American Cancer Society's report on the status of cancer disparities in the United States, 2023.

In 2021, the American Cancer Society published its first biennial report on the status of cancer disparities in the United States. In this second report, the authors provide updated data on racial, ethnic, socioeconomic (educational attainment as a marker), and geographic (metropolitan status) disparities in cancer occurrence and outcomes and contributing factors to these disparities in the country. The authors also review programs that have reduced cancer disparities and provide policy recommendations to further mitigate these inequalities. There are substantial variations in risk factors, stage at diagnosis, receipt of care, survival, and mortality for many cancers by race/ethnicity, educational attainment, and metropolitan status. During 2016 through 2020, Black and American Indian/Alaska Native people continued to bear a disproportionately higher burden of cancer deaths, both overall and from major cancers. By educational attainment, overall cancer mortality rates were about 1.6-2.8 times higher in individuals with ≤12 years of education than in those with ≥16 years of education among Black and White men and women. These disparities by educational attainment within each race were considerably larger than the Black-White disparities in overall cancer mortality within each educational attainment, ranging from 1.03 to 1.5 times higher among Black people, suggesting a major role for socioeconomic status disparities in racial disparities in cancer mortality given the disproportionally larger representation of Black people in lower socioeconomic status groups. Of note, the largest Black-White disparities in overall cancer mortality were among those who had ≥16 years of education. By area of residence, mortality from all cancer and from leading causes of cancer death were substantially higher in nonmetropolitan areas than in large metropolitan areas. For colorectal cancer, for example, mortality rates in nonmetropolitan areas versus large metropolitan areas were 23% higher among males and 21% higher among females. By age group, the racial and geographic disparities in cancer mortality were greater among individuals younger than 65 years than among those aged 65 years and older. Many of the observed racial, socioeconomic, and geographic disparities in cancer mortality align with disparities in exposure to risk factors and access to cancer prevention, early detection, and treatment, which are largely rooted in fundamental inequities in social determinants of health. Equitable policies at all levels of government, broad interdisciplinary engagement to address these inequities, and equitable implementation of evidence-based interventions, such as increasing health insurance coverage, are needed to reduce cancer disparities.

Screening for lung cancer: 2023 guideline update from the American Cancer Society.

Lung cancer is the leading cause of mortality and person-years of life lost from cancer among US men and women. Early detection has been shown to be associated with reduced lung cancer mortality. Our objective was to update the American Cancer Society (ACS) 2013 lung cancer screening (LCS) guideline for adults at high risk for lung cancer. The guideline is intended to provide guidance for screening to health care providers and their patients who are at high risk for lung cancer due to a history of smoking. The ACS Guideline Development Group (GDG) utilized a systematic review of the LCS literature commissioned for the US Preventive Services Task Force 2021 LCS recommendation update; a second systematic review of lung cancer risk associated with years since quitting smoking (YSQ); literature published since 2021; two Cancer Intervention and Surveillance Modeling Network-validated lung cancer models to assess the benefits and harms of screening; an epidemiologic and modeling analysis examining the effect of YSQ and aging on lung cancer risk; and an updated analysis of benefit-to-radiation-risk ratios from LCS and follow-up examinations. The GDG also examined disease burden data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. The GDG judged that the overall evidence was moderate and sufficient to support a strong recommendation for screening individuals who meet the eligibility criteria. LCS in men and women aged 50-80 years is associated with a reduction in lung cancer deaths across a range of study designs, and inferential evidence supports LCS for men and women older than 80 years who are in good health. The ACS recommends annual LCS with low-dose computed tomography for asymptomatic individuals aged 50-80 years who currently smoke or formerly smoked and have a ≥20 pack-year smoking history (strong recommendation, moderate quality of evidence). Before the decision is made to initiate LCS, individuals should engage in a shared decision-making discussion with a qualified health professional. For individuals who formerly smoked, the number of YSQ is not an eligibility criterion to begin or to stop screening. Individuals who currently smoke should receive counseling to quit and be connected to cessation resources. Individuals with comorbid conditions that substantially limit life expectancy should not be screened. These recommendations should be considered by health care providers and adults at high risk for lung cancer in discussions about LCS. If fully implemented, these recommendations have a high likelihood of significantly reducing death and suffering from lung cancer in the United States.

American Cancer Society's report on the status of cancer disparities in the United States, 2021.

