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.

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.

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.

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.

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.

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.

Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition.

Host NOD-like receptor family pyrin domain-containing 6 (NLRP6) regulates innate immune responses and gastrointestinal homeostasis. Its protective role in intestinal colitis and tumorigenesis is dependent on the host microbiome. Host innate immunity and microbial diversity also play a role in the severity of allogeneic immune-mediated gastrointestinal graft-versus-host disease (GVHD), the principal toxicity after allogeneic haematopoietic cell transplantation. Here, we examined the role of host NLRP6 in multiple murine models of allogeneic bone marrow transplantation. In contrast to its role in intestinal colitis, host NLRP6 aggravated gastrointestinal GVHD. The impact of host NLRP6 deficiency in mitigating GVHD was observed regardless of co-housing, antibiotic treatment or colonizing littermate germ-free wild-type and NLRP6-deficient hosts with faecal microbial transplantation from specific pathogen-free wild-type and Nlrp6-/- animals. Chimaera studies were performed to assess the role of NLRP6 expression on host haematopoietic and non-haematopoietic cells. The allogeneic [B6Ly5.2 → Nlrp6-/-] animals demonstrated significantly improved survival compared to the allogeneic [B6Ly5.2 → B6] animals, but did not alter the therapeutic graft-versus-tumour effects after haematopoietic cell transplantation. Our results unveil an unexpected, pathogenic role for host NLRP6 in gastrointestinal GVHD that is independent of variations in the intestinal microbiome and in contrast to its well-appreciated microbiome-dependent protective role in intestinal colitis and tumorigenesis.

Expression of p16 in nodular fasciitis: an implication for self-limited and inflammatory nature of the lesion.

Nodular fasciitis (NF) is a self-limited tumorous lesion occurring in the upper as well as lower extremities. NF is composed of a proliferation of "primary culture"-like myofibroblastic cells with nuclear atypia and large nucleoli, thus mimicking sarcoma. NF harbors a promoter-swapping fusion gene containing the entire coding region of USP6 gene. Therefore, NF is a tumor with a fusion oncogene but self-limited. In order to explore why NF is self-limited, we examined whether myofibroblastic cells in NF express p16 protein, a gene product of CDKN2A gene and an inhibitor of cyclin-dependent kinase 4 (CDK4) as well as one of the hallmarks of cellular senescence. We immunohistochemically demonstrated strong and diffuse expression of p16 in myofibroblastic cells in 11 out of 15 cases of NF, and strong but partial expression in the remaining 4 of the cases. We also showed that 15 out of 15 cases of NF were immunohistochemically negative or only showed focal and faint immunopositivity for CDK4, murine double minute 2 (MDM2), and TP53 proteins. Furthermore, there were no significant changes in the copy number of CDKN2A, CDK4 and MDM2 genes, and no significant mutations in TP53, RB1, and CDKN2A genes in 1 case of NF selected. These data suggest a possible involvement in cell cycle arrest and presumed cellular senescence by p16 in myofibroblastic cells in NF. This may explain the self-limited as well as inflammatory nature of NF as a senescence-associated secretory phenotype.

The eCura system as a novel indicator for the necessity of salvage surgery after non-curative ESD for gastric cancer: A case-control study.

Endoscopic submucosal dissection (ESD) for early gastric cancer does not always lead to complete cancer resection. The aim of this study was to determine indicators for cancer residue (CR) status in cases of non-curative ESD. We analyzed 47 cases of non-curative ESD followed by salvage surgery and collected data regarding the rates of CR, which included both local CR and lymph node metastasis (LNM). To elucidate the risk factors for CR status, we compared the CR positive and the CR negative groups among surgical specimens according to the following variables obtained from ESD findings: tumor location, tumor size, depth of invasion, lympho-vascular invasion, histological margin, and histological diagnosis. The eCura system, which is an LNM risk scoring system, was also applied and scores were calculated in each case as follows: 3 points for lymphatic invasion and 1 point each for tumor size >30 mm, positive vertical margin, venous invasion, and submucosal invasion ≥500 µm. There were 9 (19%) CR positive cases, which included 6 cases of local CR and 4 cases of LNM; no cancer was detected in over 80% of the patients. The eCura scoring system was the only significant factor for CR status: the higher the eCura score, the greater the CR positivity (p = 0.0128). In particular, all patients in the low-risk group (score = 0-1 point) had no CR. Although no cancer recurrence was observed during a median follow-up of 4 years, 2 patients died of pneumonia. In conclusion, the eCura system might make it possible to select appropriate cases for salvage surgery.

Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling.

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, known as colitis-associated cancer (CAC). It is still unclear what driver mutations are caused by chronic inflammation and lead to CAC development. To get insight into this issue, we investigated somatic alterations in CAC. We performed exome sequencing of 22 fresh CACs and targeted sequencing of 43 genes on 90 archive specimens from Japanese CAC patients, of which 58 were ulcerative colitis (UC) and 32 were Crohn's disease (CD). Consistently with the previous reports, TP53 was commonly mutated (66%) whereas APC, KRAS and SMAD4 were mutated less frequently (16%, 11% and 11%, respectively). Mucinous CD-CACs in the anus, an Asian-specific subtype of CD-CAC, had less somatic mutations in our target genes. We also found that RNF43, a negative regulator of the Wnt signaling, was somatically mutated in a significant fraction of CACs (10 of 90; 11%). Two lines of evidence indicated that somatic mutations of RNF43 were related to chronic inflammation. First, somatic mutations of RNF43 were significantly associated with longer duration of IBD. Second, clinico-pathological features suggested many of the APC-mutated CACs were actually sporadic colorectal cancer whereas RNF43-mutated CACs did not have this tendency. RNA-Seq analysis showed that RNF43-mutated CACs had elevated expression of c-Myc and its target genes, suggesting that RNF43 is a bona fide driver of CAC development. This study provides evidence that somatic mutation of RNF43 is the driver genetic alteration that links chronic inflammation and cancer development in about 10% of CACs.