A population-scale temporal case-control evaluation of COVID-19 disease phenotype and related outcome rates in patients with cancer in England (UKCCP).

Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality. We observed that the SARS-CoV-2 disease phenotype has become less severe in patients with cancer and the non-cancer population. Case-hospitalisation rates for patients with cancer dropped from 30.58% in early 2021 to 7.45% in 2022 while case-mortality rates decreased from 20.53% to 3.25%. However, the risk of hospitalisation and mortality remains 2.10x and 2.54x higher in patients with cancer, respectively. Overall, the SARS-CoV-2 disease phenotype is less severe in 2022 compared to 2020 but patients with cancer remain at higher risk than the non-cancer population. Patients with cancer must therefore be empowered to live more normal lives, to see loved ones and families, while also being safeguarded with expanded measures to reduce the risk of transmission.

Systematic review and meta-analysis of the clinical effectiveness of tixagevimab/cilgavimab for prophylaxis of COVID-19 in immunocompromised patients.

Immunocompromised patients, such as those with a haematological malignancy, are at higher risk of SARS-CoV-2 infection, severe outcomes and mortality. Tixagevimab/cilgavimab is a monoclonal antibody combination which binds to the SARS-CoV-2 spike protein. The PROVENT phase III clinical trial reported that tixagevimab/cilgavimab prophylaxis significantly reduced the risk of COVID-19 infection in immunocompromised participants. However, the trial was conducted before the Omicron variant became prevalent. This systematic review and meta-analysis provide an up-to-date summary of the real-world effectiveness of tixagevimab/cilgavimab in immunocompromised patients, including patients with haematological malignancies. Clinical studies from 1 January 2021 to 1 October 2022, which reported breakthrough COVID-19 infections after tixagevimab/cilgavimab, were included. COVID-19-related hospitalisations, intensive care admissions and mortality were also assessed. A meta-analysis was performed to ascertain overall clinical effectiveness. Eighteen studies, with 25 345 immunocompromised participants, including 5438 patients with haematological pathologies, were included in the review. The overall clinical effectiveness of tixagevimab/cilgavimab against COVID-19 breakthrough infection, hospitalisation, intensive care admission and COVID-19-specific mortality was 40.54%, 66.19%, 82.13% and 92.39%, respectively. This review highlights the clinical effectiveness of tixagevimab/cilgavimab at reducing COVID-19 infection and severe outcomes for immunosuppressed individuals, including patients with a haematological malignancy, during the Omicron-predominant era. Real-world studies are important to provide ongoing certainty of the clinical benefit for immunocompromised patients against new SARS-CoV-2 variants.

Association of SARS-CoV-2 Spike Protein Antibody Vaccine Response With Infection Severity in Patients With Cancer: A National COVID Cancer Cross-sectional Evaluation.

Importance: Accurate identification of patient groups with the lowest level of protection following COVID-19 vaccination is important to better target resources and interventions for the most vulnerable populations. It is not known whether SARS-CoV-2 antibody testing has clinical utility for high-risk groups, such as people with cancer. Objective: To evaluate whether spike protein antibody vaccine response (COV-S) following COVID-19 vaccination is associated with the risk of SARS-CoV-2 breakthrough infection or hospitalization among patients with cancer. Design, Setting, and Participants: This was a population-based cross-sectional study of patients with cancer from the UK as part of the National COVID Cancer Antibody Survey. Adults with a known or reported cancer diagnosis who had completed their primary SARS-CoV-2 vaccination schedule were included. This analysis ran from September 1, 2021, to March 4, 2022, a period covering the expansion of the UK's third-dose vaccination booster program. Interventions: Anti-SARS-CoV-2 COV-S antibody test (Elecsys; Roche). Main Outcomes and Measures: Odds of SARS-CoV-2 breakthrough infection and COVID-19 hospitalization. Results: The evaluation comprised 4249 antibody test results from 3555 patients with cancer and 294 230 test results from 225 272 individuals in the noncancer population. The overall cohort of 228 827 individuals (patients with cancer and the noncancer population) comprised 298 479 antibody tests. The median age of the cohort was in the age band of 40 and 49 years and included 182 741 test results (61.22%) from women and 115 737 (38.78%) from men. There were 279 721 tests (93.72%) taken by individuals identifying as White or White British. Patients with cancer were more likely to have undetectable anti-S antibody responses than the general population (199 of 4249 test results [4.68%] vs 376 of 294 230 [0.13%]; P < .001). Patients with leukemia or lymphoma had the lowest antibody titers. In the cancer cohort, following multivariable correction, patients who had an undetectable antibody response were at much greater risk for SARS-CoV-2 breakthrough infection (odds ratio [OR], 3.05; 95% CI, 1.96-4.72; P < .001) and SARS-CoV-2-related hospitalization (OR, 6.48; 95% CI, 3.31-12.67; P < .001) than individuals who had a positive antibody response. Conclusions and Relevance: The findings of this cross-sectional study suggest that COV-S antibody testing allows the identification of patients with cancer who have the lowest level of antibody-derived protection from COVID-19. This study supports larger evaluations of SARS-CoV-2 antibody testing. Prevention of SARS-CoV-2 transmission to patients with cancer should be prioritized to minimize impact on cancer treatments and maximize quality of life for individuals with cancer during the ongoing pandemic.

