The purpose of transsphenoidal surgery (TSS) for a functioning pituitary tumor (FPT) is to achieve endocrinological remission. The biggest challenge is aggressive tumor resection invading the cavernous sinus (CS). OBJECTIVE: To evaluate the effects of the medial wall of CS (MWCS) resection during FPT surgery. METHODS: Consecutive FPTs were reviewed for CS invasion (CSI) between April 2018 and December 2021. We operated on more than 250 FPTs, including 134 somatotroph tumors, 70 corticotroph tumors, 35 lactotroph tumors, and 9 thyrotroph tumors. RESULTS: The patients were classified into 3 groups based on the relationship between the tumor and the CS: group A (no clear wall invasion), in which MWCS was not removed because of no tumorous direct contact with MWCS (N = 92) and group B (possible wall invasion), where MWCS was removed because we were not confident of MWCS invasion (N = 102). Among these 102 patients, histological tumor invasion was confirmed in 45 of 79 patients (57%) for whom histology findings were available. Tumors invading the CS clearly during surgery were classified into the "clear CS invasion" (group C: N = 55) group. The overall complete remission rate in group B was 94%, which was as high as that in group A (87%). Moreover, we clarified that microscopic invasion of MWCS could not always be predicted from Knosp grading. CONCLUSION: MWCS invasion occurred in 57% of cases confirmed histologically where it was unclear during surgery, and its resection can improve the overall complete remission rate in FPT cases.

Apoplexy in sellar metastasis from papillary thyroid cancer: A case report and literature review.

Background: Pituitary metastasis from papillary thyroid cancer (PTC) is rare and only a few cases have been reported. Case Description: We report the case of a patient who presented with visual dysfunction and panhypopituitarism. Magnetic resonance imaging revealed a pituitary tumor and hydrocephalus. Transsphenoidal surgery had been indicated, but his surgery had been postponed due to COVID-19 pandemic. During that waiting period, he showed pituitary apoplexy with consciousness disturbance, resulting in acute adrenal insufficiency and diabetes insipidus. He was urgently hospitalized and underwent transsphenoidal surgery. Rapid and permanent pathological examinations have confirmed metastasis of PTC to the pituitary. The patient also underwent serial thyroidectomy. He was also suspected to have secondary hydrocephalus and underwent lumboperitoneal shunting after excluding cerebrospinal fluid metastasis. Thereafter, his cognitive dysfunction and performance status improved dramatically. Conclusion: To the best of our knowledge, this is the first patient with PTC who developed pituitary apoplexy secondary to metastasis.

Temozolomide and Capecitabine Treatment for an Aggressive Somatotroph Pituitary Tumor: A Case Report and Literature Review.

Aggressive somatotroph pituitary tumor that causes acromegaly is extremely rare and resists conventional treatments such as multiple surgeries, radiotherapies, and various types of somatostatin analogs. Here, we propose a novel treatment option for these rare cases by discussing our case and reviewing the literature. We experienced an aggressive somatotroph tumor in a 52-year-old woman with acromegaly. Not only could a complete remission of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) not be obtained, but the tumor continued to grow and eventually recurred around the brainstem despite multidisciplinary treatments. We employed immunohistochemistry and a three-dimensional (3D) spheroid ex vivo assay to determine the best treatment option for this case. Although histology showed strong O 6-methylguanine DNA methyltransferase expression and high Ki-67 labeling index (22%), temozolomide (TMZ) combined with capecitabine (CAPTEM) treatment was performed based on the results of the patient-derived 3D spheroid ex vivo assay, which predicted more effective treatment with CAPTEM than with TMZ alone. Consequently, GH and IGF-1 levels were restored to normal range with remarkable tumor shrinkage after CAPTEM treatment. To the best of our knowledge, there have been even very few reports describing successful treatment for such aggressive and refractory somatotroph tumors and this is the first report showing the effectiveness of CAPTEM on refractory somatotroph tumor both ex vivo and in vivo.

Responsiveness to DDAVP in Cushing's disease is associated with USP8 mutations through enhancing AVPR1B promoter activity.

