[A Case of Combined Use of Endoscopic Submucosal Dissection and Transanal Excision for Early Rectal Cancer with Extension into the Anal Canal].

A 77-year-old woman visited our hospital after noticing bleeding during defecation. Lower gastrointestinal endoscopy revealed an early rectal tumor with extension into the anal canal, thus transanal excision was performed. However, histopathological examination revealed a positive surgical margin, therefore, additional transanal excision was performed with endoscopic submucosal dissection, and the residual cancer tissue was completely resected. At one year after surgery, no recurrence has been observed.

[Decision-Making Regarding Adjuvant Therapy for Hormone Receptor-Positive, HER2-Negative Early Breast Cancer].

In December 2021, abemaciclib was approved as an adjuvant treatment for hormone receptor-positive, HER2-negative, high-risk early breast cancer in Japan. The Oncotype DX Breast Cancer Recurrence Score program(Oncotype DX)is a test that can be used to limit overtreatment in hormone receptor-positive, HER2-negative, low-risk early breast cancer. Although the target groups of both these are different and usually without many overlapping indications, we encountered a case in which this therapy and test were used in a short time period. Our experience suggests that even if the result of Oncotype DX indicates that hormone therapy alone is sufficient, it does not imply that abemaciclib is unnecessary, although this has not been directly studied in the monarchE trial. While a wider choice of treatment options is desirable for patients, more clinical data and trials are needed to further validate the utility of abemaciclib without chemotherapy.

[A Case of Complete Onychomadesis after Oral UFT/LV Therapy with Long-Term Follow-Up].

A 79-year-old man underwent a radical resection for cecal cancer. The pathological diagnosis was pT4a, N1a, M0, pStage Ⅲb(Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, 9th edition). He was treated with oral UFT/LV as adjuvant chemotherapy for 6 months. At 7 months, after the end of treatment, he lost all the nail plates on his fingers and toes. A dermatologist examined him and diagnosed these as side effects of the anticancer drugs. Due to this issue, he was unable to perform routine, fine work using his fingertips. Approximately 1 year and 5 months after the completion of treatment, his nail plates regenerated to the extent that about half of his nail beds were covered. At 2 years after the completion of treatment, the nail plates began to cover the entire nail beds. Although there have been very few reports of onychomadesis as a delayed adverse event of anticancer drugs, oncologists must be aware of this possibility, as onychomadesis may impact patients' quality of life significantly.

[Long-Term Survival of a Patient with Triple-Negative Breast Cancer with Hormone Receptor Status Conversion between Primary and Metastatic Tumors].

Patients with triple-negative breast cancer have poor survival after recurrence. However, previous studies have shown that receptor conversion can occur between primary breast tumor and metastatic sites. Herein, we describe the case of a 54- year-old woman with advanced breast cancer, which showed receptor conversion from primary tumor(triple-negative)to distant metastases(Luminal type). The patient had undergone left radical mastectomy and left axillary lymph node dissection at another hospital(pT3N0M0, Stage ⅡB, ER-negative, PgR-negative, and HER2-negative). She was referred to our hospital for adjuvant chemotherapy with 3 courses of 5-fluorouracil, epirubicin, and cyclophosphamide and 3 courses of docetaxel. Around 26 months after the surgery, the follow-up CT scan showed multiple lung nodules. Another 9 months later, her left axillary and mediastinal lymph nodes were enlarged. She received several courses of anticancer chemotherapy. After paclitaxel and bevacizumab were administered as seventh-line chemotherapy, a vacuum-assisted biopsy of the left axillary lymph node was performed to confirm the presence of metastasis. Furthermore, immunohistochemistry results showed that the metastatic tumor was ER-positive, PgR-positive, and HER2-negative. Fulvestrant and palbociclib were then initiated as first-line endocrine therapy. She has been stable for more than 18 months since. It is essential to perform biopsies of metastatic sites for optimal management of patients with metastatic breast cancer.

Comparative analyses of Stvb-allelic genes reveal japonica specificity of rice stripe resistance in Oryza sativa.

