Bexarotene-induced hypothyroidism and dyslipidemia; a nation-wide study.

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

[A Case of Left Upper Abdominal Evisceration for Transverse Colon Cancer with Multiple Organ Invasion].

The case is a 73-year-old woman. She visited primary care doctor for abdominal pain, vomiting, diarrhea, and melena that persisted for 2 weeks. She was referred to our department because she had an elevated inflammatory response and CT showed a mass in her left upper quadrant. Contrast-enhanced CT showed a tumorous lesion mainly in the splenic flexure of the transverse colon, involving the greater curvature of the stomach, the tail of the pancreas, and the hilus of the spleen, accompanied by abscess formation. We suspected highly advanced colon cancer with multiple organ involvement, but we opted for multiple visceral resection because it was associated with high-grade inflammatory findings due to abscess formation. After she was treated with antibiotics, she underwent laparotomy on the 6th day of illness. Intraoperative findings showed no clear nodular lesions suggesting dissemination in the abdominal cavity and intraoperative washing cytology was negative. Since the mobility of the mass that invaded the posterior wall of the greater curvature of the stomach, the tail of the pancreas, and the splenic hilum centered on the splenic flexure was confirmed, the entire left upper abdominal evisceration was resected by resecting the splenic flexure of the colon, the stomach, the tail of the pancreas, and the spleen. The postoperative course was uneventful, and she was discharged on postoperative day 9. Histopathological examination confirmed invasion of colon cancer into the pancreas, spleen, and retroperitoneum. In this report, we present a case of colon cancer with multi-organ invasion that underwent left upper abdominal evisceration.

[A Case of Radical Resection of Mucinous Cystadenocarcinoma of the Appendix by Laparoscopic Partial Cecal Resection].

A 70-year-old man was admitted to our hospital with a chief complaint of right lower abdominal pain during defecation. The contrast-enhanced CT scan showed a highly expanded appendix, so we suspected an appendiceal mucinous neoplasm, but the diagnosis did not clearly suggest cancer. So, we decided to perform laparoscopic surgery. Based on the intraoperative findings, it was considered that radical resection may be possible by partial cecal resection, and the patient underwent the procedure. Mucinous adenocarcinoma(MACA)was revealed by the postoperative pathological diagnosis. However, because the histological type was G1(well-differentiated)and no metastasis to regional lymph nodes(No. 201)was observed, we decided not to perform an additional ileocecal resection with LN dissection. The patient had a good postoperative course and was discharged from the hospital on postoperative day 4. The patient is still alive, 9 months postoperatively, with no recurrence.

Prognostic analysis of smoldering ATLL with skin eruptions based on genomic aberrations.

BACKGROUND: Patients with smoldering ATLL often present with a skin eruption due to skin infiltration of ATLL cells. Although skin eruption type is known to be associated with prognosis based on its pattern, it is unknown why different types of skin eruptions are associated with different prognoses. OBJECTIVE: Genomic analysis of patients with skin eruptions of smoldering ATLL will be performed to determine the mechanism of ATLL development and its association with prognosis. METHODS: DNA from skin biopsy specimens was used for targeted sequencing of 280 genes to examine the association between genomic variation and prognosis. RESULTS: Due to the small number of smoldering ATLL patients (27 cases), we could not find a clear relationship between skin eruption and prognosis in this study. Genomic analysis identified 247 genomic variants (108 genes), with an average of 9.2 variants and 3.2 variants as driver genes. Pathway analysis of the driver genes showed activation of the pathway associated with HTLV-1 infection, as well as activation of the signaling pathway observed throughout ATLL. Furthermore, multivariate analysis identified age>70 years and STAT3 mutation as prognostic risk factors and TBL1XR1 mutation as a risk factor for progression-free survival. CONCLUSION: Although the small number of patient samples did not allow us to determine a prognostic association with skin eruption, STAT3 mutation was identified as a prognostic risk factor for smoldering ATLL with skin eruption. Further studies are needed to increase the number of patients with this disease.

