Combined histological and DNA methylome profiling approaches may provide insights into the pathophysiology of ovarian endometriomas.

Purpose: To test the theory that invaginated ovarian surface epithelium and endometrial implants on the ovary form ovarian endometriomas. Methods: Adhesion sites of ovarian endometrioma on the peritoneum and consecutive ovarian endometrioma cyst wall, called non-adhesion sites, were histologically examined. DNA methylomes of the adhesion sites, non-adhesion sites, and blueberry spots were compared with those of ovary, endometrium, and peritoneum. Results: The non-adhesion sites showed an ovarian surface epithelium-like structure near the adhesion site, which continued to a columnar epithelium-like structure. Calretinin staining was strong in the ovarian surface epithelium-like structure but weak in the columnar epithelium-like structure. Estrogen receptors were absent in the ovarian surface epithelium-like structure, but present in the columnar epithelium-like structure. The adhesion sites had endometrial gland-like structures that expressed estrogen receptors. Analyses of DNA methylomes classified the non-adhesion sites and ovaries into the same group, suggesting that ovarian endometriomas originate from the ovarian surface epithelium. The adhesion sites, blueberry spots and peritoneum were classified in the same group, suggesting that the adhesion sites and blueberry spots originate from the peritoneum. Conclusions: The present results support the invagination theory. Ovarian endometriomas consist of invaginated ovarian surface epithelium with celomic metaplasia and endometrium implants on the peritoneum.

Clinicopathological Characteristics and Prognosis of Triple-Negative Apocrine Carcinoma: A Case-Control Study.

Background: With a prevalence of only 1% among all breast cancers in Japan, apocrine carcinoma (AC) is a rare type of breast cancer, and its clinicopathological characteristics remain unclear. The aim of this study was to evaluate the characteristics and prognosis of AC, in relation to the presence or absence of androgen receptor (AR). Methods: We conducted a retrospective multi-center case-control study (Yokohama Clinical Oncology Group (YCOG): YCOG1701 study) in Japan. A total of 53 patients were registered who were diagnosed with AC between 2000 and 2017 in YCOG-affiliated hospitals. Results: The median age of the patients was 67 (43 - 94) years, and the median observation time was 6.1 years. Among the 53 cases, 24 had triple-negative pure AC (TN-PAC; AR-positive), whereas 29 had other types of AC (other-AC; estrogen receptor-positive and/or human epidermal growth factor receptor 2-positive or AR-negative). Tumor size was smaller (1.4 vs. 2.1 cm, P = 0.024) and metastasis occurred in fewer nodes (12.5% vs. 37.9%, P = 0.036) in the TN-PAC group than in the other-AC group. The number of patients who were administered perioperative adjuvant chemotherapy did not significantly differ between the two groups (TN-PAC/other-AC = 50.0%/55.2%, P = 0.525); however, there was no recurrence in the TN-PAC group, compared to five cases with relapse in the other-AC group. Conclusions: AR-positive AC patients showed a favorable prognosis without adjuvant chemotherapy, even with the TN subtype. A clinical trial exploring the possibility of treatment de-escalation is anticipated.

Breast carcinoma with spontaneous regression after needle biopsy: a case report and literature review.

Background: Spontaneous regression (SR) of cancer is a rare condition in which the cancer partially or completely disappears without treatment. We report a case of breast cancer with tumor regression and spontaneously induced T-cell-mediated immunological responses in a surgical specimen obtained after core needle biopsy (CNB). Case Description: A 52-year-old woman presented with a mass in the right breast. Mammography showed a high-density mass with fine serrated margins in the right lower outer quadrant. Breast ultrasonography showed an irregular hypoechoic mass with a maximum diameter of 22 mm. CNB was performed and revealed an invasive ductal carcinoma with negative estrogen receptors, positive progesterone receptors, and negative HER2 (1+). The Ki67 index was 70% to 80%. Luminal B cT2N1M0 stage IIB right breast cancer was diagnosed. Although preoperative chemotherapy was considered, surgery was selected because of her history of schizophrenia. She underwent right mastectomy and axillary lymph node dissection. A postoperative pathological analysis revealed a 20 mm × 10 mm × 10 mm mass. However, most areas of the mass regressed and appeared as necrotic tissue with no obvious invasive areas. Only intraductal extension was observed in one glandular duct. Axillary lymph node metastases were not observed. These results suggest that the tumor may have spontaneously regressed, possibly because of the CNB procedure. Follow-up without treatment was performed, and no recurrence occurred during 2 years after surgery. Conclusions: Invasive ductal carcinoma may spontaneously regress after preoperative CNB.

