ABSTRACT
Metastatic pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of only 11%, necessitating identification of novel treatment paradigms. Tumor tissue specimens from patients with PDAC, breast cancer, and other solid tumor malignancies were collected and tumor cells were enriched using laser microdissection (LMD). Reverse phase protein array (RPPA) analysis was performed on enriched tumor cell lysates to quantify a 32-protein/phosphoprotein biomarker panel comprising known anticancer drug targets and/or cancer-related total and phosphorylated proteins, including HER2Total, HER2Y1248, and HER3Y1289. RPPA analysis revealed significant levels of HER2Total in PDAC patients at abundances comparable to HER2-positive (IHC 3+) and HER2-low (IHC 1+ /2+ , FISH-) breast cancer tissues, for which HER2 screening is routinely performed. These data support a critical unmet need for routine clinical evaluation of HER2 expression in PDAC patients and examination of the utility of HER2-directed antibody-drug conjugates in these patients.
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PURPOSEOF REVIEW: This review examines the challenges of treating gastrointestinal cancer in the aging population, focusing on the importance of frailty assessment. Emphasized are the rise in gastrointestinal cancer incidence in older adults, advances in frailty assessments for patients with gastrointestinal cancer, the development of novel frailty markers, and a summary of recent trials. RECENT FINDINGS: Increasing evidence suggests that the use of a Comprehensive Geriatric Assessment (CGA) to identify frail older adults and individualize cancer care leads to lower toxicity and improved quality of life outcomes. However, the adoption of a full CGA prior to chemotherapy initiation in older cancer patients remains low. Recently, new frailty screening tools have emerged, including assessments designed to specifically predict chemotherapy-related adverse events. Additionally, frailty biomarkers have been developed, such as blood tests like IL-6 and performance tracking through physical activity monitors. The relevance of nutrition and muscle mass is discussed. Highlights from recent trials suggest the feasibility of successfully identifying patients most at risk of serious adverse events. There have been promising developments in identifying novel frailty markers and methods to screen for frailty in the older adult population. Further prospective trials that focus on and address the needs of the geriatric population for early identification of frailty in cancer care, facilitating a more tailored treatment approach. Practicing oncologists should select a frailty assessment to implement into their routine practice and adjust treatment accordingly.
Subject(s)
Frailty , Gastrointestinal Neoplasms , Humans , Aged , Frailty/diagnosis , Quality of Life , Frail Elderly , Gastrointestinal Neoplasms/diagnosis , Risk Assessment , Geriatric Assessment/methodsABSTRACT
Cholangiocarcinomas are an aggressive group of heterogeneous malignancies that affect over 210,000 individuals globally each year. Their incidence is rising, particularly in Western countries. Traditionally, cholangiocarcinomas are classified based on anatomic location of the tumor and are treated with similar cytotoxic chemotherapy despite significant molecular and genomic differences. With the rise of genetic and molecular sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches. The most common genomic alterations include changes in FGFR2, IDH1, KRAS, BRAF, HER2, and the tumor suppressor p53. In addition, increased understanding of the cellular and molecular constituents of the tumor microenvironment (TME) has created opportunities for further novel therapeutic approaches. New strategies using combination therapies targeting driver mutations and various components of the TME hold promise for improved patient outcomes. This review covers the evolving molecular and therapeutic landscape of cholangiocarcinoma.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/therapy , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/therapy , Genomics , Humans , Molecular Targeted Therapy , Mutation , Tumor Microenvironment/geneticsABSTRACT
OPINION STATEMENT: Pancreatic cancer is increasing in incidence in the USA. This disease disproportionately affects older adults, and as the percentage of adults > 65 years old increases with the aging of the baby boomers, the prevalence is expected to rise over the coming decade. These patients are often more susceptible to disease-related symptoms and have less ability to withstand both cancer and treatment-related side effects. Therefore, it is imperative that treating physicians thoughtfully consider their recommended treatment approach towards this vulnerable patient population. This review focuses on the current state of research of older adults with pancreatic adenocarcinoma, highlighting deficiencies in the representation of this patient population in clinical trials. It is vital that the treating physicians take a nuanced approach towards therapy of localized and metastatic disease in geriatric patients. A one size fits all treatment algorithm is no longer appropriate in any cancer patient, let alone the elders who are particularly vulnerable to developing treatment-related toxicities. To help guide therapy decisions, it is important to perform a comprehensive geriatric assessment which may uncover unexpected frailty and lead to a change in the recommended treatment approach. In this way, we can support older adults during therapy for this aggressive malignancy and provide optimal care.