Antibody response to a third booster dose of SARS-CoV-2 vaccination in adults with haematological and solid cancer: a systematic review.

BACKGROUND: Patients living with cancer are at a significantly increased risk of morbidity and mortality after infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This systematic review aims to investigate the current available evidence about the immunogenicity of SARS-CoV-2 booster vaccines in patients living with cancer. METHODS: A systematic search was undertaken for studies published until March 1, 2022. A systematic narrative review was undertaken to include all studies that evaluated the efficacy of booster vaccines against SARS-CoV-2 in patients with cancer. RESULTS: Fifteen studies encompassing 1205 patients with cancer were included. We found that a booster vaccine dose induced a higher response in patients with solid cancer as compared to haematological malignancies. Recent systemic anticancer therapy does not appear to affect seroconversion in solid organ malignancies, however, there is an association between B-cell depleting therapies and poor seroconversion in haematological patients. CONCLUSIONS: Third booster vaccination induces an improved antibody response to SARS-CoV-2 in adults with haematological and solid cancer, relative to patients who only receive two doses. Access to vaccination boosters should be made available to patients at risk of poor immunological responses, and the provision of fourth doses may be of benefit to this vulnerable population. REGISTRATION: PROSPERO number CRD42021270420.

COVID-19: Third dose booster vaccine effectiveness against breakthrough coronavirus infection, hospitalisations and death in patients with cancer: A population-based study.

PURPOSE: People living with cancer and haematological malignancies are at an increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2. Coronavirus third dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated. METHODS: This study is a population-scale real-world evaluation of the United Kingdom's third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England's national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess the third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population. RESULTS: The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5%, respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Patients with lymphoma had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at an increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01, respectively. p < 0.001 for both). CONCLUSIONS: Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous and lower than the general population. Many patients with cancer will remain at the increased risk of coronavirus infections even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit the disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic.

Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study.

BACKGROUND: People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level. METHODS: In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3-6 months after the second dose in the cancer cohort and control population. FINDINGS: The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8-69·9) in the control population and 65·5% (65·1-65·9) in the cancer cohort. Vaccine effectiveness at 3-6 months was lower in the cancer cohort (47·0%, 46·3-47·6) than in the control population (61·4%, 61·4-61·5). INTERPRETATION: COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer. FUNDING: University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.

A systematic review of the sensitivity and specificity of lateral flow devices in the detection of SARS-CoV-2.

BACKGROUND: Lateral flow devices (LFDs) are viral antigen tests for the detection of SARS-CoV-2 that produce a rapid result, are inexpensive and easy to operate. They have been advocated for use by the World Health Organisation to help control outbreaks and break the chain of transmission of COVID-19 infections. There are now several studies assessing their accuracy but as yet no systematic review. Our aims were to assess the sensitivity and specificity of LFDs in a systematic review and summarise the sensitivity and specificity of these tests. METHODS: A targeted search of Pubmed and Medxriv, using PRISMA principles, was conducted identifying clinical studies assessing the sensitivity and specificity of LFDs as their primary outcome compared to reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of SARS-CoV-2. Based on extracted data sensitivity and specificity was calculated for each study. Data was pooled based on manufacturer of LFD and split based on operator (self-swab or by trained professional) and sensitivity and specificity data were calculated. RESULTS: Twenty-four papers were identified involving over 26,000 test results. Sensitivity from individual studies ranged from 37.7% (95% CI 30.6-45.5) to 99.2% (95% CI 95.5-99.9) and specificity from 92.4% (95% CI 87.5-95.5) to 100.0% (95% CI 99.7-100.0). Operation of the test by a trained professional or by the test subject with self-swabbing produced comparable results. CONCLUSIONS: This systematic review identified that the performance of lateral flow devices is heterogeneous and dependent on the manufacturer. Some perform with high specificity but a great range of sensitivities were shown (38.32-99.19%). Test performance does not appear dependent on the operator. Potentially, LFDs could support the scaling up of mass testing to aid track and trace methodology and break the chain of transmission of COVID-19 with the additional benefit of providing individuals with the results in a much shorter time frame.

A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals.

The CD2-CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a 'CD2 corolla'. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2-CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2-CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8+ tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.

COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study.

BACKGROUND: Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. METHODS: We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. FINDINGS: 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40-49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15-2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2·25, 1·13-4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09-4·08; p=0·028). INTERPRETATION: Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies. FUNDING: University of Birmingham and University of Oxford.

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study.