Text mining in a literature review of abnormal uterine bleeding according to the FIGO classification.

AIM: Abnormal uterine bleeding, as proposed in 2007, is defined as unexpected uterine bleeding in women of reproductive age; the cause of the bleeding is categorized using the PALM-COEIN system. Identifying the diagnostic and treatment modalities for each cause might be intriguing. To summarize the options for abnormal uterine bleeding assessment, we employed text-mining analysis for each of its causes. METHODS: We analyzed abstracts based on PALM-COEIN from PubMed and Web of Science in March 2022. The literature was divided into categories; topics about the disorders were retrieved, and covalent network analysis was conducted to find information for evaluating abnormal uterine bleeding. RESULTS: Diagnostic approaches for PALM included histological and image analysis, including computerized tomography, magnetic resonance imaging, sonography, and hysteroscopy. The therapeutic approaches varied according to the cause. Diagnostic approaches for COEIN were mostly medical history interviews and blood sampling, and the therapeutic approaches for COEIN were ablation, hysteroscopy, and hormonal treatment. The PALM-COEIN classification co-occurrence search revealed each cause's diagnostic procedures, symptoms, and treatment procedures. CONCLUSION: Our text-mining methodology revealed comprehensive insights, important study themes, and clinical trends for abnormal uterine bleeding. A tailored approach to medical realities is required for treating abnormal uterine bleeding properly.

Real-world outcomes of the levonorgestrel-releasing intrauterine system for heavy menstrual bleeding or dysmenorrhea in Japanese patients: A prospective observational study (J-MIRAI).

OBJECTIVES: We collected real-world data on the safety and clinical outcomes of the levonorgestrel-releasing intrauterine system (LNG-IUS) for heavy menstrual bleeding and dysmenorrhea. STUDY DESIGN: This was a prospective, multicenter, single-cohort, open-label, post-authorization 12-month follow-up study of Japanese patients initiating the LNG-IUS for heavy menstrual bleeding and/or dysmenorrhea. The primary endpoint was the safety profile based on adverse events and adverse drug reactions (ADRs), including expulsions and abnormal bleeding, within 12 months of LNG-IUS insertion. Secondary endpoints included changes from baseline in menstrual blood loss based on bleeding days and dysmenorrhea graded on a visual analog scale (VAS). RESULTS: Of the 595 patients included, many had underlying conditions such as adenomyosis (39.5%), uterine leiomyoma (30.8%), or endometriosis (12.9%). The incidences of ADRs and serious ADRs were 59.7% and 0.3%, respectively. Frequently reported ADRs were metrorrhagia (48.9%), procedural pain (14.1%), and ovarian cyst (6.2%). The cumulative incidence of expulsions at 12 months was 8.7%. Risk factors for expulsion were obesity (body mass index ≥25 kg/m2), adenomyosis, and uterine cavity length ≥8 cm. The median [interquartile range] VAS score for dysmenorrhea improved from 46.5 [13.0-68.0] at insertion to 1.0 [0.0-13.0] at 12 months, and improvements were also observed in chronic pelvic pain and painful defecation. CONCLUSIONS: The LNG-IUS safely and effectively reduced dysmenorrhea, chronic pelvic pain, and painful defecation. Risk factors for expulsion suggest that patients with underlying organic disease should be monitored carefully when using the LNG-IUS. IMPLICATIONS: The LNG-IUS is an effective treatment for secondary dysmenorrhea with organic disease, and for the reduction of chronic pelvic pain; however, physicians should be aware of the increased risk of expulsion in patients with organic conditions.