Validation of the iATL-PI prognostic index in therapeutic decision-making for patients with smoldering and chronic ATL: a multicenter study.

Adult T cell leukemia-lymphoma (ATL) is clinically heterogeneous and is classified into four subtypes: acute, lymphoma, chronic, and smoldering. Recently, a new prognostic index based on the value of soluble interleukin-2 receptor, denoted the "iATL-PI," has been proposed for patients with smoldering and chronic ATL. To evaluate the effectiveness of the iATL-PI, we re-analyzed our previously published data on 176 patients with smoldering or chronic ATL (76 smoldering, 100 chronic) diagnosed between 2010 and 2011, as well data from the subsequent follow-up study on prognosis between 2016 and 2017. The proportions for the low-, intermediate-, and high-risk iATL-PI groups at the time of ATL diagnosis were 44.7%, 48.7%, and 5% for smoldering ATL; 6.3%, 71.9%, and 21.9% for favorable chronic ATL; and 5.9%, 27.9%, and 66.2% for unfavorable chronic ATL, respectively. The survival of patients with smoldering or chronic ATL as a whole was significantly stratified according to the three iATL-PI groups. Most patients with unfavorable chronic ATL in the low iATL-PI risk group had indolent clinical courses. Our results showed that iATL may become a useful tool to predict the prognosis of smoldering and chronic ATL, which have diverse clinical courses.

Secondary Skin Cancer in a Case with Long-term Voriconazole after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia.

Secondary malignancies that develop after allogeneic-hematopoietic stem cell transplantation (allo-HSCT) have become serious issues. A 47-year-old man who developed acute myeloid leukemia in 2009 and subsequently underwent allo-HSCT twice: in 2009 and 2011. In 2015, voriconazole for lung aspergillus was started. In 2018, chronic graft-versus-host disease (GVHD) and multiple actinic keratoses manifested at his head. In 2020, some lesions were diagnosed as squamous cell carcinoma, so voriconazole was withdrawn, and subsequent surgery and radiation led to remission. Long-term administration of voriconazole in addition to allo-HSCT and chronic GVHD may be closely related to secondary skin cancer.

Safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma: Real-world experience from post-marketing surveillance.

To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m2 (61.6%) and patients who started with bexarotene at less than 300 mg/m2 (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m2 and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m2 than patients who started with bexarotene at less than 300 mg/m2 (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m2 and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.

[Preoperative Chemoradiotherapy for Advanced Rectal Cancer Resulting in Pathological Complete Response].

A 73-year-old woman was referred to our institution due to the presence of narrow and bloody stools. On rectal examination, a rectal mass was observed. Colonoscopy revealed a type 2 tumor in the rectum(RbP)that extended to the dentate line. On biopsy, the tumor was diagnosed as tub1/tub2. No enlarged lymph nodes or metastases were noted on CT. On MRI, the tumor did not invade outside the rectum, and was noted to be proximal to the levator ani muscle. The patient was diagnosed with rectal cancer(cT4a, cN0, cM0, cStage Ⅱb). Preoperative chemoradiotherapy(CRT)was performed to preserve the patient's anus. A total dose of 50.4 Gy of radiation was administered in daily fractions of 1.8 Gy, and chemotherapy was administered with S-1(80 mg/day)orally. Colonoscopy revealed that the tumor significantly reduced in size post-CRT. Further, the boundary between the tumor and levator ani muscle was observed to be more distinct. The patient underwent a laparoscopic intersphincteric resection(D3)+ileostomy. Pathological examination revealed no viable tumor cell in the removed specimen. No tumor recurrence was observed 2 years postoperatively. We report a case in which preoperative CRT for advanced rectal cancer resulted in a pathological complete response.

Epidemiology of adult T-cell leukemia-lymphoma in Japan: An updated analysis, 2012-2013.

