Interleukin 21 promotes IgG1+ plasma cell differentiation instead of class switching to IgE via Blimp1 expression.

IgE is induced by the presence of IL-4 by class switching from IgM through IgG1 to IgE. IL-21 inhibits the IgE class switch by induction of Blimp1 leading to Stat6 and AID downregulation, and plasmablast/plasma cell differentiation.

A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application.

PD-1, a negative coreceptor expressed on antigen-stimulated T cells and B cells, seems to serve as a 'rheostat' of the immune response. The molecular mechanisms of the functions of PD-1, in conjunction with the mild, chronic and strain-specific autoimmune phenotypes of PD-1-deficient mice, in contrast to the devastating fatal autoimmune disease of mice deficient in the immunomodulatory receptor CTLA-4, suggest that immunoregulation by PD-1 is rather antigen specific and is mainly cell intrinsic. Such unique properties make PD-1 a powerful target for immunological therapy, with highly effective clinical applications for cancer treatment.

At the Intersection of Intersectionality: Race and Gender Diversity Among Surgical Faculty and Trainees.

OBJECTIVE: To compare the representation of intersectional (ie, racial/ethnic and gender) identities among surgical faculty versus medical students. BACKGROUND: Health disparities are pervasive in medicine, but diverse physicians may help the medical profession achieve health equity. METHODS: Data from the Association of American Medical Colleges for 140 programs (2011/2012-2019/2020) were analyzed for students and full-time surgical faculty. Underrepresented in medicine (URiM) was defined as Black/African American, American Indian/Alaskan Native, Hispanic/Latino/Spanish Origin, or Native Hawaiian/Other Pacific Islander. Non-White included URiM plus Asian, multiracial, and non-citizen permanent residents. Linear regression was used to estimate the association of year and proportions of URiM and non-White female and male faculty with proportions of URiM and non-White students. RESULTS: Medical students were comprised of more White (25.2% vs 14.4%), non-White (18.8% vs 6.6%), and URiM (9.6% vs 2.8%) women and concomitantly fewer men across all groups versus faculty (all P < 0.01). Although the proportion of White and non-White female faculty increased over time (both P ≤ 0.001), there was no significant change among non-White URiM female faculty, nor among non-White male faculty, regardless of whether they were URiM or not. Having more URiM male faculty was associated with having more non-White female students (estimate = +14.5% students/100% increase in faculty, 95% CI: 1.0% to 8.1%, P = 0.04), and this association was especially pronounced for URiM female students (estimate = +46.6% students/100% increase in faculty, 95% CI: 36.9% to 56.3%, P < 0.001). CONCLUSIONS: URiM faculty representation has not improved despite a positive association between having more URiM male faculty and having more diverse students.

Guideline-Concordant Surgical Care for Lobular Versus Ductal Inflammatory Breast Cancer.

INTRODUCTION: Quality of surgical care is understudied for lobular inflammatory breast cancer (IBC), which is less common, more chemotherapy-resistant, and more mammographically occult than ductal IBC. We compared guideline-concordant surgery (modified radical mastectomy [MRM] without immediate reconstruction following chemotherapy) for lobular versus ductal IBC. METHODS:  Female individuals with cT4dM0 lobular and ductal IBC were identified in the National Cancer Database (NCDB) from 2010-2019. Modified radical mastectomy receipt was identified via codes for "modified radical mastectomy" or "mastectomy" and "≥10 lymph nodes removed" (proxy for axillary lymph node dissection). Descriptive statistics, chi-square tests, and t-tests were used. RESULTS: A total of 1456 lobular and 10,445 ductal IBC patients were identified; 599 (41.1%) with lobular and 4859 (46.5%) with ductal IBC underwent MRMs (p = 0.001). Patients with lobular IBC included a higher proportion of individuals with cN0 disease (20.5% lobular vs. 13.7% ductal) and no lymph nodes examined at surgery (31.2% vs. 24.5%) but were less likely to be node-negative at surgery (12.7% vs. 17.1%, all p < 0.001). Among those who had lymph nodes removed at surgery, patients with lobular IBC also had fewer lymph nodes excised versus patients with ductal IBC (median [interquartile range], 7 (0-15) vs. 9 (0-17), p = 0.001). CONCLUSIONS: Lobular IBC patients were more likely to present with node-negative disease and less likely to be node-negative at surgery, despite having fewer, and more frequently no, lymph nodes examined versus ductal IBC patients. Future studies should investigate whether these treatment disparities are because of surgical approach, pathologic assessment, and/or data quality as captured in the NCDB.

Persistent underuse of extended venous thromboembolism prophylaxis in patients undergoing major abdominal cancer operations.

