Sequential arrival and graded secretion of Sema3F by olfactory neuron axons specify map topography at the bulb.

In the mouse olfactory system, the anatomical locations of olfactory sensory neurons (OSNs) roughly correlate with their axonal projection sites along the dorsal-ventral (D-V) axis of the olfactory bulb (OB). Here we report that an axon guidance receptor, Neuropilin-2 (Nrp2), and its repulsive ligand, Semaphorin-3F (Sema3F), are expressed by OSNs in a complementary manner that is important for establishing olfactory map topography. Sema3F is secreted by early-arriving axons of OSNs and is deposited at the anterodorsal OB to repel Nrp2-positive axons that arrive later. Sequential arrival of OSN axons as well as the graded and complementary expression of Nrp2 and Sema3F by OSNs help to form the topographic order along the D-V axis.

A case of non-Hodgkin lymphoma of the upper gingiva with minimal residual disease detected in cryopreserved ovarian tissue: A case report.

Recently, more than 200 live births following ovarian tissue cryopreservation (OTC) and transplantation in cancer survivors have been reported worldwide. However, cancer survivors with minimal residual disease (MRD) in cryopreserved ovarian tissue are at the risk of relapse through the graft. Here, we report a rare case of a 19-year-old female patient with non-Hodgkin lymphoma who had MRD in the ovary harvested for OTC. The patient was diagnosed with aggressive B-cell lymphoma after gingival biopsy. The 18F-fluoro-2-deoxy-D-glucose positron emission tomography scan performed before OTC showed no viable lesions in either ovary. However, on histological evaluation, we detected infiltration of lymphoma cells in the ovary. Informed consent about MRD is required even if there is no evidence of MRD in the ovary before OTC. Patients whose cryopreserved ovaries have MRD may require the development of alternative assisted reproductive technologies such as in vitro growth or artificial ovary.

Adverse Oncologic Outcomes of Adenocarcinoma of the Anal Canal in Patients With Crohn's Disease.

