Patients frequently voice concerns regarding wait times for cancer treatment; however, little is known about the length of wait times from diagnosis to surgery in the United States. Our objectives ...were (1) to assess changes in wait times over the past decade and (2) to identify patient, tumor, and hospital factors associated with prolonged wait times for initial cancer treatment.
Using the National Cancer Data Base (1995-2005), 1,228,071 patients were identified who underwent resection for nonmetastatic breast, colon, esophageal, gastric, liver, lung, pancreatic, and rectal cancer at 1443 hospitals. Multivariable models were developed to assess factors associated with time to treatment.
From 1995 to 2005, the median time from diagnosis to treatment increased for all cancers (P < 0.0001). The time from diagnosis to treatment was significantly longer at National Cancer Institute Comprehensive Cancer Centers and Veterans' Administration institutions versus community hospitals (P < 0.0001). On multivariable analysis, patients were significantly more likely to undergo initial treatment > 30 days from diagnosis if older (6 of 8 cancers), black (5 of 8 cancers), had more comorbidities (6 of 8 cancers), had Stage I disease (7 of 8 cancers), or were treated at National Cancer Institute Comprehensive Cancer Centers or Veterans' Affairs institutions (all cancers).
Wait times for cancer treatment have increased over the last decade. As case loads increase, wait times for treatment are likely to continue increasing, potentially resulting in additional treatment delay. Additional resources and strategies are needed to reduce wait times for cancer treatment in the United States.
Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which ...pancreatic CSCs are maintained are not well understood or characterized.
Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth.
Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population.
The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.
Five newly isolated mycobacteriophages--Angelica, CrimD, Adephagia, Anaya, and Pixie--have similar genomic architectures to mycobacteriophage TM4, a previously characterized phage that is widely used ...in mycobacterial genetics. The nucleotide sequence similarities warrant grouping these into Cluster K, with subdivision into three subclusters: K1, K2, and K3. Although the overall genome architectures of these phages are similar, TM4 appears to have lost at least two segments of its genome, a central region containing the integration apparatus, and a segment at the right end. This suggests that TM4 is a recent derivative of a temperate parent, resolving a long-standing conundrum about its biology, in that it was reportedly recovered from a lysogenic strain of Mycobacterium avium, but it is not capable of forming lysogens in any mycobacterial host. Like TM4, all of the Cluster K phages infect both fast- and slow-growing mycobacteria, and all of them--with the exception of TM4--form stable lysogens in both Mycobacterium smegmatis and Mycobacterium tuberculosis; immunity assays show that all five of these phages share the same immune specificity. TM4 infects these lysogens suggesting that it was either derived from a heteroimmune temperate parent or that it has acquired a virulent phenotype. We have also characterized a widely-used conditionally replicating derivative of TM4 and identified mutations conferring the temperature-sensitive phenotype. All of the Cluster K phages contain a series of well conserved 13 bp repeats associated with the translation initiation sites of a subset of the genes; approximately one half of these contain an additional sequence feature composed of imperfectly conserved 17 bp inverted repeats separated by a variable spacer. The K1 phages integrate into the host tmRNA and the Cluster K phages represent potential new tools for the genetics of M. tuberculosis and related species.
More than 20,000 firearm suicides occur every year in America. Firearm restrictive legislation, firearm access, demographics, behavior, access to care, and socioeconomic metrics have been correlated ...to firearm suicide rates. Research to date has largely evaluated these contributors singularly. We aimed to evaluate them together as they exist in society. We hypothesized that state firearm laws would be associated with reduced firearm suicide rates.
We acquired the 2013 to 2016 data for firearm suicide rates from The Centers for Disease Control Wide-ranging Online Data for Epidemiologic Research. Firearm laws were obtained from the State Firearms Law Database. Depression rates and access to care were obtained from the Behavioral Risk Factor Surveillance System and Occupational Employment and Wage Statistics program. Population demographics, poverty, and access to social support were obtained from the American Community Survey. Firearm access estimates were retrieved from the National Instant Criminal Background Check System. We used a univariate panel linear regression with fixed effect for state and firearm suicide rates as the outcome. We created a final multivariable model to determine the adjusted associations of these factors with firearm suicide rates.
In univariate analysis, firearm access, heavy drinking behavior, demographics, and access to care correlated to increased firearm suicide rates. The state proportion identifying as white and the proportion of those in poverty receiving food benefits correlated to decreased firearm suicide rates. In multivariable regression, only heavy drinking (β, 0.290; 95% confidence interval, 0.092–0.481; P = .004) correlated to firearm suicides rates increases.