BACKGROUND: Guidelines recommend extended venous thromboembolism (VTE) prophylaxis for high-risk populations undergoing major abdominal cancer operations. Few studies have evaluated extended VTE prophylaxis in the Medicare population who are at higher risk due to age. METHODS: We performed a retrospective study using a 20% random sample of Medicare claims, 2012-2017. Patients ≥65 years with an abdominal cancer undergoing resection were included. Primary outcome was the proportion of patients receiving new extended VTE prophylaxis prescriptions at discharge. Secondary outcomes included postdischarge VTE and hemorrhagic events. RESULTS: The study included 72 983 patients with a mean age of 75. Overall, 8.9% of patients received extended VTE prophylaxis. This proportion increased (7.2% in 2012, 10.6% in 2017; p < 0.001). Incidence of postdischarge hemorrhagic events was 1.0% in patients receiving extended VTE prophylaxis and 0.8% in those who did not. The incidence of postdischarge VTE events was 5.2% in patients receiving extended VTE prophylaxis and 2.4% in those who did not. CONCLUSION: Adherence to guideline-recommended extended VTE prophylaxis in high-risk patients undergoing major abdominal cancer operations is low. The higher rate of VTE in the prophylaxis group may suggest we captured some therapeutic anticoagulation, which would mean the actual rate of thromboprophylaxis is lower than reported herein.

Fractured and delayed: A qualitative analysis of disruptions in care for gynecologic malignancies during incarceration.

OBJECTIVE: Women are experiencing growing rates of incarceration at twice the pace of that for men. Additionally, one-third will be older than 55 years of age by the end of the decade. Women who are incarcerated experience a higher prevalence of gynecologic malignancies and present with higher stage disease, which may be contributing to the greater mortality from cancer than the age-adjusted US population. Limited access to guideline-recommended screening and prevention and resource limitations across correctional facilities may result in gynecologic cancer disparities. Reasons for delayed gynecologic cancer care in prisons remain underexplored. Therefore, we sought to identify contributors to delayed gynecologic cancer care among women experiencing incarceration. METHODS: Women at a single tertiary center in the Southeastern U.S. who were incarcerated and were diagnosed with a gynecologic cancer during 2014-2021 were identified in the electronic medical record. Note text was extracted and contributors to delay were identified and categorized using the RADaR method. Descriptive statistics were used to assess quantitative data. RESULTS: 14 patients were identified with a total of 14,879 text excerpts. Data reduction was performed to identify excerpts that were relevant to the central research question resulting in 175 relevant note excerpts. Delays prior to the tertiary care visit included patient and institutional contributors. Delays during transition from the tertiary center to prison included discharge planning and loss to follow-up during/after incarceration. Transportation, authorization, and restraints were concrete contributors. Abstract contributors included communication, and the patient's emotional experience. CONCLUSIONS: We identify myriad contributors to delayed or fractured gynecologic cancer care in women experiencing incarceration. The impact of these issues warrants further study and intervention to improve care.

A Novel Narrative Medicine Approach to DEI Training for Medical School Faculty.

Problem:Diversity, Equity, and Inclusion (DEI) trainings for medical school faculty often lack self-reflective and pedagogically focused components that may promote incorporation of anti-racism and social justice into medical school curricula. Intervention: A four-session Narrative Medicine (NM) anti-racism program was designed for medical school faculty using critical race theory, phenomenology, and NM methods. Each workshop consisted of a lecture on key NM concepts and a small-group breakout session incorporating group discussion, close reading, and reflective writing. Context: This NM anti-racism program was developed and implemented in April 2021 by two medical students for faculty at an institution in the southeastern U.S. The program was supported by the Office of Inclusive Excellence at the institution and held in collaboration with the institution's medical education teaching academy. Program evaluation consisted of pre- and post-program surveys, which queried participants' previous experiences with DEI and medical humanities programs, perceptions of self-identity and privilege, and confidence in teaching concepts of anti-racism. Of the total program participants (n = 32), 19 completed both surveys (54.3%). Survey data were analyzed using bivariate testing methods and qualitative thematic analysis. Impact: Post-program surveys showed 13 (68.4%) participants felt "somewhat more" or "more" comfortable engaging in concepts of race, and 12 (63.2%) participants felt "somewhat more" or "more" comfortable including topics of race into their teaching compared to before the program. Five themes were generated following qualitative analysis: (1) the value of longitudinal narrative reflection in a small-group setting for DEI work; (2) desire to commit more time to DEI, anti-racist, and social justice work while balancing busy teaching and clinical schedules; (3) the value of storytelling in DEI and anti-racism programming; (4) an understanding of deconstructive and reconstructive work of anti-racism in medicine; and (5) an increased ability to educate and enact change through teaching, activism, and institutional cultural and policy changes. Lessons Learned: This novel NM DEI training for medical school faculty was successful in increasing comfort discussing and teaching concepts of race in the medical school classroom, while providing a uniquely reflective space for personal growth. Participation in this longitudinal reflective experience was limited by physician schedules, therefore efforts to make time to participate in similar longitudinal interventions must be undertaken.