Subject(s)
Pancreatic Neoplasms/therapy , Age Factors , Aged , Aged, 80 and over , Clinical Decision-Making , Clinical Trials as Topic , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Disease Management , Geriatric Assessment , Humans , Incidence , Neoplasm Grading , Neoplasm Staging , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/etiology , Prognosis , Treatment OutcomeABSTRACT
Immune checkpoint blockade (ICB) is an approved therapy for advanced metastatic mismatch repair (MMR)-deficient cancer regardless of tissue of origin. Although therapy is effective initially, recurrence rates are significant, and long-term outcomes remain poor for most patients. It is not currently recommended to give sequential ICB for advanced MMR-deficient colorectal cancer (CRC) or for patients with metastatic cancer from Lynch syndrome. The need for subsequent therapy options in advanced MMR-deficient cancer beyond the first ICB regimen arises in clinical practice, and there are often no effective standard chemotherapies or other targeted therapies. We report the case of a Lynch syndrome patient with metastatic CRC and urothelial cancer who was treated sequentially with pembrolizumab (targeting PD1), atezolizumab (targeting PD-L1), brief rechallenge with pembrolizumab, and finally the combination of ipilimumab (targeting CTLA-4) and nivolumab (targeting PD1). Over a 28-month period the patient experienced prolonged disease control with each different regimen the first time it was given, including metabolic response by positron emission tomography and computed tomography scanning and tumor marker reductions. The case suggests that some patients with advanced MMR-deficient CRC may experience meaningful clinical benefit from multiple sequential ICB regimens, a strategy that can be further tested in clinical trials. KEY POINTS: The case exemplifies clinical benefit from sequential immune checkpoint blockade in a patient with Lynch syndrome with advanced metastatic colorectal cancer and urothelial cancer.Metabolic response, with decreased fluorodeoxyglucose avidity on positron emission tomography and computed tomography, and reductions in tumor markers, such as carcinoembryonic antigen, were helpful in this case to monitor disease status over a 28-month period of therapy.The concept of sequential immune checkpoint blockade in patients with advanced mismatch repair-deficient cancer merits further study to determine which patients are most likely to benefit.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Colonic Neoplasms/drug therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Urologic Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Colonic Neoplasms/complications , Colonic Neoplasms/secondary , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , Humans , Ipilimumab/administration & dosage , Male , Middle Aged , Nivolumab/administration & dosage , Prognosis , Urologic Neoplasms/complications , Urologic Neoplasms/pathologySubject(s)
Lupus Erythematosus, Systemic/complications , Primary Myelofibrosis/complications , Adult , Bone Marrow/pathology , Erythropoiesis , Female , Humans , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/pathology , Primary Myelofibrosis/blood , Primary Myelofibrosis/pathologySubject(s)
Cryoglobulinemia/pathology , Erythrocytes/pathology , Bone Marrow/pathology , Cryoglobulinemia/blood , Cryoglobulinemia/complications , Cryoglobulins/analysis , Hemolysis , Hepatitis C/blood , Hepatitis C/complications , Hepatitis C/pathology , Humans , Lymphoma, B-Cell/blood , Lymphoma, B-Cell/complications , Lymphoma, B-Cell/pathology , Male , Middle AgedABSTRACT
BACKGROUND AND OBJECTIVE: While successful treatment paradigms for BRAF V600 mutations have been developed, 10% of BRAF mutations are not at V600 and lack a standard treatment regimen. This study summarizes the current body of knowledge on the treatment of non-V600 mutations and reports a single institution experience. METHODS: We conducted a literature review to summarize relevant preclinical and clinical published data on the response of non-V600 mutations to targeted therapies. We performed a retrospective analysis of INOVA Schar Cancer patients registered in our Molecular Tumor Board database with non-V600 BRAF mutations who were recipients of targeted therapy and assessed their time to next treatment and best response. RESULTS: Published preclinical and clinical data have demonstrated limiting results in the response of non-V600 mutated cancers to targeted therapies. Response rates were variable for the major classes of BRAF mutations including class II and class III mutations as well as, BRAF fusions. Data collected from our INOVA cohort offered promising results with one patient achieving partial remission and two patients achieving stable disease. CONCLUSIONS: This article reflects the current understanding of targeted therapies in non-V600 mutations. Further large-scale studies separating BRAF mutations based on their mechanism of activation will expand our understanding.
