A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial.

BACKGROUND: Low-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often treated with conventional chemotherapy, although response rates are disappointing. PRIMARY OBJECTIVE: To determine the overall response rate of the combination therapy of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancers. STUDY HYPOTHESIS: The combination therapy of abemaciclib and letrozole will provide a clinically meaningful therapeutic benefit, with an overall response rate of >25%. TRIAL DESIGN: This is a phase II, international, multicenter, open-label, single-arm study to evaluate the efficacy and safety of abemaciclib and letrozole in patients with advanced, recurrent, and/or metastatic estrogen receptor-positive, rare ovarian cancer. The study will follow a tandem two-stage design. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients must have histologically confirmed low-grade serous/endometrioid ovarian cancer or adult-type granulosa cell tumor with estrogen receptor positivity on immunohistochemistry. Patients need to have recurrent and measurable disease according to Radiologic Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A maximum of two prior lines of endocrine therapy are allowed, and patients cannot have previously received a cyclin-dependent kinase inhibitor. Patients with platinum-refractory disease are not allowed in any stage of the study. PRIMARY ENDPOINT: Investigator-assessed confirmed overall response rate, defined as the proportion of patients with a complete or partial response according to RECIST v1.1. SAMPLE SIZE: 40 to 100 patients will be included, depending on the results of the interim analysis. Patients will be included in Belgium, France and the Netherlands. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed by the end of 2025 and reporting of the final study results will be done by the end of 2027. TRIAL REGISTRATION NUMBER: NCT05872204.

Physical and mental health of breast cancer patients and survivors before and during successive SARS-CoV-2-infection waves.

PURPOSE: During the first SARS-CoV-2-infection wave, a deterioration in emotional well-being and increased need for mental health care were observed among patients treated or being treated for breast cancer. In this follow-up study, we assessed patient-reported quality of life (QoL), physical functioning, and psychosocial well-being during the second SARS-CoV-2-infection wave in a large, representative cohort. METHODS: This longitudinal cohort study was conducted within the prospective, multicenter UMBRELLA breast cancer cohort. To assess patient-reported QoL, physical functioning and psychosocial well-being, COVID-19-specific surveys were completed by patients during the first and second SARS-CoV-2-infection waves (April and November 2020, respectively). An identical survey was completed by a comparable reference population during the second SARS-CoV-2-infection waves. All surveys included the validated EORTC-QLQ-C30/BR23, HADS and "De Jong-Gierveld Loneliness" questionnaires. Pre-COVID-19 EORTC-QLQ-C30/BR23 and HADS outcomes were available from UMBRELLA. Response rates were 69.3% (n = 1106/1595) during the first SARS-CoV-2-infection wave and 50.9% (n = 822/1614) during the second wave. A total of 696 patients responded during both SARS-CoV-2-infection waves and were included in the analysis comparing patient-reported outcomes (PROs) during the second SARS-CoV-2-infection wave to PROs during the first wave. Moreover, PROs reported by all patients during the second SARS-CoV-2-infection wave (n = 822) were compared to PROs of a similar non-cancer reference population (n = 241) and to their pre-COVID-19 PROs. RESULTS: Patient-reported QoL, physical functioning, and psychosocial well-being of patients treated or being treated for breast cancer remained stable or improved from the first to the second SARS-CoV-2-infection wave. The proportion of emotional loneliness reduced from 37.6 to 29.9% of patients. Compared to a similar non-cancer reference population, physical, emotional, and cognitive functioning, future perspectives and symptoms of dyspnea and insomnia were worse in patients treated or being treated for breast cancer during the second SARS-CoV-2-infection wave. PROs in the second wave were similar to pre-COVID-19 PROs. CONCLUSION: Although patients scored overall worse than individuals without breast cancer, QoL, physical functioning, and psychosocial well-being did not deteriorate between the first and second wave. During the second wave, PROs were similar to pre-COVID-19 values. Overall, current findings are cautiously reassuring for future mental health of patients treated or being treated for breast cancer.

Immunotherapy for GTN: a new paradigm.