In this report, the authors provide comprehensive and up-to-date US data on disparities in cancer occurrence, major risk factors, and access to and utilization of preventive measures and screening by sociodemographic characteristics. They also review programs and resources that have reduced cancer disparities and provide policy recommendations to further mitigate these inequalities. The overall cancer death rate is 19% higher among Black males than among White males. Black females also have a 12% higher overall cancer death rate than their White counterparts despite having an 8% lower incidence rate. There are also substantial variations in death rates for specific cancer types and in stage at diagnosis, survival, exposure to risk factors, and receipt of preventive measures and screening by race/ethnicity, socioeconomic status, and geographic location. For example, kidney cancer death rates by sex among American Indian/Alaska Native people are ≥64% higher than the corresponding rates in each of the other racial/ethnic groups, and the 5-year relative survival for all cancers combined is 14% lower among residents of poorer counties than among residents of more affluent counties. Broad and equitable implementation of evidence-based interventions, such as increasing health insurance coverage through Medicaid expansion or other initiatives, could substantially reduce cancer disparities. However, progress will require not only equitable local, state, and federal policies but also broad interdisciplinary engagement to elevate and address fundamental social inequities and longstanding systemic racism.

Understanding and addressing social determinants to advance cancer health equity in the United States: A blueprint for practice, research, and policy.

Although cancer mortality rates declined in the United States in recent decades, some populations experienced little benefit from advances in cancer prevention, early detection, treatment, and survivorship care. In fact, some cancer disparities between populations of low and high socioeconomic status widened during this period. Many potentially preventable cancer deaths continue to occur, and disadvantaged populations bear a disproportionate burden. Reducing the burden of cancer and eliminating cancer-related disparities will require more focused and coordinated action across multiple sectors and in partnership with communities. This article, part of the American Cancer Society's Cancer Control Blueprint series, introduces a framework for understanding and addressing social determinants to advance cancer health equity and presents actionable recommendations for practice, research, and policy. The article aims to accelerate progress toward eliminating disparities in cancer and achieving health equity.

Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society.

The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration-approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow-up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.

Multi-Cancer Early Detection: The New Frontier in Cancer Early Detection.

The new generation of cancer early detection tests holds remarkable promise for revolutionizing and changing the paradigm of cancer early detection. Dozens of cancer early detection tests are being developed and evaluated. Some are already commercialized and available for use, most as a complement to and not in place of existing recommended cancer screening tests. This review evaluates existing single- and multi-cancer early detection tests (MCEDs), discussing their performance characteristics including sensitivity, specificity, positive and negative predictive values, and accuracy. It also critically looks at the potential harms that could result from these tests, including false positive and negative results, the risk of overdiagnosis and overtreatment, psychological and economic harms, and the risk of widening cancer inequities. We also review the large-scale, population-based studies that are being launched in the United States and United Kingdom to determine the impact of MCEDs on clinically relevant outcomes and implications for current practice.

Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society.

In the United States, colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer. For this guideline update, the American Cancer Society (ACS) used an existing systematic evidence review of the CRC screening literature and microsimulation modeling analyses, including a new evaluation of the age to begin screening by race and sex and additional modeling that incorporates changes in US CRC incidence. Screening with any one of multiple options is associated with a significant reduction in CRC incidence through the detection and removal of adenomatous polyps and other precancerous lesions and with a reduction in mortality through incidence reduction and early detection of CRC. Results from modeling analyses identified efficient and model-recommendable strategies that started screening at age 45 years. The ACS Guideline Development Group applied the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria in developing and rating the recommendations. The ACS recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy. The recommendation to begin screening at age 45 years is a qualified recommendation. The recommendation for regular screening in adults aged 50 years and older is a strong recommendation. The ACS recommends (qualified recommendations) that: 1) average-risk adults in good health with a life expectancy of more than 10 years continue CRC screening through the age of 75 years; 2) clinicians individualize CRC screening decisions for individuals aged 76 through 85 years based on patient preferences, life expectancy, health status, and prior screening history; and 3) clinicians discourage individuals older than 85 years from continuing CRC screening. The options for CRC screening are: fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; multitarget stool DNA test every 3 years; colonoscopy every 10 years; computed tomography colonography every 5 years; and flexible sigmoidoscopy every 5 years. CA Cancer J Clin 2018;68:250-281. © 2018 American Cancer Society.

The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.

KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.

In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a KrasFSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras+/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras+/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.

Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC-induced cholestatic injury by promoting a pro-restorative inflammatory response.

Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1-2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland.

Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.

KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.

