Epithelial ovarian cancer survival by race and ethnicity in an equal-access healthcare population.

BACKGROUND: Previous studies in the general population observed that compared with non-Hispanic White women, Pacific Islander and Black women have higher age-adjusted mortality rates from epithelial ovarian cancer (EOC), while Asian American patients have lower mortality. We investigated whether race and ethnicity is associated with differences in EOC survival in a United States Military population where patients have equal access to healthcare. METHODS: This retrospective study included women diagnosed with EOC between 2001 and 2018 among Department of Defense beneficiaries. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models adjusting for age and year of diagnosis, histology and stage. RESULTS: In our study population of 1230 invasive EOC cases (558 non-Hispanic White, 74 non-Hispanic Black, 73 Asian, 30 Pacific Islander and 36 Hispanic cases), 63% of the women died (all-cause death) after a mean = 4.8 years (SD = 4.1) of follow-up following diagnosis. Compared with non-Hispanic White cases, Asian cases had better overall survival, HR = 0.76 (95% CI = 0.58-0.98), whereas there were no differences in survival for other racial and ethnic groups. CONCLUSIONS: These findings highlight the need to investigate how differences in access to healthcare may influence observed racial and ethnic disparities for EOC.

Racial and ethnic differences in tumor characteristics among endometrial cancer patients in an equal-access healthcare population.

PURPOSE: There are racial and ethnic differences in endometrial cancer incidence and mortality rates; compared with Non-Hispanic White women, Black women have a similar incidence rate for endometrial cancer, but their mortality is higher. Pacific Islander women may also have worse outcomes compared to their White counterparts. We assessed tumor characteristics and adjuvant therapy by racial and ethnic group among endometrial cancer patients treated within the Military Health System, an equal access healthcare organization. METHODS: We retrospectively identified women diagnosed with invasive endometrial cancer among US Department of Defense beneficiaries reported in the Automated Central Tumor Registry database (year of diagnosis: 2001-2018). We compared tumor characteristics and receipt of adjuvant therapy across racial and ethnic groups using Chi-square or Fisher tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of all cause mortality were calculated using Cox proportional hazards regression models adjusting for age at diagnosis, adjuvant therapy, histology and stage. RESULTS: The study included 2574 endometrial cancer patients [1729 Non-Hispanic White, 318 Asian, 286 Black, 140 Pacific Islander and 101 Hispanic women]. Among all cases, a higher proportion of Black patients had non-endometrioid histology (46.5% versus ≤ 29.3% in other groups, P < 0.01) and grade 3-4 tumors (40.1% versus ≤ 29.3% in other groups, P < 0.01). In multivariable Cox models, compared with Non-Hispanic White cases, Black endometrial cancer patients had a higher mortality risk (HR 1.43, 95% CI, 1.13-1.83). There was no difference in mortality risk for other racial and ethnic groups. CONCLUSION: Black patients with endometrial cancer presented with more aggressive tumor features and they had worse overall survival compared with patients in other racial and ethnic groups. Further study is needed to better direct preventive and therapeutic efforts in order to correct endometrial cancer disparities in the future.

Two Cases of Mesonephric-like Carcinoma Arising From Endometriosis: Case Report and Review of the Literature.

Endometriosis is a common condition in reproductive age women that is defined as the presence of endometrial tissue (epithelial and/or stromal) outside the uterine corpus. While not a premalignant lesion, it is a condition with a potential for malignancy, especially in the ovaries. Notable endometriosis-associated neoplasms include clear cell carcinoma and endometrioid adenocarcinoma of the ovaries. There have been recent reports of mesonephric-like adenocarcinoma (MLA) of the ovary, a very rare neoplasm with similar morphologic and immunophenotypic characteristics as mesonephric adenocarcinoma, however, without an association with mesonephric remnants. Some of these cases have been associated with endometriosis. Here, we describe 2 cases of MLA arising directly from endometriosis. In both cases, there was evidence of endometriosis contiguous with the tumor and invasion from other sources was excluded. The immunophenotypes of both tumors were typical of mesonephric adenocarcinoma except PAX-8 was strongly positive suggesting a Mullerian origin. Molecular testing on one of the cases revealed KRAS and P53 mutations. We review published findings of MLA and associated endometriosis. This report describes the sixth and seventh reported cases of MLA associated with endometriosis and the first reported cases of MLA arising directly from endometriosis and associated with other forms of epithelial proliferation within endometriosis. These 2 cases provide potential evidence that MLA should be considered an endometriosis-associated neoplasms.