Shaves off the Cavity or Specimen in Lumpectomy for Breast Cancer.

INTRODUCTION: Re-excision for positive margins (margins where tumor is positive) after breast conserving surgery (BCS) is common and burdensome for breast cancer patients. Routine shave margins can reduce positive margins and re-excision rates. Cavity shaving margin (CSM) removes margins from the lumpectomy cavity edges, whereas specimen shave margin (SSM) requires ex vivo removal of margins from the resected specimen. METHODS: We assessed breast cancer patients undergoing BCS who received CSM or SSM procedures from 2017 to 2019. CSM and SSM techniques were compared by analyzing positive rates of primary and final shaved margins, re-excision rates, and tissue volumes removed. RESULTS: Of 116 patients included in this study, 57 underwent CSM and 59 underwent SSM. Primary margins were positive or close in 19 CSM patients and 21 SSM patients (33% versus 36%; P = 0.798). Seventeen CSM patients had a tumor in shaved margin specimens, compared to four patients for SSM (30% versus 7%; P < 0.001); however, final shave margins were similar (5% versus 5%; P = 0.983). Volumes of shave specimens were higher with SSM (40.7 versus 13.4 cm3; P < 0.001), but there was no significant difference in the total volume removed (146.8 versus 134.4 cm3; P = 0.540). For tumors 2 cm or larger, the total volume removed (140 versus 206 cm3; P = 0.432) and rates of final margin positivity (7.5% versus 0%; P = 0.684) were similar for both techniques. CONCLUSIONS: CSM and SSM are effective techniques for achieving low re-excision rates. Our findings suggest that surgeons performing either CSM or SSM may maintain operative preferences and achieve similar results.

Narrative trajectories of disaster response: ethical preparedness from Katrina to COVID-19.

While COVID-19 brings unprecedented challenges to the US healthcare system, understanding narratives of historical disasters illuminates ethical complexities shared with COVID-19. In 2005, Hurricane Katrina revealed a lack of disaster preparation and protocol, not dissimilar to the challenges faced by COVID-19 healthcare workers. A case study of Memorial Hospital during Hurricane Katrina reported by journalist-MD Sheri Fink reveals unique ethical challenges at the forefront of health crises. These challenges include disproportionate suffering in structurally vulnerable populations, as seen in COVID-19 where marginalised groups across the USA experience higher rates of disease and COVID-19-related death. Journalistic accounts of Katrina and COVID-19 offer unique perspectives on the ethical challenges present within medicine and society, and analysis of such stories reveals narrative trajectories anticipated in the aftermath of COVID-19. Through lenses of social suffering and structural violence, these narratives reinforce the need for systemic change, including legal action, ethical preparedness and physician protection to ensure high-quality care during times of crises. Narrative Medicine-as a practice of interrogating stories in medicine and re-centering the patient-offers a means to contextualise individual accounts of suffering during health crises in larger social matrices.

Military metaphors and pandemic propaganda: unmasking the betrayal of 'Healthcare Heroes'.

Dr Caitríona L Cox's recent article expounds the far-reaching implications of the 'Healthcare Hero' metaphor. She presents a detailed overview of heroism in the context of clinical care, revealing that healthcare workers, when portrayed as heroes, face challenges in reconciling unreasonable expectations of personal sacrifice without reciprocity or ample structural support from institutions and the general public. We use narrative medicine, a field primarily concerned with honouring the intersubjective narratives shared between patients and providers, in our attempt to deepen the discussion about the ways Healthcare Heroes engenders military metaphor, antiscience discourse, and xenophobia in the USA. We argue that the militarised metaphor of Healthcare Heroes not only robs doctors and nurses of the ability to voice concerns for themselves and their patients, but effectively sacrifices them in a utilitarian bargain whereby human life is considered the expendable sacrifice necessary to 'open the U.S. economy'. Militaristic metaphors in medicine can be dangerous to both doctors and patients, thus, teaching and advocating for the critical skills to analyse and alter this language prevents undue harm to providers and patients, as well as our national and global communities.

Programmed death-ligand 1 (PD-L1) expression in pleomorphic carcinoma of the lung.