Bleeding patterns of women with heavy menstrual bleeding or dysmenorrhoea using the levonorgestrel-releasing intrauterine system: results from a real-world observational study in Japan (J-MIRAI).

PURPOSE: To collect real-world safety and clinical outcome data on the levonorgestrel-releasing intrauterine system (LNG-IUS) for functional/organic heavy menstrual bleeding (HMB) and dysmenorrhoea in Japanese women (J-MIRAI). MATERIALS AND METHODS: In this prospective, multicentre, single-cohort, open-label, post-authorisation study, we assessed menstrual blood loss after LNG-IUS insertion by changes from baseline in pictorial blood loss assessment chart (PBAC) scores. Scores for the menorrhagia multi-attribute scale (MMAS) were collected for 12 months to assess quality of life. RESULTS: We included 47 patients with complete PBAC score and patient diary data. The median PBAC score before LNG-IUS insertion was 159.0, which decreased significantly to 6.0 at 12 months post-insertion; for patients with adenomyosis (n = 20), PBAC score decreased from 174.5 pre-insertion to 19.5 at 12 months. The number of patient-reported bleeding days was correlated with PBAC score ≥5. The proportion of women with prolonged bleeding decreased from 85.7% to 34.6% by the study's end. Some women reported no bleeding after the first 90-day reference period. The mean MMAS overall score significantly increased from 50.50 before insertion to 88.67 at 12 months. CONCLUSIONS: Japanese women with functional/organic HMB experienced substantial reductions in bleeding symptoms and improvements in quality of life after 12-month use of the LNG-IUS.

A controlled clinical trial comparing potent progestins, LNG-IUS and dienogest, for the treatment of women with adenomyosis.

PURPOSE: To evaluate the efficacy of two progestins, levonorgestrel intrauterine system (LNG-IUS) and dienogest (DNG), for adenomyosis. METHODS: This study enrolled 157 women with adenomyosis, randomized to either LNG-IUS (n = 76) or DNG (n = 81) groups as a controlled clinical trial for 72 months. Participants were classified by three different localizations of adenomyosis: diffuse, focal, and extrinsic. VAS (Visual analog scale) score, days, and amount of uterine bleeding were assessed. Uterine volume or bone mineral density (BMD) were measured by three-dimensional ultrasonography or dual-energy X-ray absorptiometry. RESULTS: LNG-IUS and DNG comparably reduced pain scores in patients with adenomyosis. With regard to pain control, DNG offered greater efficacy than LNG-IUS in 3 months of treatment. In all types of adenomyosis, the days of bleeding after 12 months with DNG were significantly decreased compared to those with LNG-IUS. The decrease of whole uterine body was transient in any subtypes. A comparable decrease in BMD due to age-related changes in both groups was observed. CONCLUSIONS: LNG-IUS and DNG could be useful for long-term management of adenomyosis. In terms of durations of uterine bleeding, DNG was superior to LNG-IUS for 6 years.

Primary endometrioid carcinoma of the uterosacral ligament arising from deep infiltrating endometriosis 6 years after bilateral salpingo-oophorectomy due to atypical proliferative endometrioid tumor of the ovary: a rare case report.