PURPOSE: To clarify the characteristics of Cushing's disease (CD) patients who respond to the desmopressin (DDAVP) test and its underlying mechanisms. METHODS: Forty-seven patients with CD who underwent DDAVP testing were included. Patients were divided into two groups: DDAVP test (+) (adrenocorticotropic hormone [ACTH] levels increased by ≥ 1.5-fold during the DDAVP test) and DDAVP test (-) (ACTH levels increased by < 1.5-fold). AVP receptor expression levels in these tumors were quantified using quantitative RT-PCR and immunohistochemistry. AVP receptor promoter activity was analyzed using a dual-luciferase reporter assay system. RESULTS: Females (96.9%) and USP8 mutants (85.7%) were more prevalent in the DDAVP test (+) than in the DDAVP test (-). Indeed, the ACTH and cortisol responsiveness to DDAVP was greater in USP8 mutation positive tumors than that in USP8 wild type tumors (3.0-fold vs. 1.3-fold, 1.6-fold vs. 1.1-fold, respectively). Responsiveness to DDAVP was correlated with the expression levels of AVPR1B, but not with those of AVPR2. Comparably, Avpr1b promoter activity was enhanced by the overexpression of mutant USP8 compared to the wild type. CONCLUSIONS: We found that the responsiveness of ACTH to DDAVP in CD was greater in tumors with USP8 mutations. The present data suggest that USP8 mutations upregulate the AVPR1B promoter activity. Additionally, we showed that the DDAVP test can predict the presence of USP8 mutations.

Studies on anti-rabphilin-3A antibodies in 15 consecutive patients presenting with central diabetes insipidus at a single referral center.

Central diabetes insipidus (CDI) is a rare condition caused by various underlying diseases including inflammatory and autoimmune diseases, and neoplasms. Obtaining an accurate definitive diagnosis of the underlying cause of CDI is difficult. Recently, anti-rabphilin-3A antibodies were demonstrated to be a highly sensitive and specific marker of lymphocytic infundibuloneurohypophysitis (LINH). Here, we report a detailed case series, and evaluated the significance of anti-rabphilin-3A antibodies in differentiating the etiologies of CDI. A prospective analysis was conducted in 15 consecutive patients with CDI from 2013 to 2020 at a single referral center. Anti-rabphilin-3A antibodies were measured and the relationship between antibody positivity and the clinical/histopathological diagnoses was evaluated. Among 15 CDI patients, the positive anti-rabphilin-3A antibodies were found in 4 of 5 LINH cases, 3 of 4 lymphocytic panhypophysitis (LPH) cases, one of 2 sarcoidosis cases, and one intracranial germinoma case, respectively. Two Rathke cleft cyst cases and one craniopharyngioma case were negative. This is the first report of anti-rabphilin-3A antibodies positivity in CDI patients with biopsy-proven LPH. Measurement of anti-rabphilin-3A antibodies may be valuable for differentiating CDI etiologies.

Pepsinogen I- and H+/K+-ATPase-immunohistochemical Positivity in Endoscopically Resected Early Gastric Neoplasia.

Gastric adenocarcinoma of the fundic gland type (GAFG) has been recently classified by the World Health Organization (WHO), however, clinicopathologic features of pepsinogen I- or H+/K+-ATPase-positive gastric tumors remain unclear. Therefore, this study evaluates the frequency and clinicopathologic features of those tumors, using a tissue microarray block to identify pepsinogen I- or H+/K+-ATPase-positive tumors from 810 endoscopically resected, early gastric epithelial tumors. The frequency of pepsinogen I-positive lesions was 2.1%, and that of H+/K+-ATPase-positive lesions was 2.0%. Pepsinogen I- or H+/K+-ATPase positivity was not observed in undifferentiated-type tumors, while gastric tumors with morphologic similarity to fundic glands were positive for pepsinogen I- or H+/K+-ATPase. We divided pepsinogen I- or H+/K+-ATPase-positive gastric tumors into group A, with fundic gland-like structure, or group B, without fundic gland-like structure. The frequency of group A was 1.6%: 46.2% were positive only for pepsinogen I and 53.8% for H+/K+-ATPase and pepsinogen I. The frequency of group B was 1.5%: 25% were positive only for pepsinogen I, 8.3% for H+/K+-ATPase and pepsinogen I, and 66.7% only for H+/K+-ATPase. The 2 tumor groups differed in location and endoscopic features. Hematoxylin and eosin staining showed that group B had more exposed tumors to the surface, larger nuclei, and more background atrophy than group A. Immunostaining showed significantly higher positivity rates for MUC5AC, CD10, CDX2, and p53 expression, and a higher Ki-67 labeling score. Our results provide novel insights into the pathology of early gastric tumors with histologic or immunohistochemical evidence of fundic gland differentiation.