Racial/Ethnic Differences Among Tumor-Infiltrating Lymphocytes in Breast Cancer Tumors.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have emerged as a predictor of breast cancer treatment response and patient outcomes. Current studies investigating racial/ethnic differences in TILs and immune profiles in breast cancer offer varying results. Our study provides some preliminary data in the breast cancer tumor microenvironment where there is a paucity of information, from Asian and Native Hawaiian/Pacific Islander (NHPI) racial/ethnic groups, not well represented in the literature. METHODS: We reviewed 183 cases of women diagnosed with early stage breast cancer who received neoadjuvant treatment at 2 large health systems in Hawaii between 2008 and 2020. We evaluated clinical and demographic information including: age at diagnosis, self-reported race/ethnicity, tumor stage, tumor subtype according to ER, PR, and HER2 receptor status, the amount of TILs and pathologic complete response (pCR). RESULTS: We found a significantly greater amount of TILs in Asians (37.7%, P = .01) and NHPI (37.2%, P = .02) patients compared to White patients on multivariate analysis. We found no significant differences in pCR among the different racial/ethnic groups. CONCLUSIONS: Racial/ethnic differences in the amount of TILs in breast cancer tumors may suggest differences in the breast tumor microenvironment. This may in part contribute to known outcome disparities in these populations and should be further evaluated.

Racial and Ethnic Disparities in Rates of Invasive Second Breast Cancer Among Women With Ductal Carcinoma In Situ in Hawai'i.

Importance: Women with ductal carcinoma in situ (DCIS) may develop a subsequent invasive second breast cancer (SBC). Understanding the association of racial and ethnic factors with the development of invasive SBC may help reduce overtreatment and undertreatment of women from minority groups. Objective: To evaluate risk factors associated with developing invasive ipsilateral SBC (iiSBC) and invasive contralateral SBC (icSBC) among women with an initial diagnosis of DCIS who are from racial and ethnic minority populations. Design, Setting, and Participants: This retrospective cohort study used deidentified data from the Hawai'i Tumor Registry of 6221 female Hawai'i residents aged 20 years or older who received a diagnosis of DCIS between January 1, 1973, and December 31, 2017. The 5 most populous ethnic groups were compared (Chinese, Filipino, Japanese, Native Hawaiian, and White). Data analysis was performed from 2020 to 2021. Exposures: Patient demographic and clinical characteristics and the first course of treatment. Main Outcome and Measures: The a priori study outcome was the development of invasive SBC. Logistic regression was used to identify factors associated with invasive SBC. Factors that were significant on unadjusted analyses were included in the adjusted models (ie, age, race and ethnicity, diagnosis year, DCIS histologic characteristics, laterality, hormone status, and treatment). Results: The racial and ethnic distribution of patients with DCIS across the state's most populous groups were 2270 Japanese women (37%), 1411 White women (23%), 840 Filipino women (14%), 821 Native Hawaiian women (13%), and 491 Chinese women (8%). Women of other minority race and ethnicity collectively comprised 6% of cases (n = 388). A total of 6221 women (age range, 20 to ≥80 years) were included in the study; 4817 (77%) were 50 years of age or older, 4452 (72%) received a diagnosis between 2000 and 2017, 2581 (42%) had well or moderately differentiated histologic characteristics, 2383 (38%) had noninfiltrating intraductal DCIS, and 2011 (32%) were treated with mastectomy only. Of these 6221 women, 444 (7%) developed invasive SBC; 190 developed iiSBC (median time to SBC diagnosis, 7.8 years [range, 0.5-30 years]) and 254 developed icSBC (median time to SBC diagnosis, 5.9 years [range, 0.5-28.8 years]). On adjusted analysis, women who developed iiSBC were more likely to be younger than 50 years (adjusted odds ratio [aOR], 1.49; 95% CI, 1.08-2.06), Native Hawaiian (aOR, 3.28; 95% CI, 2.01-5.35), Filipino (aOR, 1.94; 95% CI, 1.11-3.42), Japanese (aOR, 1.58; 95% CI, 1.01-2.48), and untreated (aOR, 2.29; 95% CI, 1.09-4.80). Compared with breast-conserving surgery (BCS) alone, there was a decreased likelihood of iiSBC among women receiving BCS and radiotherapy (aOR, 0.45; 95% CI, 0.27-0.75), BCS and systemic treatment with or without radiotherapy (aOR, 0.40; 95% CI, 0.23-0.69), mastectomy only (aOR, 0.23; 95% CI, 0.13-0.39), and mastectomy and systemic treatment (aOR, 0.57; 95% CI, 0.33-0.96). Women who developed an icSBC were more likely to be Native Hawaiian (aOR, 1.69; 95% CI, 1.10-2.61) or Filipino (aOR, 1.70; 95% CI, 1.10-2.63). Risk of both iiSBC and icSBC decreased in the later years of diagnosis (2000-2017) compared with the earlier years (1973-1999). Conclusions and Relevance: This study suggests that Native Hawaiian and Filipino women who initially received a diagnosis of DCIS were more likely to subsequently develop both iiSBC and icSBC. Japanese women and younger women were more likely to develop iiSBC. Subpopulation disaggregation may help guide clinical treatment and screening decisions for at-risk subpopulations.