Background Immune checkpoint immunotherapy (CPI) targeting PD1/PD-L1 has been shown to be an effective treatment for gestational trophoblastic neoplasia (GTN). This includes those with multidrug resistance, ultra-high risk disease and ETT/PSTT subtypes that are inherently chemotherapy resistant, but there is also emerging evidence in low-risk disease. Objectives We set out to generate an overview of the current data supporting the use of CPI for GTN in both high risk and low risk disease and to consider future research goals and directions in order to implement CPI in current treatment guidelines. Methods We identified and reviewed the published data on the use of CPI agents in GTN. Outcome 133 patients were identified who had been treated with CPI for GTN with pembrolizumab (23), avelumab (22), camrelizumab (57), toripalimab (15) or other anti-PD-1 agents (16), of whom 118 had high risk disease, relapse or multi drug resistant disease, and 15 low risk disease. Overall 85 patients achieved complete remission, 77 (of 118) with high risk disease and 8 (of 15) with low risk disease. 1 patient with complete remission in the high risk group developed a relapse 22 months after anti-PD-1 treatment had been stopped. Treatment was generally well tolerated across studies. Conclusions and Outlook The majority of high risk patients (77/118) treated with CPI are cured and this is particularly relevant amongst those with chemotherapy resistant disease who otherwise have very limited treatment options. Priorities for future research include determining whether these agents have a role earlier in the disease course, the utility of combination with chemotherapy, and effects on future fertility. Treatment availability remains a concern due to the high price of these agents.

The impact of the COVID-19 pandemic on perceived access to health care and preferences for health care provision in individuals (being) treated for breast cancer.

PURPOSE: To evaluate perceived access to health care and preferences for health care provision among patients (being) treated for breast cancer during the COVID-19 pandemic. METHODS: Longitudinal study within the prospective, multicenter UMBRELLA cohort of patients (being) treated for breast cancer. All cohort participants enrolled in UMBRELLA between October 2013 and November 2020 were sent a COVID-19-specific survey during the first and second wave of the COVID-19 pandemic, i.e., April 2020 and November 2020, respectively. RESULTS: In total, 1106 (69.3%) and 822 (50.9%) cohort participants completed the survey in the first and second wave, respectively. The proportion of patients experiencing that their treatment or follow-up care was affected due to COVID-19 decreased from 28.4% (n = 198) in April 2020 to 14.8% (n = 103) in November 2020. Throughout the pandemic, one or more hospital consultations were postponed in 10.0% (n = 82) of all patients and changed into a teleconsultation in 23.1% (n = 190). The proportion of patients who experienced a higher threshold to contact their general practitioner due to COVID-19 decreased from 29.9% (n = 204) in the first wave to 20.8% (n = 145) in the second wave. In-person consultations remained most preferred in 35.2% (n = 289) of all patients. Nearly half of all patients (48.3%, n = 396) indicated that telehealth would be a useful alternative for in-person consultations in future. CONCLUSION: Perceived access to health care has improved substantially throughout the pandemic. Digital care is well received by patients (being) treated for breast cancer.

The impact of hyperbaric oxygen therapy on late radiation toxicity and quality of life in breast cancer patients.

PURPOSE: To evaluate symptoms of late radiation toxicity, side effects, and quality of life in breast cancer patients treated with hyperbaric oxygen therapy (HBOT). METHODS: For this cohort study breast cancer patients treated with HBOT in 5 Dutch facilities were eligible for inclusion. Breast cancer patients with late radiation toxicity treated with ≥ 20 HBOT sessions from 2015 to 2019 were included. Breast and arm symptoms, pain, and quality of life were assessed by means of the EORTC QLQ-C30 and -BR23 before, immediately after, and 3 months after HBOT on a scale of 0-100. Determinants associated with persistent breast pain after HBOT were assessed. RESULTS: 1005/1280 patients were included for analysis. Pain scores decreased significantly from 43.4 before HBOT to 29.7 after 3 months (p < 0.001). Breast symptoms decreased significantly from 44.6 at baseline to 28.9 at 3 months follow-up (p < 0.001) and arm symptoms decreased significantly from 38.2 at baseline to 27.4 at 3 months follow-up (p < 0.001). All quality of life domains improved at the end of HBOT and after 3 months follow-up in comparison to baseline scores. Most prevalent side effects of HBOT were myopia (any grade, n = 576, 57.3%) and mild barotrauma (n = 179, 17.8%). Moderate/severe side effects were reported in 3.2% (n = 32) of the patients. Active smoking during HBOT and shorter time (i.e., median 17.5 vs. 22.0 months) since radiotherapy were associated with persistent breast pain after HBOT. CONCLUSION: Breast cancer patients with late radiation toxicity reported reduced pain, breast and arm symptoms, and improved quality of life following treatment with HBOT.