BACKGROUND: Anal lesions in cases of Crohn's disease can give rise to adenocarcinoma of the anal canal; however, the oncologic outcomes in these patients have not yet been thoroughly investigated. OBJECTIVE: This study aimed to clarify the influence of Crohn's disease on the oncologic outcomes in patients with adenocarcinoma of the anal canal. DESIGN: This was a retrospective observational study from a prospectively collected database. SETTINGS: The study was conducted at a single institution. PATIENTS: This study included 102 patients with adenocarcinoma of the anal canal, including 34 (33.3%) with Crohn's disease-associated lesions and 68 (66.7%) with non-Crohn's disease-associated lesions. MAIN OUTCOME MEASURES: Prognostic factors were detected using a Cox regression analysis, and the oncologic outcomes were calculated using the Kaplan-Meier method. RESULTS: Crohn's disease-associated patients were significantly younger (45 vs 62 y; p < 0.001), had a high incidence of external/anal gland-type disease (61.8% vs 5.9%, p < 0.001) and had large tumors (7.1 ± 3.0 vs 4.7 ± 2.3 cm; p = 0.03) in comparison with non-Crohn's disease-associated patients. A Cox regression analysis showed that an advanced clinical T stage (T3 or T4; tumor size ≥5 cm) was an independent risk factor for 5-year local recurrence-free survival (HR = 3.49; p = 0.04), disease-free survival (HR = 2.82; p = 0.008), and overall survival (HR = 2.92; p = 0.006), and Crohn's disease association was an independent prognostic factor for local recurrence-free survival (HR = 2.29; p = 0.04) and overall survival (HR = 2.86; p = 0.04). The oncologic outcomes of patients who had the 2 abovementioned negative factors (cT3,4 Crohn's disease-associated patients) were significantly poorer than those of T3,4 non-Crohn's disease-associated patients (5-year local recurrence-free survival: 32.5% vs 70.4%, p = 0.001; disease-free survival: 15.9% vs 40.7%, p = 0.04; overall survival: 25.8% vs 71.0%, p = 0.007). LIMITATIONS: This was a single-arm, retrospective study. CONCLUSIONS: Significantly poorer oncologic outcomes were confirmed in Crohn's disease-associated patients with large tumors. Thus, it is important to perform careful surveillance of anal lesions in patients with Crohn's disease while taking these facts into consideration. See Video Abstract at http://links.lww.com/DCR/B449. RESULTADOS ONCOLGICOS ADVERSOS DEL ADENOCARCINOMA DEL CANAL ANAL EN PACIENTES CON ENFERMEDAD DE CROHN: ANTECEDENTES:Las lesiones anales en casos de enfermedad de Crohn pueden dar lugar a un adenocarcinoma del canal anal; sin embargo, los resultados oncológicos en estos pacientes aún no se han investigado a fondo.OBJETIVOS:Este estudio tuvo como objetivo aclarar la influencia de la enfermedad de Crohn en los resultados oncológicos en pacientes con adenocarcinoma del canal anal.DISEÑO:Estudio observacional retrospectivo de una base de datos recopilada prospectivamente.ENTORNO CLINICO:El estudio se realizó en una sola institución.PACIENTES:Este estudio incluyó 102 pacientes con adenocarcinoma del canal anal, incluidos 34 (33,3%) con lesiones asociadas a la enfermedad de Crohn y 68 (66,7%) con lesiones no asociadas a la enfermedad de Crohn.PRINCIPALES MEDIDAS DE VOLARACION:Los factores pronósticos se detectaron mediante un análisis de regresión de Cox y los resultados oncológicos se calcularon utilizando el método de Kaplan-Meier.RESULTADOS:Los pacientes asociados a la enfermedad de Crohn eran significativamente más jóvenes (45 versus a 62 años, p <0,001), tenían una alta incidencia de enfermedad de tipo glandular externo/ anal (61,8% versus a 5,9%, p <0,001) y tumores grandes (7,1 ± 3,0 cm versus a 4,7 ± 2,3 cm, p = 0,03) en comparación con los pacientes no asociados a la enfermedad de Crohn. Un análisis de regresión de Cox mostró que un estadío clínico T avanzado (T3,4; tamaño del tumor ≥5 cm) era un factor de riesgo independiente para la supervivencia sin recidiva local (SLF) a 5 años (índice de riesgo [HR]: 3,49, p = 0,04), supervivencia libre de enfermedad (SSE) (HR: 2,82, p = 0,008) y supervivencia general (SG) (HR: 2,92, p = 0,006), y la enfermedad de Crohn asociada fue un factor pronóstico independiente para la SLF (HR: 2,29, p = 0,04) y SG (HR: 2,86, p = 0,04). Los resultados oncológicos de los pacientes que tenían los dos factores negativos mencionados anteriormente (pacientes asociados con la enfermedad de Crohn cT3,4) fueron significativamente peores que los de los pacientes no asociados con la enfermedad de Crohn con T3,4 (LFS a 5 años: 32,5% versus a 70,4 %, p = 0,001; SSE: 15,9% versus a 40,7%, p = 0,04; SG: 25,8% versus a 71,0%, p = 0,007).LIMITACIONES:Un estudio retrospectivo de un solo brazo.CONCLUSIONES:Se confirmaron resultados oncológicos significativamente peores en pacientes asociados con la enfermedad de Crohn con tumores grandes. Por lo tanto, es importante realizar una vigilancia cuidadosa de las lesiones anales en pacientes con enfermedad de Crohn. Consulte Video Resumen en http://links.lww.com/DCR/B449.

[A Case of Curative Resection for Borderline-Resectable Locally Advanced Rectal Cancer Treated with Preoperative Chemoradiotherapy followed by Extended Surgery].

A 55-year-old man was referred for surgery after colonoscopy revealed type 3 advanced lower rectal cancer in the lower rectum. CT and MRI scan showed no distant metastasis but on the left side of the rectum, there was a 34×30 mm large mass suspicious of lymph node metastasis, which had left-sided wall pelvic fascia invasion. We performed preoperative chemoradiotherapy(CRT)to ensure a secure surgical margin. As a result, the tumor volume was reduced and robot-assisted rectal amputation and bilateral lateral lymph node dissection were performed using a combined transperineal speculum approach. The pathological results showed that circumferential resection margin of 3 mm was secured. The lymph nodes on the left side of the rectum were mostly fibrotic and the tumor component had almost disappeared. Preoperative CRT is useful for securing the surgical margin. The multidisciplinary treatment including extended surgery enabled the curative resection of even highly advanced rectal cancer.

Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503.