BACKGROUND: Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer. METHODS: In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission. FINDINGS: From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56-10·02]; p<0·0001), being male (1·67 [1·19-2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36-2·80]; p<0·001) and cardiovascular disease (2·32 [1·47-3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81-1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks. INTERPRETATION: Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment. FUNDING: University of Birmingham, University of Oxford.

Immune checkpoint blockade: releasing the breaks or a protective barrier to COVID-19 severe acute respiratory syndrome?

The rapid emergence of COVID-19 has sent shockwaves through healthcare systems globally, with cancer patients at increased risk. The interplay of the virus and host immune system has been implicated in the development of ARDS. Immunotherapy agents have the potential to adversely potentiate this phenomenon, requiring careful real-world observation.

ToxNav germline genetic testing and PROMinet digital mobile application toxicity monitoring: Results of a prospective single-center clinical utility study-PRECISE study.

INTRODUCTION: In this study (PRECISE), we assess the clinical utility of a germline DNA sequencing-based test (ToxNav) for mutations in DPYD and ENOSF1 genes to alter clinician-prescribed fluoropyrimidine doses and the use of a digital application (PROMinet) to record patient-reported chemotherapy toxicity. MATERIALS AND METHODS: Adult patients with a histological diagnosis of colorectal cancer (CRC) who consented to fluoropyrimidine-based chemotherapy were recruited prospectively and given a digital application to monitor and record associated toxicities. Patient samples were analyzed for 18 germline coding variants in DPYD and 1 ENOSF1 variant. RESULTS: Genetic testing was performed for 60 patients and identified one patient at increased risk of fluoropyrimidine-based toxicities. Uptake of genetic testing was high and results were available on average 17 days from initial clinical encounter. Patient-reported chemotherapy toxicity identified differences in 5-fluorouracil vs capecitabine regime profiles and identified profiles associated with subsequent need for chemotherapy dose reduction and hospital admission. DISCUSSION: The PRECISE clinical trial demonstrated that a germline DNA sequencing-based test can provide clinically relevant information to alter clinicians' fluoropyrimidine prescription. The study also obtained high volume, high granularity patient-reported toxicity data that might allow the improvement and personalization of chemotherapy management.

Cigarette butts have adverse effects on initial growth of perennial ryegrass (gramineae: Lolium perenne L.) and white clover (leguminosae: Trifolium repens L.).

Cigarette filters (butts) are currently the most abundant form of anthropogenic litter on the planet, yet we know very little about their environmental impacts on terrestrial ecosystems, including plant germination and primary production. When discarded, filters contain a myriad of chemicals resulting from smoking tobacco and some still contain unsmoked remnants. A greenhouse experiment was used to assess the impacts of discarded filters of regular or menthol cigarette, either from unsmoked, smoked, or smoked cigarettes with remnant tobacco, on the growth and development of Lolium perenne (perennial ryegrass) and Trifolium repens (white clover). After 21 days, shoot length and germination success were significantly reduced by exposure to any type of cigarette filter for the grass and clover. Although total grass biomass was not measurably affected, the root biomass and root:shoot ratio were less in the clover when exposed to filters from smoked regular cigarettes and those with remnant tobacco. Cigarette filters caused an increase in chlorophyll-a in clover shoots and an increase in chlorophyll-b in grass shoots. Accordingly, whilst the chlorophyll a:b ratio was increased in the clover exposed to cigarette filters, it was decreased in grass. This study indicates the potential for littered cigarette filters to reduce growth and alter short-term primary productivity of terrestrial plants.

Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis.

PURPOSE: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed. RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC. CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.

Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration.

BACKGROUND & AIMS: The mammalian pancreas has a strong regenerative potential, but the origin of organ restoration is not clear, and it is not known to what degree such a process reflects pancreatic development. To define cell differentiation changes associated with pancreatic regeneration in adult mice, we compared regeneration following caerulein-induced pancreatitis to that of normal pancreatic development. METHODS: By performing comparative histology for adult and embryonic pancreatic markers in caerulein-treated and control pancreas, we addressed cellular proliferation and differentiation (amylase, DBA-agglutinin, insulin, glucagon, beta-catenin, E-cadherin, Pdx1, Nkx6.1, Notch1, Notch2, Jagged1, Jagged2, Hes1), hereby describing the kinetics of tissue restoration. RESULTS: We demonstrate that surviving pancreatic exocrine cells repress the terminal exocrine gene program and induce genes normally associated with undifferentiated pancreatic progenitor cells such as Pdx1, E-cadherin, beta-catenin, and Notch components, including Notch1 , Notch2 , and Jagged2 . Expression of the Notch target gene Hes1 provides evidence that Notch signaling is reactivated in dedifferentiated pancreatic cells. Although previous studies have suggested a process of acino-to-ductal transdifferentiation in pancreatic regeneration, we find no evidence to suggest that dedifferentiated cells acquire a ductal fate during this process. CONCLUSIONS: Pancreatic regeneration following chemically induced pancreatitis in the mouse occurs predominantly through acinar cell dedifferentiation, whereby a genetic program resembling embryonic pancreatic precursors is reinstated.