(Ex-)breast cancer patients with (pre-existing) symptoms of anxiety and/or depression experience higher barriers to contact health care providers during the COVID-19 pandemic.

PURPOSE: To identify factors associated with (perceived) access to health care among (ex-)breast cancer patients during the COVID-19 pandemic. METHODS: Cross-sectional study within a large prospective, multicenter cohort of (ex-)breast cancer patients, i.e., UMBRELLA. All participants enrolled in the UMBRELLA cohort between October 2013 and April 2020 were sent a COVID-19-specific survey, including the Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS: In total, 1051 (66.0%) participants completed the survey. During COVID-19, 284 (27.0%) participants reported clinically relevant increased levels of anxiety and/or depression, i.e., total HADS score ≥ 12. Participants with anxiety and/or depression reported statistically significant higher barriers to contact their general practitioner (47.5% vs. 25.0%, resp.) and breast cancer physicians (26.8% vs. 11.2%, resp.) compared to participants without these symptoms. In addition, a higher proportion of participants with anxiety and/or depression reported that their current treatment or (after)care was affected by COVID-19 compared to those without these symptoms (32.7% vs. 20.5%, resp.). Factors independently associated with symptoms of anxiety and/or depression during COVID-19 were pre-existent anxiety (OR 6.1, 95% CI 4.1-9.2) or depression (OR 6.0, 95% CI 3.5-10.2). CONCLUSION: During the COVID-19 pandemic, (ex-)breast cancer patients with symptoms of anxiety and/or depression experience higher barriers to contact health care providers. Also, they more often report that their health care was affected by COVID-19. Risk factors for anxiety and/or depression during COVID-19 are pre-existent symptoms of anxiety or depression. Extra attention-including mental health support-is needed for this group.

Hormone- and HER2-receptor assessment in 33,046 breast cancer patients: a nationwide comparison of positivity rates between pathology laboratories in the Netherlands.

PURPOSE: Patient management of invasive breast cancer (IBC) is to a large extent based on hormone- and HER2-receptor assessment. High-quality, reliable receptor assessment is of key importance as false results may lead to under- or overtreatment of patients. Surveillance of case-mix adjusted positivity rates has been suggested as a tool to identify laboratories with insufficient testing assays, as this covers the whole process of receptor assessment and enables laboratories to benchmark their positivity rates against other laboratories. We studied laboratory-specific variation in hormone- and HER2 positivity rates of 33,046 breast cancer patients using real-life nationwide data. METHODS: All synoptic pathology reports of IBC resection-specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch pathology registry (PALGA). Absolute and case-mix adjusted receptor positivity rates were compared to the mean national proportion and presented in funnel plots in separate analyses for estrogen (ER), progesterone (PR) and HER2. Case-mix adjustment was performed by multivariable logistic regression. RESULTS: 33,794 IBC lesions from 33,046 patients of 39 pathology laboratories were included. After case-mix adjustment, mean positivity rates were 87.2% for ER (range 80.4-94.3), 71.3% for PR (62.5-77.5%), and 9.9% for HER2 (5.5-12.7%). Overall, 14 (35.9%), 17 (43.6%) and 11 (28.2%) laboratories showed positivity rates outside the 95% confidence interval for ER, PR and HER2, respectively. CONCLUSION: This nationwide study shows that absolute variation in hormone- and HER2-receptor positivity rates between Dutch pathology laboratories is limited. Yet, the considerable number of outlying laboratories shows that there is still need for improvement. Continuous monitoring and benchmarking of positivity rates may help to realize this.

Acute hemolytic transfusion reaction due to a warm reactive anti-A1.