Racial/ethnic differences in anthropometric and hormone-related factors and endometrial cancer risk: the Multiethnic Cohort Study.

BACKGROUND: Anthropometric and hormone-related factors are established endometrial cancer risk factors; however, little is known about the impact of these factors on endometrial cancer risk in non-White women. METHODS: Among 110,712 women participating in the Multiethnic Cohort (MEC) Study, 1150 incident invasive endometrial cancers were diagnosed. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with endometrial cancer risk for race/ethnicity and for risk factors across racial/ethnic groups were calculated. RESULTS: Having a higher body mass index (BMI) at baseline or age 21 years was strongly associated with increased risk (pint race/ethnicity ≥ 0.36). Parity (vs nulliparity) was inversely associated with risk in all the groups except African Americans (pint 0.006). Current use of postmenopausal hormones at baseline (PMH-E; vs never use) was associated with increased risk in Whites and Japanese Americans (pint 0.002). Relative to Whites, endometrial cancer risk was lower in Japanese Americans and Latinas and non-significantly higher in Native Hawaiians. Risk in African Americans did not differ from that in Whites. CONCLUSIONS: Racial/ethnic differences in endometrial cancer risk were not fully explained by anthropometric or hormone-related risk factors. Further studies are needed to identify reasons for the observed racial/ethnic differences in endometrial cancer risk.

A fight-and-flight for life: A rare case of advanced cervical cancer in pregnancy.

BACKGROUND: Advanced cervical cancer during pregnancy is an extremely rare event. We describe a case of at least stage IIIB cervical squamous cell carcinoma during pregnancy. This may possibly represent the longest gestation from time of diagnosis to delivery in a case of advanced cervical cancer, with potentially the most advanced gestational age at delivery and a relatively favorable outcome in the current literature.Case: A 29-year-old female at 20 0/7 weeks of gestation with at least stage IIIB squamous cell carcinoma of the cervix flew from Micronesia to Hawaii for oncologic treatment. After consultation with gynecologic oncology and maternal-fetal medicine, she opted to continue the pregnancy and began neoadjuvant chemotherapy with carboplatin and paclitaxel. At 33 2/7 weeks of gestation, she was admitted for preterm prelabor rupture of membranes and immediately underwent a cesarean delivery for heavy vaginal bleeding. Postpartum, she underwent cisplatin chemotherapy with concurrent radiation therapy. After 6 cycles of chemotherapy, the patient's cancer had progressed to the point that hospice was recommended. She died 11 months after initial presentation. CONCLUSION: Advanced cervical cancer during pregnancy requires individualized treatment, shared decision making, and a multidisciplinary team approach. If the pregnancy is continued, antepartum chemotherapy should be strongly considered. Maternal prognoses tend to be poor, but neonatal outcomes appear to be favorable.