Adult T-cell leukemia-lymphoma (ATL) is a T-cell malignancy that is endemic to Japan. In this latest nationwide study of ATL, we collected the data from 4 nationwide registries of patients diagnosed in 2012-2013; the Hematology Blood Disease, the Skin Cancer Society, the Hospital-Based Cancer Registries, and information from the hospitals that participated in the Japanese nationwide survey of ATL in 2010-2011. In the present study, 2614 patients with ATL were diagnosed based on the registries, and 117 departments registered 1042 patients. Among these patients, 984 were eligible for analysis. The median age at diagnosis was 69 y. A larger proportion of patients with ATL older than 70 y was diagnosed with the lymphoma subtype, and more than half of the patients with ATL in the metropolitan areas were born in the human T-cell leukemia virus type I (HTLV-1)-endemic areas of Kyushu/Okinawa, which are almost identical to the findings in our 2010-2011 study. Additionally, we identified that patients with ATL migrated from the endemic areas for HTLV-1 to the non-endemic metropolitan areas. The present study was able to reduce the burden of searching each hospital and to update the clinico-epidemiological characteristics of a large number of patients with ATL in Japan, suggesting the usefulness and feasibility of the novel data collection method. The establishment of a more sophisticated database management system for ATL is necessary for future continuous surveys.

Congenital Deficiency of Conventional Dendritic Cells Promotes the Development of Atopic Dermatitis-Like Inflammation.

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease characterized by impaired epidermal barrier function and dysregulation of Thelper-2 (TH2)-biased immune responses. While the lineage of conventional dendritic cells (cDCs) are implicated to play decisive roles in T-cell immune responses, their requirement for the development of AD remains elusive. Here, we describe the impact of the constitutive loss of cDCs on the progression of AD-like inflammation by using binary transgenic (Tg) mice that constitutively lacked CD11chi cDCs. Unexpectedly, the congenital deficiency of cDCs not only exacerbates the pathogenesis of AD-like inflammation but also elicits immune abnormalities with the increased composition and function of granulocytes and group 2 innate lymphoid cells (ILC2) as well as B cells possibly mediated through the breakdown of the Fms-related tyrosine kinase 3 ligand (Flt3L)-mediated homeostatic feedback loop. Furthermore, the constitutive loss of cDCs accelerates skin colonization of Staphylococcus aureus (S. aureus), that associated with disease flare. Thus, cDCs maintains immune homeostasis to prevent the occurrence of immune abnormalities to maintain the functional skin barrier for mitigating AD flare.

Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/leukemia (ATLL) is an aggressive peripheral T-cell malignancy, caused by infection with the human T-cell leukemia virus type 1 (HTLV-1). We have recently shown that cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is specifically and consistently overexpressed in ATLL cells, and functions as a novel cell surface marker. In this study, we first show that a soluble form of CADM1 (sCADM1) is secreted from ATLL cells by mainly alternative splicing. After developing the Alpha linked immunosorbent assay (AlphaLISA) for sCADM1, we showed that plasma sCADM1 concentrations gradually increased during disease progression from indolent to aggressive ATLL. Although other known biomarkers of tumor burden such as soluble interleukin-2 receptor α (sIL-2Rα) also increased with sCADM1 during ATLL progression, multivariate statistical analysis of biomarkers revealed that only plasma sCADM1 was selected as a specific biomarker for aggressive ATLL, suggesting that plasma sCADM1 may be a potential risk factor for aggressive ATLL. In addition, plasma sCADM1 is a useful marker for monitoring response to chemotherapy as well as for predicting relapse of ATLL. Furthermore, the change in sCADM1 concentration between indolent and aggressive type ATLL was more prominent than the change in the percentage of CD4+CADM1+ ATLL cells. As plasma sCADM1 values fell within normal ranges in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with higher levels of serum sIL-2Rα, a measurement of sCADM1 may become a useful tool to discriminate between ATLL and other inflammatory diseases, including HAM/TSP.