BACKGROUND: Endometriosis can potentially lead to the development of a malignant tumor. Most malignant tumors arising from the endometriosis originate from the ovarian endometrioma, whereas those arising from extragonadal lesions are rare. We report a rare case of endometrioid carcinoma that developed from deep infiltrating endometriosis in the uterosacral ligament 6 years after treatment for atypical proliferative endometrioid tumor of the ovary in a 48-year-old woman. CASE PRESENTATION: Six years ago, the patient underwent laparoscopic bilateral salpingo-oophorectomy for her right ovarian tumor with atypical proliferative (borderline) endometrioid tumor accompanied by ovarian endometrioma. The solid tumor in the cul-de-sac was detected during follow-up using magnetic resonance imaging. Positron emission tomography/computed tomography revealed an abnormal accumulation of 18F-fluorodeoxyglucose at the tumor site. Thus, tumor recurrence with borderline malignancy was suspected. The patient underwent diagnostic laparoscopy followed by hysterectomy and partial omentectomy. Retroperitoneal pelvic lymphadenectomy and para-aortic lymphadenectomy were also performed. The cul-de-sac tumor at the left uterosacral ligament was microscopically diagnosed as invasive endometrioid carcinoma arising from deep infiltrating endometriosis. The final diagnosis was primary stage IIB peritoneal carcinoma. The patient received six courses of monthly paclitaxel and carboplatin as adjuvant chemotherapy. The patient showed no evidence of recurrence for 2 years after the treatments. CONCLUSION: This study reports a rare case of metachronous endometriosis-related malignancy that developed 6 years after treatment for borderline ovarian tumor. If endometriosis lesions remain after bilateral salpingo-oophorectomy, the physician should keep the malignant nature of endometriosis in mind.

Cost-effectiveness of the recommended medical intervention for the treatment of dysmenorrhea and endometriosis in Japan.

BACKGROUND AND OBJECTIVE: This study aims to assess the cost-effectiveness of early physician consultation and guideline-based intervention to prevent endometriosis and/or disease progression using oral contraceptive (OC) and progestin compared to follow-up of self-care for dysmenorrhea in Japan. METHODS: A yearly-transmitted Markov model of five major health states with four sub-medical states was constructed. Transition probabilities among health and medical states were derived from Japanese epidemiological patient surveys and converted to appropriate parameters for inputting into the model. The dysmenorrhea and endometriosis-associated direct costs included inpatient, outpatient visit, surgery, and medication (OC agents, over-the-counter drugs), etc. The utility measure for patients with phase I-IV endometriosis comprised a visual analogue scale. We estimated the cost per quality-adjusted life year (QALY) at a time horizon of 23 years. An annual discount rate at 3% for both cost and outcome was considered. RESULTS: The base case outcomes indicated that the intervention would be more cost-effective than self-care, as the incremental cost-effectiveness ratio (ICER) yielded 115,000 JPY per QALY gained from the healthcare payers' perspective and the societal monetary value (SMV) was approximately positive 3,130,000 JPY, favoring the intervention in the cost-benefit estimate. A tornado diagram depicting the stochastic sensitivity analysis of the ICER and SMV from both the healthcare payers' and societal perspectives confirmed the robustness of the base case. A probabilistic analysis resulting from 10,000-time Monte Carlo simulations demonstrated efficiency at willingness-to-pay thresholds in more than 90% of the iterations. CONCLUSIONS: The present analysis demonstrated that early physician consultation and guideline-based intervention would be more cost-effective than self-care in preventing endometriosis and/or disease progression for patients with dysmenorrhea in Japan.

Laparoscopic surgery with urinary tract reconstruction and bowel endometriosis resection for deep infiltrating endometriosis.

Deep infiltrating endometriosis (DIE) is the most severe form of endometriosis. It causes chronic pelvic pain, severe dysmenorrhea, deep dyspareunia, dyschezia, and dysuria, markedly impairing the quality of life of women of reproductive age. A number of randomized controlled trials on surgical and medical treatments to reduce the pain associated with endometriosis have been reported, but few have focused on this in DIE. DIE causes not only pain but also functional invasion to the urinary organs and bowel, such as hydronephrosis and bowel stenosis. In addition to DIE resection, surgical treatment involves adhesion separation as well as resection and reconstruction of the urinary organs and bowel; high-level skills are required. The severity of DIE should be evaluated preoperatively as accurately as possible. Using ENZIAN in conjunction with the AFS (The revised American Fertility Society classification of endometriosis) classification makes a more detailed assessment of DIE possible. The operative procedures used for laparoscopic resection of urinary DIE and reconstruction of the urinary organs are chosen based on the type of lesion (intrinsic/extrinsic) and length of stenosis. In addition to ureteroneocystostomy, the psoas bladder hitch and Boari bladder flap procedures are applied when necessary to extend the urinary tract. Bowel resection for bowel endometriosis is classified into classic segmental resection and conservative approaches (shaving/discoid). When these procedures are employed, it is advisable to work in consultation with urologists and gastroenterologists and to inform the patients of the associated risks and outcomes. Furthermore, postoperative medication is essential because it is difficult to conduct repeated surgeries.