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PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with ATM mutations treated with nivolumab plus ipilimumab are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16 weeks duration (SD16+). Low-accruing histology-specific cohorts with ATM mutations treated with nivolumab plus ipilimumab were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated based on a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = .84; α = .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-nine patients with 10 tumor types with ATM mutations were enrolled from January 2018 to May 2020. One patient was not evaluable for efficacy. One CR, three PR, and three SD16+ were observed for DC and OR rates of 24% (P = .13; one-sided 90% CI: 14 to 100) and 14% (95% CI: 4 to 32), respectively. The null hypothesis of 15% DC rate was not rejected. Eleven patients had one treatment-related grade 3 adverse event (AE) or serious AE. There were two treatment-related patient deaths including immune-related encephalitis and respiratory failure. CONCLUSION: Nivolumab plus ipilimumab did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with ATM mutations.
Subject(s)
Antineoplastic Agents , Melanoma , Humans , Nivolumab/therapeutic use , Ipilimumab/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Melanoma/genetics , Mutation , Ataxia Telangiectasia Mutated Proteins/geneticsABSTRACT
High ambient ultrafine particle (UFP) concentrations may play an important role in the adverse health effects associated with living near busy roadways. However, UFP size distributions change rapidly as vehicle emissions dilute and age. These size changes can influence UFP lung deposition rates and dose because deposition in the respiratory system is a strong function of particle size. Few studies to date have measured and characterized changes in near-road UFP size distributions in real-time, thus missing transient variations in size distribution due to short-term fluctuations in wind speed, direction, or particle dynamics. In this study we measured important wind direction effects on near-freeway UFP size distributions and gradients using a mobile platform with 5-s time resolution. Compared to more commonly measured perpendicular (downwind) conditions, parallel wind conditions appeared to promote formation of broader and larger size distributions of roughly one-half the particle concentration. Particles during more parallel wind conditions also changed less in size with downwind distance and the fraction of lung-deposited particle number was calculated to be 15% lower than for downwind conditions, giving a combined decrease of about 60%. In addition, a multivariate analysis of several variables found meteorology, particularly wind direction and temperature, to be important in predicting UFP concentrations within 150 m of a freeway (R2 = 0.46, p = 0.014).