BACKGROUND: Anti-A1 are regularly observed by reverse testing and are generally considered clinically irrelevant. For compatibility testing and the selection of blood, we use the type-and-screen (T&S) strategy, in which ABO confirmation of patients with a definitive blood group is performed by forward grouping only. Because anti-A1 seem clinically irrelevant, it is our policy to provide group A blood in patients with an anti-A1 . STUDY DESIGN AND METHODS: This is a case report of a 96-year-old woman who died shortly after transfusion of blood group A red blood cells (RBCs). She was known to have blood group A2 with an anti-A1 and the absence of other RBC antibodies. Directly after starting transfusion, acute dyspnea was observed, while other clinical signs for a transfusion reaction were absent. In the laboratory, indications for a severe hemolytic transfusion reaction (HTR) triggered serologic investigations and complement deposition experiments. RESULTS: Analyses revealed that the anti-A1 was present as a high-titer IgM class immunoglobulin that induced complement deposition on A1 RBCs. The anti-A1 reacted in a wide temperature amplitude up to 37°C with A1 RBCs, while weak agglutination was observed with A2 RBCs at room temperature. CONCLUSION: A pretransfusion detectable anti-A1 caused a severe HTR that, in view of the rapid onset of clinical symptoms and concomitant deterioration, contributed to the death of the patient. Considering its clinical significance in this case, we encourage an unambiguous procedure for patients with an anti-A1 , especially when T&S is used for donor RBC selection.

Complement Deposition and IgG Binding on Stored Red Blood Cells Are Independent of Storage Time.

BACKGROUND: In the Netherlands, red blood cells (RBCs) are allowed to be stored up to 35 days at 2-6 °C in saline-adenine-glucose-mannitol (SAGM). During storage, RBCs undergo several changes that are collectively known as storage lesion. We investigated to what extent complement deposition and antibody binding occurred during RBC storage and investigated phagocytic uptake in vitro. METHODS: RBCs were stored for different lengths of time at 2-6 °C in SAGM. Complement deposition and antibody binding were assessed upon storage and after incubation with serum. M1- and M2-type macrophages were generated from blood monocytes to investigate RBC phagocytosis. RESULTS: No complement deposition was directly observed on stored RBCs, while incubation of RBCs with serum resulted in variable donor-dependent C3 deposition and IgG binding, both independent of storage time. Only 1-4% phagocytosis of stored RBCs by macrophages was observed. CONCLUSION: RBCs are susceptible to complement deposition and antibody binding independent of storage time. Limited phagocytic uptake by macrophages was observed in vitro.

Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): Patient Characteristics, Treatment, and Outcome-A Systematic Review.

BACKGROUND: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare aggressive ovarian malignancy mainly affecting children, adolescents, and young adults. Since the discovery of mutations in the SMARCA4 gene in 2014, SCCOHT has become the subject of extensive investigation. However, international uniform treatment guidelines for SCCOHT are lacking and the outcome remains poor. The aim of this systematic review is to generate an overview of all reported patients with SCCOHT from 1990 onwards, describing the clinical presentation, genetic characteristics, treatment, and outcome. METHODS: A systematic search was performed in the databases Embase, Medline, Web of Science, and Cochrane for studies that focus on SCCOHT. Patient characteristics and treatment data were extracted from the included studies. Survival was estimated using Kaplan-Meier's methodology. To assess the difference between survival, the log-rank test was used. To quantify the effect of the FIGO stage, the Cox proportional hazard regression model was estimated. The chi-squared test was used to study the association between the FIGO stage and the surgical procedures. RESULTS: Sixty-seven studies describing a total of 306 patients were included. The median patient age was 25 years (range 1-60 years). The patients mostly presented with non-specific symptoms such as abdominal pain and sometimes showed hypercalcemia and elevated CA-125. A great diversity in the diagnostic work-up and therapeutic approaches was reported. The chemotherapy regimens were very diverse, all containing a platinum-based (cisplatin or carboplatin) backbone. Survival was strongly associated with the FIGO stage at diagnosis. CONCLUSIONS: SCCOHT is a rare and aggressive ovarian cancer, with a poor prognosis, and information on adequate treatment for this cancer is lacking. The testing of mutations in SMARCA4 is crucial for an accurate diagnosis and may lead to new treatment options. Harmonization and international collaboration to obtain high-quality data on diagnostic investigations, treatment, and outcome are warranted to be able to develop international treatment guidelines to improve the survival chances of young women with SCCOHT.

C1-inhibitor treatment in patients with severe complement-mediated autoimmune hemolytic anemia.