During our study, few firearm laws changed. Heavy drinking behavior association with firearm suicide rates suggests an opportunity for interventions exists in the health care setting.
Bald eagles (Haliaeetus leucocephalus) are considered a recovery success in the United States after rebounding from near extirpation due to widespread use of the insecticide ...dichlorodiphenyltrichloroethane (DDT) in the twentieth century. Although abundances of bald eagles have increased since DDT was banned, other contaminants have remained in the environment with unknown influence on eagle population trends. Ingestion of spent lead (Pb) ammunition, the source of Pb most available to eagles and other scavengers in the United States, is known to kill individual eagles, but the influence of the contaminant on overall population dynamics remains unclear, resulting in longstanding controversy over the continued legality of the use of Pb in terrestrial hunting ammunition. We hypothesized that mortalities from the ingestion of Pb reduced the long‐term growth rate and resiliency of bald eagles in the northeast United States over the last 3 decades. We used Holling's definition of resilience (the ability of a system to absorb changes of state variables, driving variables, and parameters and still persist) to quantify how reduction in survival from Pb‐associated mortalities reduced the likelihood of population persistence. We used a population matrix model and necropsy records gathered between 1990 and 2018 from a 7‐state area to compare population dynamics under current versus hypothetical Pb‐reduced and Pb‐free scenarios. Despite a robust increase in eagle abundances in the northeast United States over that period, we estimated that deaths arising from ingestion of Pb was associated with a 4.2% (females) and 6.3% (males) reduction in the asymptotic long‐term growth rate (lambda). Comparison between real (current) and counterfactual (Pb‐reduced and Pb‐free) population dynamics indicated that the deaths from acute Pb poisoning were additive because the mortality events were associated with marked reduction in annual survival performance of hatchlings and reproductive females. These shifts in survival performance were further associated with a reduction in resilience for hatchling (95.4%) and breeding (81.6%) female eagles. Counterintuitively, the current conditions produced an increase in resilience (68.9%) for immature and non‐breeding female eagles over hypothetical Pb‐free conditions, suggesting that the population of eagles in the northeast United States reorganized (in a population dynamics sense) to ensure population expansion despite additive mortalities associated with Pb. This study can be used by state and federal wildlife managers or non‐governmental organizations to inform policy surrounding the use of lead ammunition or to educate hunters on the population‐scale effects of their ammunition choices.
Deaths from the ingestion of Pb was associated with a 4.2% reduction in the long‐term growth rate of female bald eagles in the northeast United States over the past 3 decades. This study can be used by state and federal wildlife managers or non‐governmental organizations to educate hunters of the population‐scale effects of their ammunition choices or to inform policy surrounding the use of lead ammunition. Photo credit: Shutterstock.
Peri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus ...capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates.
Cohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas’ Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells.
Patients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50–0.94) and disease-free survival (HR = 0.75, 95% CI 0.58–0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups.
Patients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.
•Better survival in patients treated with fluorouracil plus leucovorin, oxaliplatin and docetaxel.•Better pathological and radiological response to chemotherapy with FLOT.•Higher rates of complete pathological response in patients treated with FLOT.•Patients treated with FLOT were less likely to have a positive resection margin.•Comparable rates of surgical complications, adverse events and chemo completion.
The Australian continent exhibits complex biogeographic patterns but studies of the impacts of Pleistocene climatic oscillation on the mesic environments of the Southern Hemisphere are limited. The ...koala (Phascolarctos cinereus), one of Australia's most iconic species, was historically widely distributed throughout much of eastern Australia but currently represents a complex conservation challenge. To better understand the challenges to koala genetic health, we assessed the phylogeographic history of the koala. Variation in the maternally inherited mitochondrial DNA (mtDNA) Control Region (CR) was examined in 662 koalas sampled throughout their distribution. In addition, koala CR haplotypes accessioned to Genbank were evaluated and consolidated. A total of 53 unique CR haplotypes have been isolated from koalas to date (including 15 haplotypes novel to this study). The relationships among koala CR haplotypes were indicative of a single Evolutionary Significant Unit and do not support the recognition of subspecies, but were separated into four weakly differentiated lineages which correspond to three geographic clusters: a central lineage, a southern lineage and two northern lineages co-occurring north of Brisbane. The three geographic clusters were separated by known Pleistocene biogeographic barriers: the Brisbane River Valley and Clarence River Valley, although there was evidence of mixing amongst clusters. While there is evidence for historical connectivity, current koala populations exhibit greater structure, suggesting habitat fragmentation may have restricted female-mediated gene flow. Since mtDNA data informs conservation planning, we provide a summary of existing CR haplotypes, standardise nomenclature and make recommendations for future studies to harmonise existing datasets. This holistic approach is critical to ensuring management is effective and small scale local population studies can be integrated into a wider species context.
