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Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information that may guide subsequent adjuvant treatment for the individual patient. Pathological complete response (pCR) following neoSACT identifies a population with excellent outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to the absolute clinical benefit. Aims HER2-RADiCAL seeks to reduce the burden of toxicity and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less intensive therapy, including avoiding anthracyclines, with minimal or no loss of efficacy in the population. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort (single-arm) study embedded within a real-world data driven clinical pathway model. Participants will be registered within 6 weeks of completion of breast cancer surgery. The main eligibility criteria include clinical stage T1N1 or T2N0-1 at diagnosis and locally-determined pCR (ypT0/Tis ypN0) after standard of care taxane-based (non-anthracycline) neoadjuvant chemotherapy, trastuzumab and pertuzumab. After registration participants will continue to receive trastuzumab to complete a total of 9 cycles including those (neo-)adjuvant cycles administered prior to study entry. Participants will receive no further pertuzumab nor any adjuvant chemotherapy. Statistical methods The primary clinical endpoint is relapse free interval. Recruitment of 720 participants over 3 years will provide 90% power to exclude an event rate >6.5% at 3 years. Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, treatment pathway adherence and cost-effectiveness. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway taken from 4-nation UK National Health Service data at the beginning and end of the study. Patient and public involvement Patient advocates have shaped the research by confirming that the main outcomes being evaluated are important to patients and that the interventional cohort design, with power to exclude an absolute risk of recurrence outwith a 2-3% margin of historical control data, is acceptable and preferable to a randomised controlled trial, which would take longer to get answers and need many more patients to be included. They have been involved in protocol design, including methodology, sample collection and patient follow-up, and their input has shaped the patient information materials and consent forms. Patient advocates will have an ongoing key role in overseeing the progress of the study as members of the Trial Management Group, and they will also have an important role in communicating the study results to patients and the public. Current status HER2-RADiCAL is planned to open at ~40 UK sites commencing in September 2021. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Sarah Kernaghan, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Charlotte Coles, Cliona Kirwan, Mairead Mackenzie, Ciara O’Brien, Alistair Ring, Claire Snowdon, Hilary Stobart, Duncan Wheatley, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) - Tailoring treatment for HER2 positive early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-05-01.

AimsThere is little information on the impact of COVID-19 on breast pathologists. This survey assessed the effect of the COVID-19 pandemic on UK and Ireland-based breast pathologists to optimise working environments and ensure preparedness for potential future pandemics.MethodsA 35-question survey during the first wave of COVID-19 infections in the UK including questions on workload, working practices, professional development, training, health and safety and well-being was distributed to consultant breast pathologists and responses collected anonymously.ResultsThere were 135 responses from breast pathologists based in the UK and Ireland. Most participants (75.6%) stated that their workload had decreased and their productivity dropped. 86/135 (63.7%) were given the option of working from home and 36% of those who did reported improved efficiency. Multidisciplinary team meetings largely moved to virtual platforms (77.8%) with fewer members present (41.5%). Online education, including webinars and courses, was utilised by 92.6%. 16.3% of pathologists reported shortages of masks, visors or gowns as the the most common health and safety concern. COVID-19 had a significant negative impact on the physical and mental health of 33.3% of respondents. A small number of pathologists (10.4%) were redeployed and/or retrained.ConclusionThe UK and Ireland breast pathologists adapted to the rapid change and maintained service delivery despite the significant impact of the pandemic on their working practices and mental health. It is important to apply flexible working patterns and environments that improve productivity and well-being. The changes suggested should be considered for long-term shaping of breast pathology services.