Effects of low dose oral contraceptive pill containing drospirenone/ethinylestradiol in patients with endometrioma.

OBJECTIVES: Low dose oral contraceptive pills (OCPs) that contain synthetic estrogen and progestin are often used to relieve chronic pelvic pain associated with endometriosis. We sought to evaluate the efficacy of drospirenone/ethinylestradiol (DRSP/EE) with low-dose estrogen in treating endometrioma. STUDY DESIGN: A prospective clinical study in six hospitals and one clinic in Japan was conducted. Forty-nine 23- to 45-year-old patients who suffered from endometriosis-associated dysmenorrhea were included in the study. The primary endpoint was the change in size of ovarian endometrioma as measured by transvaginal ultrasonography. The secondary endpoint was the change in dysmenorrhea as evaluated by VAS (visual analog scale) scores before treatment and at 3 and 6 cycles of treatment. In addition, serum CA125, anti-mullerian hormone (AMH), interleukin (IL)-6, and IL-8 were evaluated after 6 cycles of treatment. RESULTS: The maximum diameter and volume of the ovarian endometrioma significantly decreased after 3 and 6 cycles compared with pretreatment. VAS scores of dysmenorrhea pain were also reduced after 1, 3 and 6 cycles. A significant correlation between the reduced size of the endometrioma and the decline of VAS scores was found. The levels of serum CA125 and AMH concentration were decreased after 6 cycles. No significant changes were observed in serum IL-6 and IL-8. CONCLUSION: Low dose DRSP/EE therapy is a promising treatment not only to reduce the size of endometrioma but also for dysmenorrhea.

High expression of ATP-binding cassette transporter ABCC11 in breast tumors is associated with aggressive subtypes and low disease-free survival.

ATP-binding cassette (ABC) transporters are membrane proteins that efflux various compounds from cells, including chemotherapeutic agents, and are known to affect multidrug resistance. Recent reports disagree on whether ABCC11 is a risk factor for breast tumorigenesis, but its expression in breast cancer is poorly investigated. We hypothesized that both frequency and expression levels of ABC transporters in breast tumors would vary by cancer subtype, and be associated with prognosis. Here, we constructed a tissue microarray breast tumor samples from 281 patients, and analyzed expressions of ABCB1, ABCC1, ABCC11, and ABCG2 immunohistochemically. Breast cancer subtypes were determined by immunohistochemistry of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Protein expression was correlated to clinicopathological characteristics, clinical follow-up, and pathological complete response to neoadjuvant chemotherapy. The tissue microarray comprised 191 luminal A (68.0 %), 17 luminal B (6.0 %), 27 HER2 (9.6 %), and 46 triple-negative (16.4 %) samples. ABCC1 and ABCC11 expressions were associated with significantly shorter disease-free survival (P = 0.027 and P = 0.003, respectively). ABCC1, ABCC11, and ABCG2, but not ABCB1, were expressed significantly more, and more frequently, in aggressive subtypes. Patients with HER2+ and triple-negative tumor subtypes that expressed high levels of ABCC11 had significantly worse disease-free survival (P = 0.017 and P < 0.001, respectively). We have shown, for the first time, that ABCC1, ABCC11, and ABCG2 are highly expressed in aggressive breast cancer subtypes, and that tumor ABCC11 expression is associated with poor prognosis.

Breast cancer manifested by hematologic disorders.