The great majority of gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the c-kit gene, which encodes KIT receptor tyrosine kinase. Most of the mutations are located at exon 11, but some are at exon 9 or at other exons. Mutation types at exon 11 vary, while most mutations at exon 9 are a particular duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). Recently a duplication of Ser501Ala502 (KIT-Dup-Ser501Ala502) at exon 9 has been reported in two cases of pediatric mastocytosis and one case of adult mast cell leukemia. Although KIT-Dup-Ser501Ala502 had not been reported in GISTs, we found two GIST cases possessing the mutation in 45 GIST cases with exon 9 c-kit gene mutations, among a total of approximately 500 GIST cases examined. In this report, we briefly summarize clinicopathological findings of the two cases, and characterize the biology of the mutation. When autophosphorylation of KIT-Dup-Ser501Ala502 was examined by transient transfection of c-kit cDNA with Dup-Ser501Ala502 into CHO-K1 cells, KIT-Dup-Ser501Ala502 was ligand-independently activating. The inhibitory effect of selective tyrosine kinase inhibitors, imatinib and nilotinib, on KIT-Dup-Ser501Ala502 was examined and compared with that of KIT-Dup-Ala502Tyr503. Imatinib efficiently inhibited constitutive activation of KIT-Dup-Ser501Ala502 at a concentration of 0.1 µM, whereas it inhibited that of KIT-Dup-Ala502Tyr503 at a concentration of 10 µM. Constitutive activation of KIT-Dup-Ser502Ala503 was not inhibited by nilotinib even at a concentration of 10 µM but that of KIT-Dup-Ala501Tyr502 was almost completely inhibited at a concentration of 1 µM. The results suggest that imatinib and nilotinib could be more effective on GISTs with KIT-Dup-Ser501Ala502 than those with KIT-Dup-Ala502Tyr503. In fact, a patient with KIT-Dup-Ser501Ala502 showed long-term stable disease with administration of the usual dose of 400 mg imatinib. Although mutation sites of KIT-Dup-Ser501Ala502 and KIT-Dup-Ala502Tyr503 are closely located, imatinib- and nilotinib-sensitive KIT-Dup-Ser501Ala502 are distinguishable from KIT-Dup-Ala502Tyr503.

Role of neuropilin-2 in the ipsilateral growth of midbrain dopaminergic axons.

Axonal projections in the CNS can be categorized as either crossed or uncrossed. Crossing and uncrossing of axons has been explained by attractive and repulsive molecules like Netrin-1 and Slits, which are secreted by midline structures. However, uncrossed projections can be established even in double knockout mice of slit1 and slit2 or of roundabout1 (robo1) and robo2, two receptors for Slits. Here, we found that a novel mechanism mediated by Neuropilin-2 (Nrp2) contributes to the formation of uncrossed projections of midbrain dopaminergic neurons (mDANs). Nrp2 transcriptional activities were detected in a subset of mDANs, and its protein was expressed in mDAN axons growing through the ipsilateral diencephalon. In nrp2(lac) (Z) (/lac) (Z) mice, mDAN axons aberrantly grew toward the ventral midline and even crossed it, suggesting that Nrp2 is necessary for the development of mDAN ipsilateral projections. We investigated the involvement of Semaphorin 3B (Sema3B) and Sema3F, two ligands of Nrp2, by analysing mDAN axon trajectories in single or double knockout mice. In both cases, mDAN axons still projected ipsilaterally, suggesting the involvement mechanisms independent of these Sema3s. Nrp2-deficient mDAN axons retained their responsiveness to Slit2, demonstrating that aberrant mDAN axons in nrp2(lac) (Z) (/lac) (Z) mice were not indirectly mediated by alterations in Slit/Robo signaling. Taken together, our results indicate that a novel mechanism mediated by Nrp2 contributes to the establishment of uncrossed projections by mDAN axons.

A case of synchronous bilateral lung cancers: EML4-ALK positive adenocarcinoma in the right lung and adenocarcinoma in situ (the former bronchioloalveolar carcinoma) in the left lung.