We report 10 cases of a previously undescribed lesion within ovarian teratomas which we designate bronchus-like structures. The lesions occurred in patients aged 16 to 56 yr (mean: 36) and involved the left ovary (n=5) or right ovary (n=5). Nine cases were mature teratomas (dermoid cysts/mature cystic teratomas or mature solid teratomas), 1 with somatic malignant transformation, and 1 was an immature teratoma. The bronchus-like structures ranged in size from 2.5 to 10 mm and were unifocal (7 cases) or multifocal (3 cases). The morphology was relatively constant in all cases and characterised by a well-formed bronchus surrounded by glandular structures, some of which were dilated, separated by stroma containing a variable amount of smooth muscle. In all but 1 case, a proportion of the glands contained abundant foamy cytoplasm. There was little or no nuclear atypia or mitotic activity. At low-power, the glands often had a somewhat "infiltrative" appearance and one case was originally diagnosed as a "pulmonary-type" adenocarcinoma arising in a dermoid cyst. In all cases, there was diffuse staining of the bronchus and glands with TTF1 and Napsin A, confirming the cell lineage. Follow-up in 4 cases (18-130 mo; median: 64 mo) showed no evidence of recurrence; 1 patient died from an unrelated malignancy. In reporting this apparently rare but possibly underrecognized benign lesion arising within ovarian teratomas, we discuss the differential diagnosis and stress that pathologists should be aware of this phenomenon in order to avoid an erroneous diagnosis of malignancy.

Multifocal/multicentric breast cancer is generally considered to be where two or more breast tumours are present within the same breast, and is seen in ∼10% of breast cancer cases. This study investigates the prevalence of multifocality/multicentricity in a cohort ofBRCA1/2mutation carriers with breast cancer from Northern Ireland via cross-sectional analysis. Data from 211 women withBRCA1/2mutations (BRCA1- 91), (BRCA2- 120), with breast cancer were collected including age, tumour focality, size, type, grade, and receptor profile. The prevalence of multifocality/multicentricity within this group was 25%, but within subgroups, prevalence amongstBRCA2carriers was more than double that ofBRCA1carriers (p=0.001). Women affected by multifocal/multicentric tumours had proportionately higher oestrogen receptor positivity (p=0.001) and lower triple negativity (p=0.004). These observations are likely to be driven by the higher BRCA2 mutation prevalence observed within this cohort. Odds of aBRCA2carrier developing multifocal/multicentric cancer were almost four-fold higher than aBRCA1carrier (OR: 3.71, CI: 1.77-7.78, p=0.001). These findings were subsequently validated in a second, large independent cohort of patients withBRCA-associated breast cancers from a UK-wide multicentre study. This confirmed a significantly higher prevalence of multifocal/multicentric tumours amongstBRCA2mutation carriers compared withBRCA1mutation carriers. This has important implications for clinicians involved in the treatment of BRCA2-associated breast cancer, both in the diagnostic process, in ensuring that tumour focality is adequately assessed to facilitate treatment decision-making, and for breast surgeons, particularly if breast conserving surgery is being considered as a treatment option for these patients.

Former Chicago mayor Richard J. Daley once announced that Chicago was “the city that works,” although Portland, Oregon, and Stamford, Connecticut, share this nickname. His remarks attempted to show...

Child Maltreatment (CM) is a public health problem, and experts recommend parent training programs as a prevention method. Few programs target fathers, even though male caregivers are involved as perpetrators in approximately 45% of substantiated CM cases. This study examines the efficacy of an adapted version of SafeCare (Dad2K) with marginalized fathers. Participants include a convenience sample of fathers with children ages 2-5 years. Fathers (n=99) were randomized to an 1) intervention group (SafeCare Dad2K) or to a 2) comparison group (receiving parenting information in the mail). Quantitative data were collected at baseline, post-intervention (7-weeks post-baseline), and 3-months post-intervention. Qualitative data (semi-structured interviews) were collected from 11 intervention father completers following the second quantitative data collection timepoint. Multi-level modeling results indicated no statistically significant time-by-treatment findings for father involvement (b=0.03, 95% confidence interval [CI]: -0.03, 0.08, p=0.38), total corporal punishment (b=-0.03, 95% CI: -0.47, 0.41, p=0.89), or neglect (b=-0.13, 95% CI: -1.93, 1.68, p=0.89). Qualitative findings indicated that Dad2K completers exhibited positive knowledge and behavioral change related to parenting. Study limitations, lessons learned from this formative work, and recommendations for future research are discussed.