Breast cancer is the most common type of cancer in women. However, it is very rarely manifested as hematologic disorders. A 35-year-old woman was admitted because of disseminated intravascular coagulation. Examinations revealed the presence of breast cancer in her left breast; therefore, paclitaxel was administered weekly. Although disseminated intravascular coagulation was controlled, pulmonary dysfunction due to lymphangitis carcinomatosa suddenly occurred 10 weeks after treatment. Pulmonary dysfunction was effectively treated with epirubicin and cyclophosphamide. Twenty-three weeks after treatment, the patient developed liver dysfunction accompanied with jaundice due to progressive metastatic lesions in the liver; liver dysfunction improved after the administration of vinorelbine. Subsequently, because of the recurrence of pulmonary dysfunction, rechallenge with epirubicin and cyclophosphamide was performed and was effective; however, this therapy was discontinued because of its adverse effects. She expired of liver failure 33 weeks after the occurrence of disseminated intravascular coagulation. Metastatic tumors in the bone marrow, lung, and liver showed different sensitivities to different anti-cancer agents. We report a case of breast cancer manifested by hematologic disorders which was treated by a sequential chemotherapy.

Association between breast cancer risk and the wild-type allele of human ABC transporter ABCC11.

BACKGROUND: International mortality and frequency rates for breast cancer have been associated with the wet type of human earwax. It was recently found that earwax type is determined by a single nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in ABCC11. The G allele determines the wet type of earwax as a Mendelian trait with a dominant phenotype. The present study examined the association between the frequency rate of breast cancer and the frequency of the G allele of ABCC11. PATIENTS AND METHODS: Using blood samples from patients with invasive breast cancer (n = 270) and control volunteers (n = 273), the 538G>A SNP in ABCC11 was genotyped using the SmartAmp method. RESULTS: The frequency of the G allele in breast cancer patients was higher than that in healthy controls. The odds ratio for the genotypes (G/G+G/A) to develop breast cancer was estimated to be 1.63 (p-value = 0.026), suggesting that the G allele in ABCC11 is associated with breast cancer risk. CONCLUSION: This study showed that Japanese women with wet earwax have a higher relative risk of developing breast cancer than those with dry earwax. The ABCC11 SNPs that determine these phenotypes should be further investigated in order to obtain insights into the mechanisms by which breast cancer develops and progresses.

A human epidermal growth factor receptor 2 expression-based approach to neoadjuvant chemotherapy for operable breast cancer.

OBJECTIVE: We investigated the pathological effects of neoadjuvant chemotherapy based on the human epidermal growth factor receptor 2 in operable breast cancer. METHODS: This prospective clinical study was a pilot involving 63 female patients. Before surgery, patients with tumors overexpressing human epidermal growth factor receptor 2 received four cycles of 60 mg/m(2) anthracycline and 600 mg/m(2) cyclophosphamide every 3 weeks, whereas those whose tumors did not overexpress human epidermal growth factor receptor 2 received four cycles of 75 mg/m(2) docetaxel and 600 mg/m(2) cyclophosphamide every 3 weeks. A quasi-pathological complete response (i.e. absence of invasive tumor or only focal residual tumor cells) was the primary endpoint, with compliance and predictors for each regimen as secondary endpoints. If a quasi-pathological complete response was not achieved, then crossover to the alternative treatment was recommended. RESULTS: The quasi-pathological complete response rate was 36.5% (23 of 63) overall, 27.8% (5 of 18) for the anthracycline and cyclophosphamide regimen and 40.0% (18 of 45) for the docetaxel and cyclophosphamide regimen. Docetaxel and cyclophosphamide treatment induced a quasi-pathological complete response in most patients with triple-negative tumors (15 of 19). The relative dose intensity was 97.3% for the anthracycline and cyclophosphamide regimen and 96.6% for the docetaxel and cyclophosphamide regimen. Quasi-pathological complete response to the docetaxel and cyclophosphamide regimen was associated with low estrogen receptor and progesterone receptor expression and high MIB-1 and topoisomerase IIalpha expression, in univariate analyses, but only with low estrogen receptor expression in multivariate analysis. CONCLUSIONS: Selecting neoadjuvant chemotherapy regimens on the basis of individual human epidermal growth factor receptor 2 status improved efficacy, with docetaxel and cyclophosphamide treatment showing particular promise in tumors with the potential to be highly malignant.

The topoisomerase II alpha gene status in primary breast cancer is a predictive marker of the response to anthracycline-based neoadjuvant chemotherapy.