Rice stripe, a viral disease, causes widespread damage to japonica rice (Oryza sativa ssp. japonica). A rice stripe virus (RSV) bioassay revealed that many indica and japonica upland varieties exhibit resistance, whereas japonica paddy varieties are susceptible. However, the genetic background for this subspecies-dependent resistance is unclear. Herein, we focused on rice stripe resistance genes located at the Stvb locus. Three resistant alleles, Stvb-i (indica), Stvb (japonica upland), and Stvb-o (Oryza officinalis) were compared with the susceptible allele, stvb-j (japonica paddy). The expression of the resistance genes was higher than that of stvb-j. Sequence comparison revealed that the resistant and susceptible alleles had different 5'-end sequences and 61-bp element(s) in the fourth intron. The insertion of an LTR-retrotransposon modified the exon 1 sequence of stvb-j. We then developed four DNA markers based on gene structure information and genotyped resistant and susceptible varieties. The LTR-retrotransposon insertion was detected only in susceptible varieties. Resistant genotypes were primarily found in indica and upland japonica, whereas paddy japonica carried the susceptible genotype. Our results characterize the genetic differences associated with RSV resistance and susceptibility in O. sativa and provide insights on the application of DNA markers in rice stripe disease management.

[Hyponatremia Causing a Tonic-Clonic Seizure after Breast Cancer Surgery-The Medical Safety Perspective].

A 61-year-old woman was found to have calcifications in the CD region of the left breast. She had previously undergone total hysterectomy and bilateral oophorectomy for endometriosis at the age of 37 years. Since age 59 years, she had been attending an otorhinolaryngology clinic because of vertigo. Blood tests showed no abnormal findings. Left breast cancer (cT1N0M0, stage Ⅰ)was diagnosed, and left mastectomy and sentinel lymph node biopsy were performed. She developed postoperative nausea, and at 37 hours postoperatively, she was unable to communicate and exhibited suspected delirium. At 43 hours postoperatively a tonic-clonic seizure occurred. Hyponatremia, with serum sodium of 114 mEq/L, was present. Sodium supplementation was provided, and the patient became capable of communication 8 hours after seizure onset(Na 121 mEq/L). A hyponatremic tonic-clonic seizure is extremely rare after breast cancer surgery, and the abnormal behavior of the present patient 31 hours after surgery was also highly unusual. With such an unusual presentation, the possibility that something specific is happening must be considered. This case gave us the opportunity to review patient management after breast cancer surgery, emergency response and preparations, and nursing education from the medical safety perspective.

[A Case of Low-Grade Appendiceal Mucinous Neoplasm for Which Laparoscopic Surgery Was Effective].

Abdominal ultrasonography during a regular medical examination showed that a 70-year-old man had an approximately 10 cm cystic tumor in the lower abdomen. Abdominal computed tomography showed that the appendix had swollen to a size of 130 mm×44 mm. As no other tests suggested malignancy, the patient's condition was diagnosed as a low-grade appendiceal mucinous tumor and he underwent laparoscopic ileocecal resection and lymph node D2 dissection. Laparoscopic surgery was completed without damaging the tumor. There has been no recurrence after the operation for 2 years now.

Examination of the efficacy of olanexidine gluconate for surgical site infections in colorectal cancer elective surgery.

INTRODUCTION: The preoperative skin antiseptic, olanexidine gluconate (OLG), which has been available in Japan since 2015, is also known to be effective against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and Pseudomonas aeruginosa. This study attempted to clarify OLG efficacy against surgical site infections and antiseptic-related adverse events as compared to conventionally used povidone iodine (PVP-I). METHODS: Propensity score matching was performed on 307 patients who underwent surgery for colorectal tumors at our hospital. All 116 cases (58 PVP-I cases, 58 OLG cases) who were diagnosed with colorectal cancer were included. We examined surgical site infection rate after disinfection using PVP-I and OLG, length of hospitalization stay (days) after surgery, adverse events associated with antiseptics, and additional medical costs associated with adverse events caused by antiseptics. RESULTS: The surgical site infection rate was 8.6% in both the PVP-I and OLG groups, with no significant difference observed. The number of postoperative hospitalization days in the PVP-I group was 12.9 (±6.9) days and 16.4 (±14.6) days in the OLG group, which exhibited no significant difference (p = 0.10). Although no complications due to antiseptics were observed in the PVP-I group, skin-related side effects were observed in 8 patients (13.8%) in the OLG group. The median additional medical cost was 730 [120-1823] yen. CONCLUSIONS: OLG was as effective as the conventional PVP-I for surgical site infections during colorectal cancer elective surgery. However, significantly higher skin disorders occurred in OLG, thereby making it necessary to evaluate antiseptic use in conjunction with patient burden.