The discovery and clinical application of molecular biomarkers in solid tumors, increasingly relies on nucleic acid extraction from FFPE tissue sections and subsequent molecular profiling. This in turn requires the pathological review of haematoxylin & eosin (H&E) stained slides, to ensure sample quality, tumor DNA sufficiency by visually estimating the percentage tumor nuclei and tumor annotation for manual macrodissection. In this study on NSCLC, we demonstrate considerable variation in tumor nuclei percentage between pathologists, potentially undermining the precision of NSCLC molecular evaluation and emphasising the need for quantitative tumor evaluation. We subsequently describe the development and validation of a system called TissueMark for automated tumor annotation and percentage tumor nuclei measurement in NSCLC using computerized image analysis. Evaluation of 245 NSCLC slides showed precise automated tumor annotation of cases using Tissuemark, strong concordance with manually drawn boundaries and identical EGFR mutational status, following manual macrodissection from the image analysis generated tumor boundaries. Automated analysis of cell counts for % tumor measurements by Tissuemark showed reduced variability and significant correlation (p < 0.001) with benchmark tumor cell counts. This study demonstrates a robust image analysis technology that can facilitate the automated quantitative analysis of tissue samples for molecular profiling in discovery and diagnostics.

Positive father involvement in the lives of their children is critically important. This article describes pilot data from the Dad2K program, an adaptation of the evidence-based SafeCare Parent-Child Interaction module, which targets positive parenting skills and the prevention of child neglect and physical abuse. Dad2K includes a unique approach to intervention delivery utilizing computer software, and instruction and practice with a home visitor provider. The development process of the Dad2K program is described, and data are presented from four fathers of young children who completed the program. The article concludes with describing the next steps in the examination of the Dad2K program, which includes a large randomized control trial funded by the National Institute of Minority Health and Health Disparities.

There has been burgeoning parenting intervention research specifically addressing fathers in recent decades. Corresponding research examining their participation and engagement in evidence-based parent training programs, which have almost exclusively targeted mothers, is just emerging. The current study used mixed methods to examine factors that influenced completion of an augmented version of an evidence-based child maltreatment prevention program developed for male caregivers called SafeCare Dad to Kids (Dad2K) in a pilot study. The current sample comprised 50 male caregivers (Mage = 29.42 years, SD = 8.18) of a child between the ages of 2 and 5 years. Fathers participated in a baseline assessment and were considered program completers (n = 27) if they participated in the program's six home visiting sessions. A subsample of completers (n = 11) was recruited to participate in qualitative interviews that provided in-depth information about fathers' experiences in Dad2K. Logistic regression indicated that, in the context of other demographic predictors, fathers with an education beyond high school were over 5 times more likely to complete Dad2K program compared to fathers with a high school education or less. Qualitative analyses revealed that interviewed father completers were motivated to enroll and participate in a fathering program because of an interest to learn and obtain skills to make them a better parent. Fathers with a high school education or less may require additional engagement strategies to help proactively encourage their enrollment and completion of parent training programs.

Recent literature has suggested a dual pathway of ovarian serous carcinogenesis, with most serous carcinomas falling into 1 of 2 categories, low grade and high grade. These are considered to represent 2 distinct tumor types with a different underlying pathogenesis and associated with different molecular events, clinical behavior, and prognosis. Low-grade serous carcinoma is thought to evolve in many instances from a preexisting serous borderline tumor and cystadenoma. Given the distinct pathogenesis and different molecular events, it is expected that the coexistence of low-grade and high-grade serous carcinoma would be rare or may even be mutually exclusive; moreover, there are very few reported examples in the literature. We report a series of 7 cases in patients aged 34 to 78 years in whom ovarian low-grade serous carcinoma (4 cases, including 3 with associated serous borderline tumor), serous borderline tumor (2 cases), or seromucinous borderline tumor (1 case) was associated with a high-grade carcinoma, either high-grade serous (5 cases) or undifferentiated carcinoma (2 cases). The low-grade and high-grade components coexisted in the original neoplasm in 4 cases, and the high-grade component was present only in recurrence in 3 cases. In both instances, the undifferentiated carcinoma had a focal rhabdoid morphology, and alternative primary sites of tumor were excluded by a combination of clinical, radiologic, and pathologic parameters. We illustrate that low-grade serous carcinoma or serous borderline tumor ("low-grade" serous neoplasms) may rarely be associated with, and probably give rise to, a high-grade carcinoma, either high-grade serous or undifferentiated carcinoma. The coexistence of a low-grade serous neoplasm and undifferentiated carcinoma can be regarded as a form of dedifferentiation. p53 was diffusely positive in 4 of 6 high-grade carcinomas, which raises the possibility that secondary Tp53 mutation is important in high-grade transformation in some of these cases. WT1 was negative in the 2 undifferentiated carcinomas, and PAX8 was positive in 1, suggesting that the latter marker is more useful in helping to confirm a Mullerian origin in dedifferentiated low-grade serous neoplasms.