Complement-mediated (CM) autoimmune hemolytic anemia (AIHA) is characterized by the destruction of red blood cells (RBCs) by autoantibodies that activate the classical complement pathway. These antibodies also reduce transfusion efficacy via the lysis of donor RBCs. Because C1-inhibitor (C1-INH) is an endogenous regulator of the classical complement pathway, we hypothesized that peritransfusional C1-INH in patients with severe CM-AIHA reduces complement activation and hemolysis, and thus enhances RBC transfusion efficacy. We conducted a prospective, single-center, phase 2, open-label trial (EudraCT2012-003710-13). Patients with confirmed CM-AIHA and indication for the transfusion of 2 RBC units were eligible for inclusion. Four IV C1-INH doses (6000, 3000, 2000, and 1000 U) were administered with 12-hour intervals around RBC transfusion. Serial blood samples were analyzed for hemolytic activity, RBC opsonization, complement activation, and inflammation markers. Ten patients were included in the study. C1-INH administration increased plasma C1-INH antigen and activity, peaking at 48 hours after the first dose and accompanied by a significant reduction of RBC C3d deposition. Hemoglobin levels increased briefly after transfusion but returned to baseline within 48 hours. Overall, markers of hemolysis, inflammation, and complement activation remained unchanged. Five grade 3 and 1 grade 4 adverse event occurred but were considered unrelated to the study medication. In conclusion, peritransfusional C1-INH temporarily reduced complement activation. However, C1-INH failed to halt hemolytic activity in severe transfusion-dependent-CM-AIHA. We cannot exclude that posttransfusional hemolytic activity would have been even higher without C1-INH. The potential of complement inhibition on transfusion efficacy in severe CM-AIHA remains to be determined.

The Effects of Being Informed About Chemotherapy-Related Cognitive Symptoms With And Without Self-Affirmation on Perceived Cognitive Symptoms of Breast Cancer Patients: A Randomized Prospective, Longitudinal Study.

BACKGROUND: Informing patients about chemotherapy-related cognitive symptoms (CRCS) may increase perceived cognitive symptoms. This longitudinal randomized study evaluated this Adverse Information Effect (AIE) in breast cancer patients and examined whether self-affirmation (SA) can reduce AIEs (ClinicalTrials.gov identifier: NCT04813965). PATIENTS AND METHODS: Before (neo) adjuvant chemotherapy, 160 newly diagnosed breast cancer patients were randomly allocated to receive: standard information on side-effects (control), standard information with additional information about CRCS (information), or standard and additional information with a subsequent self-affirmative text (information+SA). Online-questionnaires assessed the perceived frequency (MOS-cog) and severity (MDASI-cog) of cognitive symptoms before chemotherapy (baseline, T0), and 2.5-months (T1) and 6.5-months (T2) post-chemotherapy. Higher scores indicate less frequent, and more severe symptoms, respectively. Baseline-to-follow-up analyses using a mixed-effects modeling approach compared groups over time. RESULTS: At T0-T2, 148, 140 and 133 patients responded, respectively (attrition rates: 8%, 5%, 5%). Frequency (ES = -0.36, P =.003) and severity (ES = 0.54, P <.001) of symptoms worsened from baseline to T1, without differences between groups. At T2, symptom frequency remained stable for informed (ES=-0.3, P =.021) and self-affirmed (ES=-0.3, P =.019) patients, but returned to baseline levels for controls. At T2, symptom severity remained increased for informed patients (ES = 0.3, P =.006), but normalized for self-affirmed patients (ES = 0.2, P =.178) and controls. CONCLUSION: No AIEs occurred until T2. The initial overall increase in perceived cognitive symptoms recovered at T2 for controls, but not for patients who received additional information about CRCS. Self-affirmation attenuated these longer-term AIEs for the perceived severity but not the frequency of symptoms.