How Referring Providers Choose Specialists for Their Patients: a Systematic Review.

BACKGROUND: Physician referrals are a critical step in directing patients to high-quality specialists. Despite efforts to encourage referrals to high-volume hospitals, many patients receive treatment at low-volume centers with worse outcomes. We aimed to determine the most important factors considered by referring providers when selecting specialists for their patients through a systematic review of medical and surgical literature. METHODS: PubMed and Embase were searched from January 2000 to July 2021 using terms related to referrals, specialty, surgery, primary care, and decision-making. We included survey and interview studies reporting the factors considered by healthcare providers as they refer patients to specialists in the USA. Studies were screened by two independent reviewers. Quality was assessed using the CASP Checklist. A qualitative thematic analysis was performed to synthesize common decision factors across studies. RESULTS: We screened 1,972 abstracts and identified 7 studies for inclusion, reporting on 1,575 providers. Thematic analysis showed that referring providers consider factors related to the specialist's clinical expertise (skill, training, outcomes, and assessments), interactions between the patient and specialist (prior experience, rapport, location, scheduling, preference, and insurance), and interactions between the referring physician and specialist (personal relationships, communication, reputation, reciprocity, and practice or system affiliation). Notably, studies did not describe how providers assess clinical or technical skills. CONCLUSIONS: Referring providers rely on subjective factors and assessments to evaluate quality when selecting a specialist. There may be a role for guidelines and objective measures of quality to inform the choice of specialist by referring providers.

Safinamide improves sleep and daytime sleepiness in Parkinson's disease: results from the SAFINONMOTOR study.

BACKGROUND AND OBJECTIVE: Some studies observed a benefit of PD patients after treatment with safinamide in some non-motor symptoms. Our aim was to analyze the effectiveness of safinamide on sleep and daytime sleepiness in Parkinson's disease (PD) patients. MATERIAL AND METHODS: SAFINONMOTOR is a prospective open-label single-arm study conducted in 5 centers from Spain. In this analysis, a secondary objective of the study, the score in the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) at V1 (baseline) and V4 (6 months ± 1 month) were compared. RESULTS: Fifty patients were included between May/2019 and February/2020 (age 68.5 ± 9.12 years; 58% women; 6.4 ± 5.1 years from diagnosis). At 6 months, 44 patients completed the follow-up (88%). The PSQI total score was reduced by 19.8% (from 10.43 ± 4.02 at V1 to 8.36 ± 4.41 at V4; p = 0.001). By domains, improvement was observed in subjective sleep quality (PSQI-C1; - 23.9%; p = 0.009), sleep latency (PSQI-C2; - 25%; p = 0.025), sleep duration (PSQI-C3; - 40%; p = 0.001), and habitual sleep efficiency (PSQI-C4; - 25.9%; p = 0.023). A significant reduction (- 24.7%) in the ESS total score from V1 to V4 was observed as well (from 9.20 ± 5.64 to 6.93 ± 5.11; p = 0.012). Specifically, the improvement in daytime sleepiness was observed in sitting and reading (p = 0.024) and sitting inactive in a public space (p = 0.027). A total of 21 adverse events in 11 patients (22%) were reported, 5 of which were severe (not related to safinamide). CONCLUSION: Safinamide was well-tolerated and improved sleep and daytime sleepiness in PD patients at 6 months.

The association between sexual orientation, BMI, obesity diagnosis, and provider recommendation for weight management.

BACKGROUND: National data show that lesbian and bisexual women are more likely to be obese compared to straight women. However little is known about whether provider recommendation for weight management varies across these populations. Furthermore, health care providers have explicit and implicit preferences for straight people in comparison to lesbian or gay people. There is little research that exists depicting how this preference affects quality of patient care. The purpose of the study is: to compare, among lesbian, bisexual, and straight females with BMIs ≥ 30: (1) the average Body Mass Index (BMI); (2) receipt of a diagnostic code for obesity; and (3) receipt of a provider recommendation for weight management. METHODS: We performed a cross-sectional study of 534 patient records from four outpatient academic internal medicine practices at the University of Pennsylvania between January 1, 2019 to December 31, 2019 to determine variations in average BMI, proportion of International Classification of Diseases (ICD)-10 codes for obesity, and proportion of weight management recommendations offered by providers among lesbian, bisexual and straight females with BMIs ≥ 30. We classified provider recommendations as definite, possible, and absent. Multivariable median (BMI outcome only) or logistic regression was used to evaluate the associations between sexual orientation and each of the following outcomes: BMI, receipt of obesity diagnosis, and weight management recommendations. RESULTS: There were no significant differences in BMI, receipt of obesity diagnoses, or weight management recommendations between lesbian, bisexual, and straight females with BMIs ≥ 30. However, only about half the patients with BMIs ≥ 30, regardless of sexual orientation, received a weight management recommendation as recommended by the United States Preventive Services Task Force (USPSTF) guidelines. CONCLUSION: We did not observe disparities in BMI, receipt of obesity diagnoses, or receipt of weight management recommendations between sexual orientation minority and heterosexual females among this sample from an urban population of patients receiving care in a university medical system. However, provider recommendation for weight management was suboptimal in all the groups.