In this new, very timely and well-written book, Mitchell Duneier takes on the complex challenge of documenting the history and ever-changing meaning of the now highly stigmatized word ghetto. The t...

BackgroundUterine leiomyomas are extremely common in surgical pathology practice and in the vast majority there are no issues in diagnosis. Progestogens are widely prescribed drugs for a variety of indications, including abnormal uterine bleeding, and are often given to women with leiomyomas but the pathological features of leiomyomas treated with progestogens are poorly described.MethodsWe report the pathological features in eight cases of uterine leiomyomas in women who had been treated with oral progestogens or a progestogen-containing intrauterine device; all cases were received in consultation because the features raised concern for leiomyosarcoma, smooth muscle tumour of uncertain malignant potential or a benign leiomyoma with unusual features. Additionally, we reviewed a series of cases of uterine leiomyomas (n=99) in women who exhibited progestogenic effects in the endometrium.ResultsThe morphological features in the consult cases, which were widespread and marked and which varied somewhat from case to case, included small and/or large areas of infarct-type necrosis (sometimes mimicking coagulative tumour cell necrosis) with surrounding increased cellularity, mitotic activity, nuclear pyknosis, cytoplasmic eosinophilia, epithelioid morphology, stromal oedema, haemorrhage, and myxoid change and infiltration by CD56 positive granulated lymphocytes. Sometimes the features resulted in an almost deciduoid appearance. Similar features were present to a minor degree in significant numbers of the additional series of cases.ConclusionsPathologists should be aware of these progestogen-associated features when reporting uterine leiomyomas whether or not the clinician has indicated that the woman is taking progestogens since otherwise a diagnosis of leiomyosarcoma or smooth muscle tumour of uncertain malignant potential may be rendered. Useful features in suggesting a benign leiomyoma, in addition to recognition of the morphological features described which, in combination, are characteristic of progestogens, are the lack of true nuclear atypia and the low mitotic activity away from the abnormal areas.

The presence of signet ring cells in a carcinoma within the uterine corpus strongly raises the possibility of a metastasis from a primary tumor in the breast, gastrointestinal tract, or elsewhere. Signet ring cells are extremely rare in primary endometrial adenocarcinomas with only a single prior case report. We report 2 cases of primary endometrial adenocarcinoma, one of mucinous and the other of endometrioid type, with a significant component of signet ring cells. One of the neoplasms arose within adenomyosis. In reporting these cases, we illustrate that the presence of signet ring cells does not preclude a primary endometrial adenocarcinoma. We discuss signet ring cells in the endometrium.

Dermoid cysts are common benign ovarian germ cell neoplasms. Occasionally, one of the mature elements undergoes malignant transformation resulting in the formation of a somatic malignancy; most commonly this is squamous carcinoma. We report a unique case where 2 separate malignancies arose within a dermoid cyst, one a signet ring mucinous adenocarcinoma and the other a pulmonary-type adenocarcinoma. There have been only occasional earlier case reports of a possible pulmonary-type adenocarcinoma arising in a dermoid cyst. In the case we report, the pulmonary-type adenocarcinoma was closely associated with a bronchial structure and exhibited diffuse positive immunohistochemical staining with TTF1, PE10, and napsin A. Molecular studies revealed no evidence of epidermal growth factor receptor mutation, a molecular alteration which may be found in primary pulmonary adenocarcinoma.

The mapping of the Schrodinger equation for the ‘‘hydrogen atom’’ in one, two, and three dimensions into that for the oscillator is reviewed, with the purpose of relating two of the most basic, illustrative, and useful problems discussed in introductory quantum mechanics courses.