Completeness of salpingectomy intended for ovarian cancer risk reduction.

BACKGROUND: Prophylactic salpingectomy has been heavily promoted based on the theory that serous tubal intraepithelial carcinoma is a precursor lesion for serous ovarian carcinoma. However, the validity of prophylactic salpingectomy has yet to be proven through adequate research. The purpose of this study is to evaluate the completeness of salpingectomy intended for ovarian cancer risk reduction. MATERIALS AND METHODS: Women without a history of ovarian cancer who were undergoing salpingoophorectomy at a single institution in Honolulu, Hawaii were enrolled in this study. Salpingectomy was performed prior to oophorectomy. A blinded pathologist then examined the ovaries for the presence of residual salpingeal tissue. Data collected included type of surgery (minimally invasive or laparotomy) and level of surgeon (attending or resident). Data were analyzed using Fisher's exact test. RESULTS: A total of 107 ovaries were examined. Following salpingectomy, 5.6% (n = 6/107) of ovaries had residual salpingeal tissue present and 94.4% (n = 101/107) of ovaries were absent of salpingeal tissue. Of the ovaries with residual salpingeal tissue, there was no difference in level of surgeon (attending n = 3/107, resident n = 3/107, p = 1.0) or type of surgery (minimally invasive n = 5/107, laparotomy n = 1/107, p = 0.42). DISCUSSION: This is the largest blinded study ever conducted to examine ovaries for residual salpingeal tissue after salpingectomy. In addition, this is the only study to compare learner versus attending outcomes in this setting. This study found that over 94% of salpingectomies resulted in complete removal of salpingeal tissue. Of the ovaries with residual salpingeal tissue, there wasn't a difference among surgeon level and surgery type, but the study was not powered to detect this. This study supports the continued clinical practice of prophylactic salpingectomy for ovarian cancer risk reduction.

Myocardial Infarction in the Neonate Without Coronary Artery Occlusion and Structurally Normal Heart: A Report of 2 Cases in Twin Pregnancies and Review of the Literature.

Myocardial infarction (MI) is a common diagnosis in the adult population and is associated with coronary artery atherosclerosis. However, it is an unusual diagnosis in the pediatric population, especially in the neonatal period. The authors present 2 autopsy cases of MI in newborn babies of twin pregnancies with normal heart and coronary arteries. The first case is that of a 10-day-old female, monochorionic-diamniotic, twin B born at 29 weeks' gestation. The autopsy revealed diffuse subacute MI in both ventricles, which was compatible with a global hypoxic event during perinatal period. The hypoxic insult was likely caused by maternal HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome as evident in the placental examination, which showed placental infarct and decidual arteriopathy. The second case is that of a 2-day-old term male, dichorionic-diamniotic, twin A with an antenatal history of prolonged rupture of membranes. The hospital course was complicated by neonatal sepsis. The autopsy showed diffuse hemorrhage in the internal organs including the heart, along with myocyte necrosis. The overall findings were consistent with multiorgan dysfunction syndrome resulting from sepsis. Previous reported cases of MI in neonates without coronary artery occlusion were also reviewed and portrayed.

Raman-Enhanced Spectroscopy Distinguishes Anal Squamous Intraepithelial Lesions in Human Immunodeficiency Virus-Serodiscordant Couples.

HIV-positive individuals are at increased risk for precancerous anal squamous intraepithelial lesions (SILs). Anal cytology and digital rectal examination are performed as screening tools, but extensive training and appropriate instruments are required to follow up on an abnormal anal cytology. Thus, novel approaches to SIL evaluation could improve better health care follow-up by efficient and timely diagnosis to offer treatment options. Recently, Raman-enhanced spectroscopy (RESpect) has emerged as a potential new tool for early identification of SIL. RESpect is a noninvasive, label-free, laser-based technique that identifies molecular composition of tissues and cells. HIV-serodiscordant couples had anal biopsies obtained during high-resolution anoscopy. RESpect was performed on the specimens. Principal component analysis of the data identified differences between normal and abnormal tissue as well as HIV-positive and HIV-negative individuals of each couple even with similar pathologies. RESpect has the potential to change the paradigm of anal pathology diagnosis and could provide insight into different pathways leading to SIL in HIV-serodiscordant couples.