Impact of the COVID-19 Pandemic on Patient-Reported Outcomes of Breast Cancer Patients and Survivors.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic (officially declared on the March 11, 2020), and the resulting measures, are impacting daily life and medical management of breast cancer patients and survivors. We evaluated to what extent these changes have affected quality of life, physical, and psychosocial well-being of patients previously or currently being treated for breast cancer. METHODS: This study was conducted within a prospective, multicenter cohort of breast cancer patients and survivors (Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion). Shortly after the implementation of COVID-19 measures, an extra survey was sent to 1595 participants, including the validated European Organization for Research and Treatment of Cancer (EORTC) core (C30) and breast cancer-specific (BR23) Quality of Life Questionnaire (EORTC QLQ-C30/BR23) and Hospital Anxiety and Depression Scale (HADS) questionnaire. Patient-reported outcomes (PROs) were compared with the most recent PROs collected within UMBRELLA pre-COVID-19. The impact of COVID-19 on PROs was assessed using mixed model analysis, adjusting for potential confounders. RESULTS: 1051 patients and survivors (65.9%) completed the survey; 31.1% (n = 327) reported a higher threshold to contact their general practitioner amid the COVID-19 pandemic. A statistically significant deterioration in emotional functioning was observed (mean = 82.6 [SD = 18.7] to 77.9 [SD = 17.3]; P < .001), and 505 (48.0%, 95% confidence interval [CI] = 45.0% to 51.1%) patients and survivors reported moderate to severe loneliness. Small improvements were observed in quality of life and physical, social, and role functioning. In the subgroup of 51 patients under active treatment, social functioning strongly deteriorated (77.3 [95% CI = 69.4 to 85.2] to 61.3 [95% CI = 52.6 to 70.1]; P = .002). CONCLUSION: During the COVID-19 pandemic, breast cancer patients and survivors were less likely to contact physicians and experienced a deterioration in their emotional functioning. Patients undergoing active treatment reported a substantial drop in social functioning. One in 2 reported loneliness that was moderate or severe. Online interventions supporting mental health and social interaction are needed during times of social distancing and lockdowns.

Grading variation in 2,934 patients with ductal carcinoma in situ of the breast: the effect of laboratory- and pathologist-specific feedback reports.

BACKGROUND: Histologic grade of ductal carcinoma in situ of the breast (DCIS) may become the single biomarker that decides whether patients will be treated. Yet, evidence shows that grading variation in daily practice is substantial. To facilitate quality improvement, feedback reports, in which laboratory-specific case-mix adjusted proportions per grade were benchmarked against other laboratories, were sent to the individual laboratories by March 1, 2018. One year later, the effect of these feedback reports on inter-laboratory variation was studied. METHODS: Synoptic pathology reports of all pure DCIS resection specimens between March 1, 2017 and March 1, 2019 were retrieved from PALGA (the nationwide Dutch pathology registry). Laboratory-specific proportions per grade were compared to the overall proportion in the year before and after feedback. The absolute deviation for all three grades at once, represented by the overall deviation score (ODS), was calculated as the sum of deviations from the grade-specific overall proportions. Case-mix adjusted, laboratory-specific odds ratios (ORs) for high- (grade III) versus low-grade (grade I-II) DCIS were obtained by multivariable logistic regression. RESULTS: Overall, 2954 DCIS reports from 31 laboratories were included. After feedback, the range between laboratories decreased by 22 and 6.5% for grades II and III, while an increase of 6.2% was observed for grade I. Both the mean ODS (27.2 to 24.1%) and maximum ODS (87.7 to 59.6%) decreased considerably. However, the range of case-mix adjusted ORs remained fairly stable and substantial (0.39 (95% CI: 0.18-0.86) to 3.69 (95% CI: 1.30-10.51)). CONCLUSION: A promising decrease in grading variation was observed after laboratory-specific feedback for DCIS grades II-III, while this was not observed for DCIS grade I. Overall, grading variation remained substantial which needs to be addressed considering its clinical implications. Nationwide consensus on a classification, and training of (expert breast) pathologists, for example by e-learning, may help to further improve grading standardization.

Variation in breast cancer grading: the effect of creating awareness through laboratory-specific and pathologist-specific feedback reports in 16 734 patients with breast cancer.

AIMS: Histological grade is widely used to guide the management of invasive breast cancer (IBC). Yet, substantial interlaboratory and intralaboratory grading variations exist in daily pathology practice. To create awareness and to facilitate quality improvement, feedback reports, containing case-mix-adjusted laboratory-specific grades benchmarked against other laboratories, were sent to the individual laboratories by 1 March 2018. We studied the effect of these feedback reports on interlaboratory grading variation up till 1 year later. METHODS: Overall, 17 102 synoptic pathology reports of IBC resection specimens from 33 laboratories, obtained between 1 March 2017 and 1 March 2019 were retrieved from the Dutch Pathology Registry (PALGA). An overall deviation score (ODS), representing the sum of deviations from the grade-specific overall proportions, was calculated to compare the absolute deviation for all grades at once. Case-mix correction was performed by two multivariable logistic regression analyses, providing laboratory-specific ORs for high-grade versus low-grade IBC. RESULTS: After feedback, the overall range between laboratories decreased by 3.8%, 6.4% and 6.6% for grades I, II and III, respectively. Though the mean ODS remained similar (13.8% vs 13.7%), the maximum ODS decreased from 34.1% to 29.4%. The range of laboratory-specific ORs decreased by 21.9% for grade III versus grades I-II. CONCLUSIONS: An encouraging decrease in grading variation of IBC was observed after laboratory-specific feedback. Nevertheless, the overall grading variation remains substantial. In view of the important role of grading in patient management, it is adamant that not only feedback should be provided on a regular basis but also other interventions, such as additional training, are required.