BACKGROUND: Recently it has been revealed that lung adenocarcinomas with distinct gene mutations or fusions are associated with particular histopathological entities. For example, epidermal growth factor receptor (EGFR) gene mutations are often associated with well differentiated adenocarcinoma of the lung with bronchioloalveolar pattern. On the other hand, echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene in a subset of lung adenocarcinoma is related to mucinous cribriform histology. CASE PRESENTATION: Reported herein is a case of synchronous EML4-ALK positive lung adenocarcinoma and adenocarcinoma in situ in the bilateral lungs of a 55-year-old Japanese woman. The woman had EML4-ALK positive lung adenocarcinoma in the right lower lung while adenocarcinoma in situ in the left upper lung, which was EML4-ALK negative. CONCLUSION: To our knowledge, this is the first report of synchronous, bilateral lung adenocarcinomas composed of EML4-ALK positive and negative ones.

Clinical Significance of Early Venous Filling Detected via Preoperative Angiography in Glioblastoma.

Preoperative angiography in glioblastoma (GBM) often shows arteriovenous shunts and early venous filling (EVF). Here, we investigated the clinical implications of EVF in GBM as a prognostic and vascular mimicry biomarker. In this retrospective multicenter study, we consecutively enrolled patients who underwent angiography with a GBM diagnosis between 1 April 2013 and 31 March 2021. The primary and secondary endpoints were the differences in overall survival (OS) and progression-free survival (PFS), respectively, between cases with and without EVF. Of the 133 initially enrolled patients, 91 newly diagnosed with GBM underwent preoperative angiography and became the study population. The 6-year OS and PFS were significantly worse in the EVF than in the non-EVF group. Moreover, 20 GBM cases (10 with EVF and 10 without EVF) were randomly selected and evaluated for histological vascular mimicry. Except for two cases that were difficult to evaluate, the EVF group had a significantly higher frequency of vascular mimicry than the non-EVF group (0/8 vs. 5/10, p = 0.04). EVF on preoperative angiography is a robust prognostic biomarker for GBM and may help detect cases with a high frequency of histological vascular mimicry.

Metastatic lobular carcinoma of the breast masquerading as a primary rectal cancer.

BACKGROUND: Colorectal metastasis of lobular carcinoma of the breast is a diagnostic challenge. It may macroscopically simulate primary colon cancer or inflammatory bowel disease. In some cases, the interval between the primary breast cancer and metastatic colorectal lesions is so long that the critical records for diagnosis including history might be lost or missed. CASE PRESENTATION: Reported herein is a case of metastatic lobular carcinoma of the breast masquerading as a primary rectal cancer developed in a 62-year-old Japanese woman. The case initially presented as a circumferential rectal lesion, and information on the patient's history of breast cancer was not noted. As the result of endoscopic biopsy, diagnosis of poorly differentiated rectal adenocarcinoma was made. The lesion was surgically resected after chemo-radiotherapy. Histopathological examination of the resected specimen with hematoxylin and eosin (HE) stain revealed a single-file arrangement of the tumor cells, reminiscent of lobular carcinoma of the breast. Immunohistochemical analysis revealed an immunophenotype consistent with lobular carcinoma of the breast. Because further review of the patient's history revealed an occurrence of 'poorly differentiated adenocarcinoma of the breast', which she had experienced 24 years earlier, the final diagnosis of the lesion was made as rectal metastasis from lobular breast carcinoma. CONCLUSIONS: Poorly differentiated adenocarcinoma of the colorectum is rarer than that of the stomach. Linitis plastica-type cancer of the colorectum is also rarer than that of the stomach. A lesson from the present case is that before we conclude a linitis plastica-type cancer of poorly differentiated type as a primary colorectal cancer, it is critical to exclude a possibility of metastatic colorectal cancer.

T-cell lymphoma, B-cell lymphoma, and myelodysplastic syndrome harboring common mutations: Trilineage tumorigenesis from a common founder clone.

A 64-year-old man with angioimmunoblastic T-cell lymphoma (AITL) subsequently developed diffuse large B-cell lymphoma (DLBCL) and myelodysplastic syndrome (MDS). Genomic profiling of AITL, DLBCL, and MDS samples revealed that the tumor cells from all samples shared common mutations in TET2 and DNMT3A. In addition, the IDH2 mutation was observed in AITL, and TP53 mutation was observed in DLBCL and MDS. These findings illustrate the clonal relationship between AITL and DLBCL in addition to AITL and MDS, with the latter being increasingly reported. The present findings strongly support the theory of multistep and multilineage tumorigenesis from a common founder clone.

Severe acute heart failure during or following cytokine release syndrome after CAR T-cell therapy.