BACKGROUND AND OBJECTIVES: Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive subtype of lung cancer. Programmed cell death-ligand 1 (PD-L1) expression may be induced in a variety of malignant tumors, but its prognostic implication in PPC remains unclear. METHODS: Twenty-six patients with surgically resected PPC were retrospectively reviewed. Immuno-histochemical staining was used to detect PD-L1 expression, and PD-L1 status was classified into "high" or "low" according to the percentage of tumor cells (TCs) expressing PD-L1 (tumor proportion score, TPS). RESULTS: PD-L1 expression was positive in 20 (76.9%) patients at the cut-off TPS value of 1%. A receiver-operating characteristic (ROC) analysis showed that the optimal cut-off value was 15% for prediction of cancer-specific death with the area under ROC curve of 0.701 (P = 0.107). High PD-L1 expression was associated with a favorable overall survival (88.9% vs 37.5% at 5 years; P =.046) as well as a favorable cancer-specific (100% vs 45.9% at 5 years; P =.012). A multivariate analysis indicated a trend toward a favorable prognosis associated with high PD-L1 expression (hazard ratio [HR], 0.254 [95% confidence interval, 0.054-1.200]; P = 0.084). CONCLUSIONS: PD-L1 expression was positive in most PPC cases, and high PD-L1 expression may predict a favorable prognosis in resected PPC.

Cancer immunotherapies targeting the PD-1 signaling pathway.

Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. However, the failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research on combination therapies and predictive biomarkers. Here we summarize the development of PD-1-blockade immunotherapy and current issues in its clinical use.

IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors.

Interleukin (IL)-17-producing helper T (T(H)17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases. IL-6 and transforming growth factor-beta (TGF-beta) induce T(H)17 development, in which the orphan nuclear receptors, RORgammat and RORalpha, have an indispensable role. However, in the absence of IL-6 and TGF-beta, the ectopic expression of RORgammat or RORalpha leads to only a modest IL-17 production. Here we identify a nuclear IkappaB family member, IkappaBzeta (encoded by the Nfkbiz gene), as a transcription factor required for T(H)17 development in mice. The ectopic expression of IkappaBzeta in naive CD4(+) T cells together with RORgammat or RORalpha potently induces T(H)17 development, even in the absence of IL-6 and TGF-beta. Notably, Nfkbiz(-/-) mice have a defect in T(H)17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IkappaBzeta was clearly demonstrated by the resistance to EAE of the Rag2(-/-) mice into which Nfkbiz(-/-) CD4(+) T cells were transferred. In cooperation with RORgammat and RORalpha, IkappaBzeta enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying T(H)17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.

Expression of BAF57 in ovarian cancer cells and drug sensitivity.

The SMARCE1 (SWI / SNF-related, matrix-associated, and actin-dependent regulator of chromatin, subfamily e, member 1) encodes BAF57 protein. Previously, we reported that BAF57 is a predictive marker of endometrial carcinoma. In this study, we investigated BAF57 expression in ovarian cancer cell lines and their sensitivities to cisplatin, doxorubicin, paclitaxel, and 5-fluorouracil. BAF57 expression was strongly correlated with sensitivities to cisplatin, doxorubicin, and 5-fluorouracil in 10 ovarian cancer cell lines. Paclitaxel sensitivity was also correlated with BAF57 expression, but without significance. In A2780 ovarian cancer cells, knockdown of BAF57 using specific siRNA increased cell cycle arrest at G1 phase and the sensitivities to these anticancer agents. cDNA microarray analysis of A2780 cells transfected with BAF57 siRNA showed that 134 genes were positively regulated by BAF57, including ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2) encoding breast cancer resistance protein (BCRP). We confirmed that knockdown of BAF57 decreased BCRP expression in ovarian cancer cells by Western blot analysis, and that ABCG2 gene expression might be regulated transcriptionally. These results suggested that BAF57 is involved in ovarian cancer cell growth and sensitivity to anticancer agents, and that BAF57 may be a target for ovarian cancer therapy.

Necessity of lysophosphatidic acid receptor 1 for development of arthritis.

OBJECTIVE: Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA1 on the development of arthritis. METHODS: Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA1 on collagen-induced arthritis (CIA) were evaluated using LPA1 -deficient mice or LPA1 antagonist. Migrating fluorescence-labeled CD11b+ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4+ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined. RESULTS: LPA1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA1 antagonist also ameliorated murine CIA. Abrogation of LPA1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b+ macrophages from LPA1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA1 deficiency or LPA1 inhibition in vitro. CONCLUSION: Collectively, these results indicate that LPA/LPA1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA1 may be a promising target molecule for RA therapy.