[A Case of Colitic Cancer with a Total Proctocolectomy in the Second Term].

The patient was 70-years-old women, 27 years ago, she was diagnosed with total colitis-type ulcerative colitis. Eighteen years after the diagnosis, she self-suspended his hospital visit because her condition was stable. After 4 years, ulcerative colitis rekindled, she resumed taking a 5-ASA. And 2 years later, colonoscopy revealed type 3 tumor in the descending colon. Tumor biopsy indicated an adenocarcinoma(tub1, tub2)derived from ulcerative colitis. Originally total proctocolectomy is necessary, but patient strongly hoped to leave the colon. We performed laparoscopic left hemicolonectomy(D2, SST). The pathological diagnosis was pT3, pN2, pM0, pStage Ⅲc. After the operation, chemotherapy(mFOLFOX6)was carried out for 6 months. We regularly checked tumor markers and followed up with a colonoscopy once every 6 months. But 3 years and 9 months after surgery, ulcerative colitis rekindled and adenocarcinoma in the transverse colon found by colonoscopy. We performed total proctocolectomy with ileal J-pouch anal-canal anastomosis. Four months after the second operation, advanced defecation disorder has not been observed.

Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.

Wound, pressure ulcer and burn guidelines - 1: Guidelines for wounds in general, second edition.

The Japanese Dermatological Association prepared the clinical guidelines for the "Wound, pressure ulcer and burn guidelines", second edition, focusing on treatments. Among them, "Guidelines for wounds in general" is intended to provide the knowledge necessary to heal wounds, without focusing on particular disorders. It informs the basic principles of wound treatment, before explanations are provided in individual chapters of the guidelines. We updated all sections by collecting references published since the publication of the first edition. In particular, we included new wound dressings and topical medications. Additionally, we added "Question 6: How should wound-related pain be considered, and what should be done to control it?" as a new section addressing wound pain, which was not included in the first edition.

[A Case Involving Successful Resection of Advanced Lower Rectal Cancer with Perineum Reconstruction after Preoperative Chemotherapy and Chemoradiotherapy].

A 58-year-old woman visited our hospital for diagnosis and treatment of rectal tumor. The tumor was diagnosed as adenocarcinoma metastasizing to the uterus and vagina. Using CT, metastases were detected in the lung, liver, and right inguinal lymph node. First, we performed sigmoid-loop-colostomy. Thereafter, the patient received chemotherapy(CapeOX plus Bev) for 8 courses and chemoradiotherapy(total 50 Gy plus S-1 therapy). Ten months after the initial examination, we performed abdominoperineal resection of the rectum combined with the resection of the posterior wall of the vagina, hysterectomy, and bilateral adnexectomy. Because of a large defect in the perineal region, we also performed reconstruction using the left gracilis muscle flap. The postoperative course was uneventful, and the patient was discharged 22 days after surgery. Once the wound healed, chemotherapy(CapeIRI plus Bev)was initiated. After 10 courses of chemotherapy, metastasis and local recurrence could no longer be detected. This suggests that preoperative chemotherapy, chemoradiotherapy, and perineum reconstruction could enable the radical resection of advanced rectal cancer.

Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition.

"Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition" is revised from the first edition which was published in the Japanese Journal of Dermatology in 2016. The guidelines were drafted by the Wound, Pressure Ulcer and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association, and intend to facilitate physicians' clinical decisions in preventing, diagnosing and treating burn injury. All sections are updated by collecting documents published since the publication of the first edition. Especially, the recommendation levels of dressing materials newly covered by the Japanese national health insurance are mentioned. In addition, the clinical questions (CQ) regarding the initial treatment of electrical (CQ15) and chemical burns (CQ16), and also the use of escharotomy (CQ22), are newly created.

Wound, pressure ulcer and burn guidelines - 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.