Randomized controlled trial evaluating the utility of urine HPV DNA for cervical cancer screening in a Pacific Island population.

BACKGROUND: Non-invasive, self-collection sampling methods for human papillomavirus (HPV) DNA detection have the potential to address logistical and cultural barriers to Pap screening, particularly in under resourced settings such as Yap state in the Federated States of Micronesia - a population with low levels of screening and high incidence of cervical cancer. METHODS: A randomized controlled trial was conducted among adult women in Yap to compare cervical HPV DNA in self-collected urine and clinician-collected liquid cytology. Adult women aged 21-65 (n=217) were randomized by the order of sample collection. Concordance of HPV DNA, evaluated by the Roche Linear Array, was compared in paired self-collected urine and clinician-collected liquid cytology samples. The sensitivity and specificity of urine HPV DNA for prediction of cervical HPV and abnormal cytology was also evaluated. p16 in urine cytology samples was additionally assessed. RESULTS: Overall, HPV DNA detection was significantly lower in urine than cervical samples for any HPV (27.8% and 38.3%, respectively) and high-risk HPV (15.1% and 23.8%, respectively). For paired samples, there was moderate agreement for the overall study population (Kappa=0.54, 95% confidence interval CI=0.40-0.68) and substantial agreement for women >40 years (Kappa=0.65, 95% CI=0.46-0.85). The sensitivity and specificity of urine for the detection of cervical high-risk HPV was 51.0% and 96.2%, respectively. The sensitivities of HPV DNA in urine and liquid cytology for prediction of abnormal cytology (ASCUS/LSIL/HSIL) were 47.4% (95% CI=31.0-64.2) and 57.9% (95% CI=40.8-73.7), respectively; specificities were 92.0% (95% CI=86.9%-95.5%) and 83.5% (95% CI=77.2-88.7). Urine p16 was poorly correlated with urine HPV DNA positivity. CONCLUSIONS: Urine is less sensitive but more specific than directed cervical sampling for detection of cytologic abnormalities and may have utility for screening in older populations within low-resource communities when clinically-collected samples cannot be obtained.

Human Papillomavirus-16 DNA Quantitation Differentiates High-Grade Anal Neoplasia.

Background: Due to their higher rates of anal dysplasia/cancer, human immunodeficiency virus (HIV)-positive individuals are recommended to undergo anal dysplasia screening, which consists of anal cytology (AC) and high resolution anoscopy (HRA) with anal biopsy (AB) after abnormal AC result. However, AC variability limits its usefulness. Our objective was to evaluate human papillomavirus (HPV)-16 DNA quantitation as part of the screening algorithm. Methods: HPV-16 was detected in AC specimens from 75 HIV-positive participants using quantitative real-time polymerase chain reaction. AB results were available from 18/44 patients who had abnormal AC. Statistical tests included Mann-Whitney U, Kruskal-Wallis, receiver operating characteristic (ROC) analysis and Kappa coefficient tests. Results: HPV-16 copy numbers differed significantly across AC (p = 0.001) and AB grades (p = 0.009). HPV-16 ≥ 65 copies/cell predicted high-grade AB (p = 0.04). Using this cut-off in comparison to AB, it had better specificity (1.00) than AC (0.75) and specificity (0.77) than qualitative HPV-16 detection (0.38). Also, the Kappa coefficient of the cut-off (κ = 0.649) was higher than AC (κ = 0.557) and qualitative HPV-16 detection (κ = 0.258) to AB. Conclusion: Higher HPV-16 copy numbers corresponded to higher AC and AB grades, suggesting the importance of HPV burden on disease stage. Furthermore, HPV-16 ≥ 65 copies/cell distinguished high-grade disease and demonstrated better sensitivity, specificity, and agreement with AB than AC or qualitative HPV-16 detection. These results support the potential use of HPV quantitation in conjunction with AC in anal dysplasia screening.