Laparoscopic Appendectomy for Acute Appendicitis Complicated by Pancytopenia in Two Patients with Hematologic Diseases.

A 25-year-old male (Case 1) was waiting for a bone marrow transplant for myelodysplastic syndrome. Due to acute appendicitis, he was advised to undergo gastroenterological surgery. After blood transfusion, he underwent an emergency laparoscopic appendectomy, as no blood cell recovery was expected. The postoperative course was uneventful, and he was discharged. A 71-year-old female (Case 2) developed acute appendicitis during chemotherapy for acute myeloid leukemia (AML). At the time of onset, since her myelosuppression was expected to improve in approximately 1 week, a conservative treatment was administered. However, due to the progression of AML, the expected blood cell recovery did not occur. Therefore, laparoscopic appendectomy was performed 25 days after onset. She was discharged without postoperative adverse events. In cases of acute appendicitis in patients with hematologic disease accompanied by pancytopenia, it is important to establish a careful treatment plan considering the possibility of recovery from myelosuppression and the need to control an intraperitoneal infection in conjunction with a hematologist. Laparoscopic surgery, which is minimally invasive, was an effective surgical procedure.

Stvb-i, a Rice Gene Conferring Durable Resistance to Rice stripe virus, Protects Plant Growth From Heat Stress.

Disease resistance is affected by temperature. A rice gene, Stvb-i, is known to have conferred sustained resistance to Rice stripe virus (RSV) despite global warming. Stvb-i protects plants from growth stunting caused by RSV. The underlying resistance mechanism is unclear. Here, Stvb-i showed stable RSV resistance for 20 years in laboratory experiments. This gene encodes a protein distinct from well-studied plant disease-resistance proteins. It has a domain homologous to the histidine kinase/heat-shock protein 90-like ATPase superfamily. Rice has three paralogous genes including Stvb-i. The genes are expressed mainly in meristematic tissues. In the initial period after viral inoculation, RSV multiplication enhanced Stvb-i, whereas Stvb-i suppressed RSV multiplication. Stvb-i silencing inhibited plant growth regardless of viral infection, and silencing of the other paralogous gene that located closely to Stvb-i caused morphological abnormalities. The results suggested that the Stvb-i and its paralogs are related to plant development; especially, Stvb-i supports meristem growth, resulting in plant growth stabilizing. Growth stunting in the Stvb-i-silenced plants was more severe under repetitive heat stress, suggesting that Stvb-i contributed to the attenuation of heat damage in plant development. The symptoms of RSV infection (chlorosis, wilting, stunting, fewer tillers, and defective panicles) were similar to those of heat damage, suggesting that RSV multiplication induces heat-like stress in meristematic cells. Our findings suggest that the mechanism of meristem growth protection conferred by Stvb-i allows plants to withstand both heat stress and RSV multiplication. The suppression of RSV multiplication by the Stvb-i function in meristems results in durable resistance.

[Treatment Regimens for Breast Cancer in Elderly Patients in Whom the Diagnosis Was Switched from Malignant Phyllodes Tumor to Spindle-Cell Carcinoma after Surgery].