Objectives
2-deoxy-2
18
FFluoro-
d
-glucose (FDG) PET-CT has an emerging role in assessing response to neoadjuvant therapy in oesophageal cancer. This study evaluated FDG PET-CT in predicting ...pathological tumour response (pTR), pathological nodal response (pNR) and survival.
Methods
Cohort study of 75 patients with oesophageal or oesophago-gastric junction (GOJ) adenocarcinoma treated with neoadjuvant chemotherapy then surgery at Guy’s and St Thomas’ NHS Foundation Trust, London (2017–2020). Standardised uptake value (SUV) metrics on pre- and post-treatment FDG PET-CT in the primary tumour (mTR) and loco-regional lymph nodes (mNR) were derived. Optimum SUV
max
thresholds for predicting pathological response were identified using receiver operating characteristic analysis. Predictive accuracy was compared to PERCIST (30% SUV
max
reduction) and MUNICON (35%) criteria. Survival was assessed using Cox regression.
Results
Optimum tumour SUV
max
decrease for predicting pTR was 51.2%. A 50% cut-off predicted pTR with 73.5% sensitivity, 69.2% specificity and greater accuracy than PERCIST or MUNICON (area under the curve AUC 0.714, PERCIST 0.631, MUNICON 0.659). Using a 30% SUV
max
threshold, mNR predicted pNR with high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%,
p
=
0.010
). pTR, mTR, pNR and mNR were independent predictive factors for survival (pTR hazard ratio HR 0.10 95% confidence interval CI 0.03–0.34; mTR HR 0.17 95% CI 0.06–0.48; pNR HR 0.17 95% CI 0.06–0.54; mNR HR 0.13 95% CI 0.02–0.66).
Conclusions
Metabolic tumour and nodal response predicted pTR and pNR, respectively, in patients with oesophageal or GOJ adenocarcinoma. However, currently utilised response criteria may not be optimal. pTR, mTR, pNR and mNR were independent predictors of survival.
Key Points
• FDG PET-CT has an emerging role in evaluating response to neoadjuvant therapy in patients with oesophageal cancer.
• Prospective cohort study demonstrated that metabolic response in the primary tumour and lymph nodes was predictive of pathological response in a cohort of patients with adenocarcinoma of the oesophagus or oesophago-gastric junction treated with neoadjuvant chemotherapy followed by surgical resection.
• Patients who demonstrated a response to neoadjuvant chemotherapy in the primary tumour or lymph nodes on FDG PET-CT demonstrated better survival and reduced rates of tumour recurrence.
The development of new treatments for castrate resistant prostate cancer (CRPC) must address such challenges as intrinsic tumor heterogeneity and phenotypic plasticity. Combined PTEN/TP53 alterations ...represent a major genotype of CRPC (25-30%) and are associated with poor outcomes. Using tumor-derived, castration-resistant Pten/Tp53 null luminal prostate cells for comprehensive, high-throughput, mechanism-based screening, we identified several vulnerabilities among >1900 compounds, including inhibitors of: PI3K/AKT/mTOR, the proteasome, the cell cycle, heat shock proteins, DNA repair, NFκB, MAPK, and epigenetic modifiers. HSP90 inhibitors were one of the most active compound classes in the screen and have clinical potential for use in drug combinations to enhance efficacy and delay the development of resistance. To inform future design of rational drug combinations, we tested ganetespib, a potent second-generation HSP90 inhibitor, as a single agent in multiple CRPC genotypes and phenotypes. Ganetespib decreased growth of endogenous Pten/Tp53 null tumors, confirming therapeutic activity in situ. Fifteen human CRPC LuCaP PDX-derived organoid models were assayed for responses to 110 drugs, and HSP90 inhibitors (ganetespib and onalespib) were among the select group of drugs (<10%) that demonstrated broad activity (>75% of models) at high potency (IC50 <1 µM). Ganetespib inhibits multiple targets, including AR and PI3K pathways, which regulate mutually compensatory growth and survival signals in some forms of CRPC. Combined with castration, ganetespib displayed deeper PDX tumor regressions and delayed castration resistance relative to either monotherapy. In all, comprehensive data from near-patient models presents novel contexts for HSP90 inhibition in multiple CRPC genotypes and phenotypes, expands upon HSP90 inhibitors as simultaneous inhibitors of oncogenic signaling and resistance mechanisms, and suggests utility for combined HSP90/AR inhibition in CRPC.
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