Increased Rac activity is required for the progression of T-lymphomas induced by Pten-deficiency.

Mutation of the tumor suppressor PTEN results in loss of its PI3-kinase counteracting function. PI3-kinase stimulates tumor formation by PKB/Akt-mediated cell proliferation and prevention of apoptosis. PI3-kinase may also activate Rho-GTPases and their regulatory GEFs to promote invasion. Here we have analyzed the function of the Rac-specific activator, Tiam1, in PI3-kinase-induced T-lymphomagenesis. Mice with a T cell-specific Pten deletion developed T-lymphomas with enhanced PKB/Akt phosphorylation. However, these T-lymphomas infiltrated more frequently into various organs in Tiam1-deficient mice compared to wild type mice. Surprisingly, Tiam1-deficient lymphomas showed increased Rac activity, suggesting that the lack of Tiam1 is compensated by alternative Rac-activating mechanisms that lead to increased progression of PI3-kinase-induced T-lymphomas.

Expansion of normal and leukemic human hematopoietic stem/progenitor cells requires rac-mediated interaction with stromal cells.

OBJECTIVE: To determine the involvement of Rac signaling in self-renewal and expansion on bone marrow stroma of normal CD34+ cells vs leukemic CD34+ cells from acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: Rac signaling was modulated by retroviral introduction of Racl-N17, Racl-V12, or by using the Rac inhibitor NSC23766. In long-term MS5 cocultures (leukemic) expansion, migration, adhesion, and presence of stem/progenitor cells were monitored in both normal as well as leukemic CD34+ cells. RESULTS: Inhibition of Rac signaling impaired migration and adhesion of cord blood (CB) CD34+ cells on MS5 stroma. Long-term inhibition of Rac during a 5-week coculture period on stroma prevented association of hematopoietic progenitors with the bone marrow stromal cells and resulted in a dramatic decrease in the primitive stem cell frequency (long-term culture-initiating cell) in a dose-dependent manner. Many of these phenotypes were reversed in the presence of activated Racl-V12, including improved migration toward, and association with, MS5 cells. CD34+ AML cells were characterized by elevated levels of Rac activity (five of seven patients) and enhanced migration and adhesion to MS5 bone marrow stroma as compared to CB CD34+ cells. A dramatic decrease was observed in the formation of leukemic cobblestone area-forming cells as well as strongly diminished clonal expansion in the presence of the Rac inhibitor NSC23766. CONCLUSION: Our data indicate that Rac signal transduction is required for the maintenance and expansion of both normal as well as leukemic stem/progenitor cells by mediating their interaction with stromal cells.

c-Myb Regulates the T-Bet-Dependent Differentiation Program in B Cells to Coordinate Antibody Responses.

Humoral immune responses are tailored to the invading pathogen through regulation of key transcription factors and their networks. This is critical to establishing effective antibody-mediated responses, yet it is unknown how B cells integrate pathogen-induced signals to drive or suppress transcriptional programs specialized for each class of pathogen. Here, we detail the key role of the transcription factor c-Myb in regulating the T-bet-mediated anti-viral program. Deletion of c-Myb in mature B cells significantly increased serum IgG2c and CXCR3 expression by upregulating T-bet, normally suppressed during Th2-cell-mediated responses. Enhanced expression of T-bet resulted in aberrant plasma cell differentiation within the germinal center, mediated by CXCR3 expression. These findings identify a dual role for c-Myb in limiting inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Identifying such intrinsic regulators of specialized antibody responses can assist in vaccine design and therapeutic intervention in B-cell-mediated immune disorders.