The patient was a 79-year-old woman with a left breast mass. Magnetic resonance imaging showed a cystic mass with a diameter of 10×8 cm and an ulcer in the upper outer quadrant and the nipple-areola region of the left breast. Intracystic carcinoma was thus suspected. A mass with a diameter of 1 cm was found in the upper outer quadrant of the right breast. Needle biopsy revealed that a cystic mass in the left breast was diagnosed as a malignant phyllodes tumor. A mass in the right breast was diagnosed as Luminal A breast cancer. The clinical tumor stage was T1N0M0. Computed tomography showed no enlarged bilateral axillary lymph nodes. In the left breast, mastectomy was performed with extensive skin excision above the tumor. In the right breast, partial mastectomy was performed with sentinel lymph node biopsy. On postoperative pathological examination, the diagnosis of left breast tumor was triple-negative spindle-cell carcinoma. The pathological tumor stage was diagnosed as T4bNxM0. Taking into consideration treatment according to breast cancer stage and age, we selected 4 courses of weekly-paclitaxel, endocrine therapy, irradiation to the left chest wall, and irradiation to the residual right breast. The preoperative diagnosis was malignant phyllodes tumor. The postoperative diagnosis was switched from malignant phyllodes tumor to spindle-cell carcinoma. It was therefore difficult to determine the presence or absence of additional resection and postoperative treatment regimens. Even though the preoperative diagnosis was a malignant phyllodes tumor, surgical procedures such as sentinel lymph-node biopsy should be considered, taking into account the possibility of breast cancer.

[A Case Report of Triple Negative Breast Cancer Diagnosed as Granulomatous Mastitis].

Granulomatous mastitis is a chronic inflammatory disease of unknown causes that forms a breast mass and may be difficult to distinguish from breast cancer on imaging studies. The patient was a woman in her 50's. Needle biopsy was performed for a mass in the upper outer quadrant of the right breast and revealed granulomatous mastitis. Breast magnetic resonance imaging showed that the tumor was malignant. Taking into account that there is a difference between histologic findings and imaging findings and that surgery after steroid therapy for granulomatous mastitis is more likely to cause complications, we decided to perform lumpectomy. The definitive pathological diagnosis was a triple negative, pT1cN0cM0 medullary carcinoma. Postoperative adjuvant chemotherapy was performed. The absence of axillary lymph-node metastasis was confirmed by right axillary sentinel lymph-node biopsy. Radiotherapy was performed on the preserved breast region. Even if granulomatous mastitis is diagnosed, biopsy should be repeated while paying attention to biopsy methods if there is a difference between pathological findings and image findings.

[A Patient with Breast Cancer Who Achieved Continued Clinical Complete Response after Systemic Therapy Alone].

A 53-year-old woman presented at our hospital because of a mass in the left breast. A mass measuring 2 cm in diameter was palpated in the upper outer region(C region)of the left breast. Mammography showed a mass with calcification. Mammary ultrasonography showed a mass measuring 18×16×14mm and enlarged lymph nodes in the left axillary region. Core needle biopsy revealed Luminal B invasive ductal carcinoma(scirrhous type). The estrogen receptor(ER)positivity was 95%, progesterone receptor(PgR)positivity was 60%, human epidermal growth factor receptor type 2(HER2)score was 2+, fluorescence in situ hybridization(FISH)showed no amplification, and Ki-67 index was 60%. Clinical T1N1M0, StageⅡA cancer was thus diagnosed. As preoperative chemotherapy, the patient received 4 courses of treatment containing epirubicin (100mg/m2), 5-fluorouracil(500mg/m2), and cyclophosphamide(500mg/m2; FEC100), and 4 courses of treatment containing docetaxel and cyclophosphamide(TC). Clinical complete response(cCR)was confirmed on imaging studies. The patient was explained about the need for surgery, but she refused to undergo surgery. The patient is being followed up while receiving endocrine therapy, and there has been no recurrence or metastasis as of 2 years. We described our encounter with a patient with breast cancer who refused surgery after preoperative chemotherapy and has had no recurrence or metastasis during follow-up.

[A Case Report of Breast Cancer Followed Up as Intraductal Papilloma].