Serous carcinomatous component championed by heparin-binding EGF-like growth factor (HB-EGF) predisposing to metastasis and recurrence in stage I uterine malignant mixed mullerian tumor.

The stage I uterine malignant mixed mullerian tumor (MMMT) shows different potential for progression. We reason that MMMTs with high-grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage. A retrospective clinical and histopathologic review with immunohistochemical staining for HB-EGF, EGFR, and integrin-α5 was performed for 62 surgically staged MMMT cases. Recurrence/metastasis (RM) is 6/18 (33%) in stage I disease. Of all the clinicopathologic variables and biomarkers analyzed for stage I MMMT, serous carcinomatous component (83% [5/6] versus 17% [1/12], P = .0015) and HB-EGF expression (100% [6/6] versus 50% [6/12], P=.0339) were significantly different between groups with RM and without RM. The presence of serous carcinoma in all stages was 83% (5/6) in stage I with RM, 8% (1/12) in stage I without RM, 20% (1/5) in stage II, 36.4% (8/22) in stage III and 64.7% (11/17) in stage IV; this was paralleled by HB-EGF expression of 100% (6/6), 50% (6/12), 40% (2/5), 50% (11/22) and 71% (12/17) with a correlation coefficient r=0.9131 (P=.027). HB-EGF and integrin-α5 were highly expressed in MMMTs bearing serous carcinoma component, compared to endometrioid and unclassifiable/miscellaneous subtypes (84.6%/47.6%/33.3%, P=.025 for HB-EGF; and 61.5%/42.9%/20.0%, P=.021 for integrin-α5). The EGFR positivity was comparable among the three subtypes (48.1%, 47.6% and 26.7%, P=.326). This study indicates that serous carcinomatous component championed by expression of HB-EGF predisposes to recurrence/metastasis in stage I MMMT. This process might involve integrin-α5 and does not seem to require overexpression of EGFR. Further study is required.

Human Papillomavirus at Multiple Sites Associated with Anal Squamous Intraepithelial Lesions in HIV-Seropositive Individuals.

OBJECTIVE: HIV-Seropositive patients have higher risk of HPV infection even on anti-retroviral therapy. Infection with high-risk HPV genotypes can cause dysplasia leading to cancer. This study assessed HPV at different anatomical sites in HIV-seropositive individuals and factors associated with anal squamous intraepithelial lesions (ASIL). METHODS: Specimens were obtained from multiple anatomical sites for each participant in conjunction with routine screening for anal dysplasia. Female specimens included cervical and anal cytologies and oral wash. Male specimens included anal cytologies, oral wash, and exfoliated cells from penile head, penile shaft, scrotum, and from uncircumcised subjects, inner foreskin. Demographic and clinical characteristics were recorded. Following DNA extraction, HIV DNA copy was assessed by qPCR; HPV was genotyped. Statistical analyses included calculation of odds ratios (OR) and 95% confidence intervals (CI), t-tests or Mann-Whitney tests. RESULTS: Males were more likely to have ASIL: 29/50 (58%) compared to 1/11 females (9%) (OR=13.81, 95% CI: 1.64-116.32). HPV 6 or 11 in anal specimens was significantly associated with ASIL (OR= 6.29, 95% CI: 1.49-26.44). Number of HPV genotypes in anal specimens was also significant: ASIL+ (3.4 ± 3.1) versus ASIL- (1.6 ± 3.1) (p=0.009). Among 44 males, HPV was detected from at least one anatomical site for 33 participants (75%): 27 anus (61%), 19 oral wash (44%), 17 penile shaft (39%), 11 scrotum (26%), 10 penile head (23%), 0 foreskin. Detection of HPV in penile shaft specimens was significantly associated with ASIL (OR=6.79, 95% CI: 1.57-29.36) as was number of HPV genotypes in penile shaft specimens: ASIL+ (2.4 ± 4.0) versus ASIL- (0.6 ± 1.7) (p=0.025). Only 1/11 females had ASIL; only 1/11 females had cervical dysplasia: OR was not estimable due to small numbers. CONCLUSIONS: Males were more prone to ASIL than females. HPV at anal as well as non-anal sites may be indicative of ASIL.