This study aimed at evaluating the usefulness of topoisomerase II alpha (TOP2A) for predicting the effect of anthracycline-based neoadjuvant chemotherapy in breast cancer. The TOP2A status was examined using fluorescent in situ hybridization (FISH) in 14 pre-chemotherapeutic breast cancer tissues, and was also assessed by immunohistochemistry (IHC) in 14 pairs of pre- and post-chemotherapeutic breast cancer specimens. TOP2A gene aberration by IHC tended to show a correlation with pathological responses but this was not statistically significant (p=0.060). On the other hand, the low TOP2A/CEP17 ratio correlated with good pathological responses (p=0.012). TOP2A overexpression was not significantly associated with response (p=0.580). Our results thus suggest that the TOP2A/CEP17 ratio may be a useful predictor of the effects of anthracycline-based neoadjuvant chemotherapy in breast cancer.

Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type?

One single-nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in the ABCC11 gene determines the type of earwax. The G/G and G/A genotypes correspond to the wet type of earwax, whereas A/A corresponds to the dry type. Wide ethnic differences exist in the frequencies of those alleles, reflecting global migratory waves of the ancestors of humankind. We herein provide the evidence that this genetic polymorphism has an effect on the N-linked glycosylation of ABCC11, intracellular sorting, and proteasomal degradation of the variant protein. Immunohistochemical studies with cerumen gland-containing tissue specimens revealed that the ABCC11 WT protein was localized in intracellular granules and large vacuoles, as well as at the luminal membrane of secretory cells in the cerumen gland, whereas granular or vacuolar localization was not detected for the SNP (Arg180) variant. This SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum and readily undergoes ubiquitination and proteasomal degradation, which determines the dry type of earwax as a mendelian trait with a recessive phenotype. For rapid genetic diagnosis of axillary osmidrosis and potential risk of breast cancer, we developed specific primers for the SmartAmp method that enabled us to clinically genotype the ABCC11 gene within 30 min.

A case of lymphoepithelioma-like carcinoma of the colon with ulcerative colitis.

Follow-up colonoscopy of a 25-year-old Japanese man with ulcerative colitis (UC) who had undergone endoscopic mucosal resection twice for early colon cancers revealed the presence of a new 1.5-cm-diameter tumor in the sigmoid colon. It was diagnosed by preoperative biopsy as a poorly differentiated adenocarcinoma. Sigmoidectomy was performed, and the pathological findings revealed lymphoepithelioma-like carcinoma (LEC). In situ hybridization to detect Epstein-Barr virus (EBV)-encoded small RNAs showed positive signals in stromal lymphocytes, but weak signals in the tumor cells. The association between EBV and LEC was obscure in this case. Unlike typical UC-mediated colon cancers, the lesion was poorly differentiated, and negative for p53 signals immunohistochemically. These findings may hint at a novel mechanism of carcinogenesis in UC-mediated colorectal cancer.

Determination of trace levels of iron in a seawater sample using isotope dilution/inductively coupled plasma mass spectrometry.

An analytical method for trace levels of iron in a seawater sample using isotope dilution ICP-MS was developed. Preconcentration of iron and the removal of major elements in seawater such as alkali and alkaline-earth elements can be carried out quickly using a chelating resin disk by adjusting the sample pH to 3. The collision cell option of the ICP-MS instrument method was used to improve the performance of the instrument for iron measurements since ArO and ArN interferences could be reduced using this analytical method. About 4 ml min(-1) helium, as the collision gas, were introduced into the cell. 40Ar14N and 40Ar16O which interfere with 54Fe and 56Fe in water had their amounts decreased by 5 orders of magnitude. Then, the isotope dilution method was used for iron determination below ng g(-1) level of trace iron in four environmental reference materials (river water standard sample JAC-0031 (Japan Soc. for Analytical Chemistry), estuarine standard sample SLEW-2 (NRC Canada) and seawater standard samples CASS-3 and NASS-5 (NRC Canada)) were measured. Good agreement between analytical results and certified values of reference materials was obtained, which confirmed the effectiveness of this method.