The patient was a 50-year-old woman. She had been diagnosed with bilateral breast tumors at another hospital 5 years previously and was followed up every 2 months. Ultrasonography showed hypoechoic masses in her breasts. The largest tumor in the right breast was 15mm in diameter and located in region A, while that in the left breast was 8mm in diameter and located in region B. Magnetic resonance imaging(MRI)showed multiple bilateral breast tumors. The largest tumor was 12mm in diameter and was suggestive of breast cancer. Core needle biopsies(CNB)of the largest tumors in both breasts were performed. Intraductal papilloma(IDP)and low-grade intraductal papillary carcinoma were diagnosed in the right and left breasts, respectively, on immunohistochemical staining. We performed left nipple-sparing mastectomy with sentinel lymph node biopsy and right tumor excision for diagnoses of carcinoma of the left breast(cTisN0M0)and IDP of the right breast. The histopathological diagnosis of the left breast tumor was pT1aN0M0, triple negative breast cancer with extensive intraductal components, and that of the right breast tumor was IDP with atypical ductal hyperplasia. Chemotherapy was administered postoperatively. Several studies have reported that peripheral IDP often coexists with or follows the development of carcinoma. Therefore, we should also closely follow-upthe patient's right breast.

Detection of white head symptoms of panicle blast caused by Pyricularia oryzae using cut-flower dye.

BACKGROUND: Breeding of rice with panicle resistance to rice blast disease caused by Pyricularia oryzae is a challenge towards sustainable rice production. Methods for accurate estimation of disease severity can support breeding. White head symptoms are a commonly used index of panicle blast in the field. As the development mechanism of this symptom remains unclear, we used cut-flower dye (CFD) solution to visualize the infected panicle tissues. RESULTS: CFD delineated the edge of white head symptoms in rice panicles artificially infected with P. oryzae. Hyphae within the tissues were confirmed through staining with a fluorescent wheat germ agglutinin conjugate. Hyphal density was obviously diminished at the dye edge. Growing hyphae preferred to move along the vascular bundles; infected tissues lost the ability to transport water, leading to white head formation. By marking the edge of the white heads, this simple dyeing technique precisely reveals the extent of infection. Further, digital imaging allowed dried samples to be stored and reassessed later. CONCLUSIONS: The CFD detection technique served as a powerful tool for estimating disease severity by color, as it clearly revealed lesions in both the panicles and leaves. Combined with reliable methods for artificial inoculation and observation of infecting hyphae, this technique will advance the research and breeding of panicle blast-resistant rice.

Protein engineering of CYP105s for their industrial uses.

Cytochrome P450 enzymes belonging to the CYP105 family are predominantly found in bacteria belonging to the phylum Actinobacteria and the order Actinomycetales. In this review, we focused on the protein engineering of P450s belonging to the CYP105 family for industrial use. Two Arg substitutions to Ala of CYP105A1 enhanced its vitamin D3 25- and 1α-hydroxylation activities by 400 and 100-fold, respectively. The coupling efficiency between product formation and NADPH oxidation was largely improved by the R84A mutation. The quintuple mutant Q87W/T115A/H132L/R194W/G294D of CYP105AB3 showed a 20-fold higher activity than the wild-type enzyme. Amino acids at positions 87 and 191 were located at the substrate entrance channel, and that at position 294 was located close to the heme group. Semi-rational engineering of CYP105A3 selected the best performing mutant, T85F/T119S/V194N/N363Y, for producing pravastatin. The T119S and N363Y mutations synergistically had remarkable effects on the interaction between CYP105A3 and putidaredoxin. Although wild-type CYP105AS1 hydroxylated compactin to 6-epi-pravastatin, the quintuple mutant I95T/Q127R/A180V/L236I/A265N converted almost all compactin to pravastatin. Five amino acid substitutions by two rounds of mutagenesis almost completely changed the stereo-selectivity of CYP105AS1. These results strongly suggest that the protein engineering of CYP105 enzymes greatly increase their industrial utility. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.

Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3ß inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3ß. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3ß respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3ß with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.

[Which Should be Treated First - Breast Cancer or Uterine Myoma?]