Improved abnormal Pap smear triage using cervical cancer biomarkers.

OBJECTIVE: The current system of Pap smear screening and management of abnormal cytology has resulted in a marked reduction in invasive cervical cancer. Many women, however, are not found to have significant precursor lesions. This is due to the poor specificity of high-risk human papillomavirus (HPV) triage. More specific cervical cancer biomarkers may be more effective triage tools than hr-HPV. We evaluated whether a dual stain for p16 and Ki-67 might improve the triage of abnormal Pap smears. MATERIALS AND METHODS: p16/Ki-67 immunostaining was performed on additional slides prepared from 515 women with abnormal Pap smears (301 atypical squamous cells of undetermined significance [ASCUS], 169 low-grade squamous intraepithelial lesion [LSIL], 29 atypical squamous cells-cannot exclude high-grade lesion [ASC-H], 16 high-grade squamous intraepithelial lesion [HSIL]). High-risk HPV typing was performed on all cases. Immunostaining and hr-HPV were compared in relation to their diagnostic accuracy for the detection of biopsy-proven cervical intraepithelial neoplasia (CIN) 2/3. A cost analysis comparing hr-HPV versus immunostaining as the initial triage tool used for abnormal Pap smears was also performed. RESULTS: High-risk HPV was positive in 127 (42.2%) ASCUS, 129 (76.3%) LSIL, 20 (69.0%) ASC-H, and 15 (93.8%) HSIL. p16/Ki-67 was positive in 54 (17.9%) ASCUS, 73 (43.2%) LSIL, 19 (65.5%) ASC-H, and 15 (93.8%) HSIL. For detection of CIN 2/3, sensitivity/specificity of hr-HPV and p16/Ki-67 was 89.29%/14.94% and 96.43%/60.92%, respectively. Overall, diagnostic accuracy was statistically significantly higher for p16/Ki-67 compared with hr-HPV. Compared to HPV, immunostain triage could have generated approximately $46,000 savings in the study population. CONCLUSIONS: The triage of abnormal Pap smears by p16/Ki-67 immunostaining shows comparable sensitivity, improved specificity, and significantly improved diagnostic performance when compared to hr-HPV. Immunostaining is of value in triaging LSIL and ASC-H Pap smears in addition to ASCUS. The widespread utilization of biomarker triage could result in significant health care cost savings without compromising the detection of significant cervical cancer precursors.

Cervical cytokines and clearance of incident human papillomavirus infection: Hawaii HPV cohort study.

Mechanisms for the control and resolution of human papillomavirus (HPV) infection of the cervix include the local production of cytokines, which control recruitment and function of cells integral to pathogen control. We established a cohort of women for long-term follow-up to examine the mucosal expression of antiviral (IFN-α2), Type-1 (IFN-γ, IL-12), regulatory (IL-10), and proinflammatory (IL-1α, IL-1ß, IL-6, IL-8, MIP-1α, and TNF) cytokines in association with the clearance of incident cervical HPV infection. Interviews and specimens for HPV DNA analysis and cytokine protein measurement were obtained at baseline and at 4-month intervals. A Cox proportional hazards model was used to study the relationship between clearance of 107 high-risk and 111 low-risk incident HPV infections and cytokine levels among 154 women. Positive changes from baseline levels of IL-10, IL-12, MIP-1α, and TNF were associated with significantly longer times to type-specific HPV clearance. Inverse trends in the hazard ratios associated with clearance of high-risk HPV infections were monotonic and significant for IL-12 (ptrend = 0.02) and TNF (ptrend = 0.02); the likelihood of high-risk HPV clearance was reduced by 65% and 67%, respectively, among women in the highest as compared with the lowest quartile of change from baseline. Our results suggest that in women with a nontransient cervical HPV infection, proinflammatory, Type-1, and regulatory cytokines are elevated, underscoring the long-term commitment of local immune mediators to viral eradication.