Although cardiac dysfunction after chimeric antigen receptor (CAR) T-cell therapy has been increasingly reported, the underlying dynamics and pathogenesis are not well documented. Herein, we describe the clinical presentation and treatment for two patients who developed severe acute heart failure after CAR T-cell therapy. Both cases shared several common characteristics, including the bone marrow involvement at the time of CAR T-cell therapy and early onset of cytokine release syndrome (CRS) with fever developing on the day of CAR T-cell infusion. Patients with early onset and/or severe CRS should be carefully monitored for the possibility of heart failure.

Toxoplasmic Encephalitis Followed by Primary EBV-Associated Post-Transplant Lymphoproliferative Disorder of the Central Nervous System in a Patient Undergoing Allogeneic Hematopoietic Stem Cell Transplant: A Case Report.

Toxoplasmic encephalitis (TE) and post-transplant lymphoproliferative disorder of the central nervous system (CNS-PTLD) are major complications after allogeneic hematopoietic stem cell transplant (allo-SCT); both are fatal without timely diagnosis and disease-specific treatment. Differential diagnosis of TE and CNS-PTLD can be challenging because brain biopsy, a gold standard for diagnosis, is sometimes not possible, owing to poor patient condition after allo-SCT. Here, we describe a case of isolated CNS-PTLD arising during the therapeutic course of TE. A 51-year-old man was admitted with mental abnormalities and fever on Day 106 after allo-SCT to treat myelodysplastic syndrome. Magnetic resonance imaging (MRI) revealed multiple nodular and ring-enhanced lesions in the brain, and the result of polymerase chain reaction (PCR) for Toxoplasma gondii in cerebrospinal fluid was positive; therefore, he was diagnosed with TE. Anti-Toxoplasma therapy led to clinical improvement, and the result of subsequent PCR was negative. However, he developed left-sided hemiplegia on Day 306. Head MRI revealed a new lesion and a growing lesion, presenting as ring-enhanced nodules. Brain biopsy was performed, and a pathologic diagnosis of Epstein-Barr virus-associated CNS-PTLD was made. There was no evidence of TE. He was treated successfully by reducing immunosuppressants, followed by rituximab administration and a donor lymphocyte infusion, resulting in complete remission. While T.gondii-specific PCR has great value for diagnosis of TE, CNS-PTLD can be diagnosed only by brain biopsy; hence, brain biopsy may be warranted in cases of suspected PTLD.

Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer.

BACKGROUND/AIM: The difficulty of early diagnosis of colitis associated colorectal cancer (CACRC) due to colonic mucosal changes in long-standing ulcerative colitis (UC) patients is often experienced in daily clinical practice. Noninvasive objective monitoring for cancer development is advantageous for optimizing treatment strategies in UC patients. We aimed to examine the epigenetic alterations occurring in CACRC, focusing on DNA hypermethylation of CpG islands. MATERIALS AND METHODS: The level of DNA methylation in CpG cites was compared between CACRC and the counterpart non-tumorous mucosa using Infinium HumanMethylation 450K BeadChip. RESULTS: Our subjects included 3 males and 3 females (median age, 49.5 years). The 450K CpG site DNA methylation microarray revealed that the difference in ß value (level of hypermethylation) was the highest for corcicotropin releasing hormone receptor 2 (CRHR2) between CACRC and counterpart non-tumorous mucosa. CONCLUSION: Detection of hypermethylation of CRHR2 may be promising for cancer screening in UC patients.

Semaphorin 3F confines ventral tangential migration of lateral olfactory tract neurons onto the telencephalon surface.

Ventral tangential migration of neurons is the most prominent mode of neuronal translocation during earliest neurogenesis in the mouse telencephalon. A typical example of the neurons that adopt this migration mode is guidepost neurons in the lateral olfactory tract designated as lot cells. These neurons are generated from the neocortical neuroepithelium and migrate tangentially down to the ventral edge of the neocortex abutting the ganglionic eminence, on which the future lateral olfactory tract develops. We show here that this migration stream is repelled by a secreted axon guidance molecule, semaphorin 3F through interaction with its specific receptor, neuropilin-2. Accordingly, in mutant mice for semaphorin 3F or neuropilin-2, lot cells ectopically penetrated into the deep brain domain, which normally expresses semaphorin 3F. These results reveal that semaphorin 3F is an important regulator of the ventral tangential migration stream, confining the migrating neurons on the telencephalon surface by repelling from the deeper domain.