The patient was a 51-year-old woman with a mass in the left breast.At the first presentation, she had abdominal distension and liver dysfunction.Mammography showed a category 5 mass in the left breast and a category 4, unstructured region in the right breast.Pathological examination revealed bilateral, invasive ductal carcinomas.Stage II B disease(clinical T2N1M0)was diagnosed in the left breast, and Stage I disease(clinical T1N0M0)was diagnosed in the right breast.Computed tomography revealed a massive uterine myoma compressing the inferior vena cava.Liver dysfunction was suspected to be caused by these factors.Preoperative chemotherapy was scheduled to treat breast cancer.A gynecologist stated that "uterine myoma is unlikely to cause liver dysfunction" and refused to perform a hysterectomy.However, we diligently negotiated with him to avoid chemotherapy-induced venous thrombosis and pulmonary infarction; eventually, a hysterectomy(3.6 kg)was performed. After surgery, liver function was normal.Subsequently, breast cancer could be safely and adequately treated.In patients who have benign disease, as well as malignant tumors, treatment of the malignant tumors is generally given the highest priority.However, there are cases when the treatment of benign disease has priority over the treatment of malignant tumors.It is therefore important to intensively discuss such cases with physicians from other departments.

[A Case Report of Ipsilateral Nipple Skin Recurrence].

We report our experience with a patient with breast cancer who showed recurrence in the nipple skin 5 years and 10 months after a breast-preserving surgery. The patient was a woman, and was 65-years old at the time of initial surgery. Breast-preserving surgery and axillary lymph-node dissection were performed for left breast cancer. Invasive ductal carcinoma of the breast(pT3N0M0)was triple-negative, and the patient postoperatively received adjuvant chemotherapy. Left breast pain developed 5 years and 6 months after surgery. Computed tomography showed no evidence of recurrence, and the symptoms resolved after treatment with non-steroidal anti-inflammatory drugs(NSAIDs). After 3 months, however, the left nipple had enlarged to about 1.5 cm, and the surrounding skin was red and painful. Treatment with NSAIDs was thus resumed. After 1 week, redness of the nipple skin and pain were improved. However, the nipple had enlarged to twice its normal size. Nipple skin biopsy was subsequently performed, and revealed adenocarcinoma invading the skin. Left axillary lymph-node metastasis was suspected, but there was no evidence of metastasis to other sites or recurrence. Conservative total mastectomy with axillary lymph-node dissection was thus performed. The histopathological diagnosis was the recurrence of invasive ductal carcinoma, arising mainly in the reticular layer of the dermis. Chemotherapy was administered postoperatively. There has been no evidence of recurrence as of 1 year after surgery.

Nucleotide substitutions in CD101, the human homolog of a diabetes susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes.

AIMS/INTRODUCTION: Although genome-wide association studies have identified more than 50 susceptibility genes for type 1 diabetes, low-frequency risk variants could remain unrecognized. The present study aimed to identify novel type 1 diabetes susceptibility genes by newly established methods. MATERIALS AND METHODS: We carried out whole-exome sequencing and genome-wide copy-number analysis for a Japanese family consisting of two patients with type 1 diabetes and three unaffected relatives. Further mutation screening was carried out for 127 sporadic cases. The functional consequences of identified substitutions were evaluated by in silico analyses and fluorescence-activated cell sorting of blood samples. RESULTS: Whole-exome sequencing and genome-wide copy-number analysis of familial cases showed co-segregation of the p.V863L substitution in CD101, the human homolog of an autoimmune diabetes gene in the non-obese diabetic mouse, with type 1 diabetes. Mutation screening of CD101 in 127 sporadic cases detected the p.V678L and p.T944R substitutions in two patients. The p.V863L, p.V678L and p.T944R substitutions were absent or extremely rare in the general population, and were assessed as 'probably/possibly damaging' by in silico analyses. CD101 expression on monocytes, granulocytes and myeloid dendritic cells of mutation-positive patients was weaker than that of control individuals. CONCLUSIONS: These results raise the possibility that CD101 is a susceptibility gene for type 1 diabetes.