Presence of high-risk human papillomavirus genotype and human immunodeficiency virus DNA in anal high-grade and low-grade squamous intraepithelial lesions.

Human immunodeficiency virus type 1 (HIV)-infected individuals are at risk for anal cancer, which is caused by human papillomavirus (HPV). The relationship between HIV and HPV that leads to anal cancer remains unclear. Recent data, however, suggest that the continued persistence of HIV DNA in patients treated with combined antiretroviral therapy leads to progression of HIV disease and other HIV-associated complications. Therefore, we investigated the relationship among anal low- and high-grade squamous intraepithelial lesions (LGSIL/HGSIL), high-risk HPV genotypes, and high HIV DNA copy numbers. Anal cytology specimens were assayed for HPV genotype and HIV DNA copy number. High-risk HPV genotypes (odds ratio OR: 3.73; 95% confidence interval CI: 1.08-12.91; p=0.04) and high HIV DNA copy numbers (OR(per 100 HIV DNA copies): 1.13; 95% CI: 1.01-1.27, p=0.04) were both associated with LGSIL/HGSIL. When considering both high-risk HPV genotypes and HIV DNA copy numbers in predicting LGSIL/HGSIL, HIV DNA copy number was significant (OR(per 100 HIV DNA copies): 1.09; 95% CI: 0.96-1.23, p=0.04) but not high-risk HPV genotypes (OR: 2.30, p=0.28), which did not change when adjusted for nadir CD4 cell count and HIV RNA levels. The findings warrant further investigation of HIV DNA and its relationship with HPV in LGSIL/HGSIL pathogenesis.

Parity and expression of epithelial histopathologic markers in breast tissue.

It is well established that pregnancies protect against breast cancer; however, the mechanism involved is not completely understood. We investigated the influence of parity on hormonal and proliferation markers in benign tissue from tumor blocks of breast cancer cases. Women with breast cancer were recruited from a case-control study nested within the Multiethnic Cohort study. Tissue microarrays of benign tissue cores were available for 159 participants. Immunostaining for estrogen receptor α (ERα) and ERß, progesterone receptor, human epidermal growth factor receptor 2 (Her2/neu), Ki-67, and proliferating cell nuclear antigen (PCNA) in epithelial tissue was evaluated by a pathologic expert. We applied logistic regression models to examine marker expression by parity (0, 1-2, and ≥3 live births with adjustment for age at diagnosis and BMI). Of the 159 women, 24 were nulliparous, 63 had one or two live births, and 72 had three or more live births. Inverse associations were observed between parity and expression of ERα (Ptrend=0.02) and PCNA (Ptrend=0.04). Among nulliparous women, 45.5% were ERα positive in contrast to 18.0 and 18.9% of women with one or two and at least three live births, respectively. The respective values for PCNA were 56.5, 44.3, and 31.1%. No associations were detected for ERß, progesterone receptor, Her2/neu, and Ki-67. The current findings suggest that pregnancies may protect against breast cancer by reducing susceptibility to estrogenic stimuli and proliferative activity as assessed by the expression of ERα and PCNA in breast tissue.

Transcutaneous bilirubin measurement methods in neonates and its utility for emergency department use.

Transcutaneous bilirubin measurements correlate with serum bilirubin measurements in neonates. They permit rapid measurements but do not provide fractionation information. Background information of bilirubin measurements is reviewed. The role of transcutaneous bilirubin measurements in the emergency department is reviewed.

BRCA1-IRIS overexpression promotes formation of aggressive breast cancers.

INTRODUCTION: Women with HER2(+) or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2(+) and/or TN/BL tumors. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/Ras(V12)-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU), followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2(+) or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA. CONCLUSION/SIGNIFICANCE: BRCA1-IRIS overexpression triggers aggressive breast tumor formation, especially in patients with HER2(+) or TN/BL subtypes. We propose that BRCA1-IRIS inhibition may be pursued as a novel therapeutic option to treat these aggressive breast tumor subtypes.