Definitive evidence for Club cells as progenitors for mutant Kras/Trp53-deficient lung cancer.

Accumulating evidence suggests that both the nature of oncogenic lesions and the cell-of-origin can strongly influence cancer histopathology, tumor aggressiveness and response to therapy. Although oncogenic Kras expression and loss of Trp53 tumor suppressor gene function have been demonstrated to initiate murine lung adenocarcinomas (LUADs) in alveolar type II (AT2) cells, clear evidence that Club cells, representing the second major subset of lung epithelial cells, can also act as cells-of-origin for LUAD is lacking. Equally, the exact anatomic location of Club cells that are susceptible to Kras transformation and the resulting tumor histotype remains to be established. Here, we provide definitive evidence for Club cells as progenitors for LUAD. Using in vivo lineage tracing, we find that a subset of Kras12V -expressing and Trp53-deficient Club cells act as precursors for LUAD and we define the stepwise trajectory of Club cell-initiated tumors leading to lineage marker conversion and aggressive LUAD. Our results establish Club cells as cells-of-origin for LUAD and demonstrate that Club cell-initiated tumors have the potential to develop aggressive LUAD.

Post-mastectomy breast reconstruction: reducing the disparity through educational outreach to the underserved.

PURPOSE: Poor health literacy and awareness are thought to be some of the major contributors to existing racial/ethnic disparities in access to breast reconstruction after mastectomy. This study aimed to determine whether physician led, community-based educational symposium improves understanding of breast cancer care and breast reconstruction in underserved populations. METHODS: Annual educational symposiums were held between 2017 and 2019 in underserved communities in the greater Philadelphia area. The symposium consisted of a series of short lectures on breast health, cancer screening, surgical management and reconstruction, patient testimonials, a Q&A panel, and an exhibitor fair. Attendees were given pre- and post-symposium surveys that evaluated knowledge of breast cancer care and reconstruction on a 0-100 scale based on percentage of correct answers. RESULTS: Of 169 individuals, 92%, 91%, and 83% completed pre-symposium, post-symposium, and both surveys, respectively. Median age was 60 years, and 92% were Black. Knowledge/understanding survey scores significantly improved after the symposium (50 vs. 87, p < 0.01). Of all respondents, 92% found the symposium to be useful, 89% were introduced to resources that they were not previously aware of, 90% would recommend the symposium to others, and 91% would pass along the information they learned. CONCLUSION: This study presents an effective and reproducible strategy to increase community awareness and understanding of general breast cancer concepts and breast reconstruction options. Through community outreach and education, physicians can help underserved populations have a better understanding of their potential options for breast reconstruction and ultimately reduce this well documented but inadequately addressed disparity in cancer care.

Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk.

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53-/- ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells.

Genetic diseases associated with defects in primary cilia are classified as ciliopathies. Pancreatic lesions and ductal cysts are found in patients with ciliopathic polycystic kidney diseases suggesting a close connection between pancreatic defects and primary cilia. Here we investigate the role of two genes whose deletion is known to cause primary cilium defects, namely Hnf6 and Lkb1, in pancreatic ductal homeostasis. We find that mice with postnatal duct-specific deletion of Hnf6 or Lkb1 show duct dilations. Cells lining dilated ducts present shorter cilia with swollen tips, suggesting defective intraciliary transport. This is associated with signs of chronic pancreatitis, namely acinar-to-ductal metaplasia, acinar proliferation and apoptosis, presence of inflammatory infiltrates, fibrosis and lipomatosis. Our data reveal a tight association between ductal ciliary defects and pancreatitis with perturbed acinar homeostasis and differentiation. Such injuries can account for the increased risk to develop pancreatic cancer in Peutz-Jeghers patients who carry LKB1 loss-of-function mutations.