ABSTRACT
We observed elevated air pollutant concentrations, especially of ultrafine particles (UFP), black carbon (BC) and NO, across the residential neighborhood of the Boyle Heights Community (BH) of Los Angeles, California. Using an electric vehicle mobile platform equipped with fast response instruments, real-time air pollutant concentrations were measured in BH in spring and summer of 2008. Pollutant concentrations varied significantly in the two seasons, on different days, and by time of day, with an overall average UFP concentration in the residential areas of ~33 000 cm-3. The averaged UFP, BC, and NO concentrations measured on Soto St, a major surface street in BH, were 57 000 cm-3, 5.1 µg m-3, and 67 ppb, respectively. Concentrations of UFP across the residential areas in BH were nearly uniform spatially, in contrast to other areas in the greater metropolitan area of Los Angeles where UFP concentrations exhibit strong gradients downwind of roadways. We attribute this "UFP cloud" to high traffic volumes, including heavy duty diesel trucks on the freeways which surround and traverse BH, and substantial numbers of high-emitting vehicles (HEVs) on the surface streets traversing BH. Additionally, the high density of stop signs and lights and short block lengths, requiring frequent accelerations of vehicles, may contribute. The data also support a role for photochemical production of UFP in the afternoon. UFP concentration peaks (5 s average) of up to 9 million particles cm-3 were also observed immediately behind HEVs when they accelerated from stop lights in the BH neighborhood and areas immediately adjacent. Although encounters with HEV during mornings accounted for only about 6% and 17% of time spent monitoring residential areas and major surface streets, HEV contributed to about 28% and 53% of total ultrafine particles measured on the route, respectively. The observation of elevated pollutant number concentrations across the Boyle Heights community highlights how multiple factors combine to create high pollutant levels, and has important human exposure assessment implications, including the potential utility of our data as inputs to epidemiological studies.
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BACKGROUND: BRAF V600E+ microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients comprise up to 10% of advanced CRC. They have a poor prognosis with a median survival typically <1 year. Despite use of multi-agent 1st line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board (MTB) database, we identified 3 mCRC patients with MSS/BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had relatively long overall survivals. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. METHODS: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes (BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis of BRAF V600E co-mutated with BRCA1 and BRCA2 were separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation were collected and analyzed. We also describe 3 consecutive cases of mCRC patients, identified through the Inova Schar Cancer Institute (ISCI) MTB registry, whom had prolonged OS. RESULTS: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% of the total mCRC population having co-ocurring BRAF V600E and BRCA1/2 alterations. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of co-occurrences were observed in MSS samples. BRCA1 co-mutation was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, all somatic in origin, with an average gLOH of 21.4% and overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. CONCLUSION: Co-existence of BRAF V600E/BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. The elevated gLOH in these cases may also be a valuable biomarker for these pts. Larger prospective clinical validation trials in this subset is warranted.
Subject(s)
Colorectal Neoplasms , Proto-Oncogene Proteins B-raf , Colonic Neoplasms/diagnosis , Colonic Neoplasms/genetics , Colonic Neoplasms/secondary , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/secondary , Genes, BRCA1 , Genes, BRCA2 , Humans , Microsatellite Instability , Mutation , Prevalence , Prognosis , Prospective Studies , Proto-Oncogene Proteins B-raf/genetics , Rectal Neoplasms/diagnosis , Rectal Neoplasms/genetics , Rectal Neoplasms/secondaryABSTRACT
Fuel-based emission factors for 143 light-duty gasoline vehicles (LDGVs) and 93 heavy-duty diesel trucks (HDDTs) were measured in Wilmington, CA using a zero-emission mobile measurement platform (MMP). The frequency distributions of emission factors of carbon monoxide (CO), nitrogen oxides (NO(x)), and particle mass with aerodynamic diameter below 2.5 microm (PM2.5) varied widely, whereas the average of the individual vehicle emission factors were comparable to those reported in previous tunnel and remote sensing studies as well as the predictions by Emission Factors (EMFAC) 2007 mobile source emission model for Los Angeles County. Variation in emissions due to different driving modes (idle, low- and high-speed acceleration, low- and high-speed cruise) was found to be relatively small in comparison to intervehicle variability and did not appear to interfere with the identification of high emitters, defined as the vehicles whose emissions were more than 5 times the fleet-average values. Using this definition, approximately 5% of the LDGVs and HDDTs measured were high emitters. Among the 143 LDGVs, the average emission factors of NO(x), black carbon (BC), PM2.5, and ultrafine particle (UFP) would be reduced by 34%, 39%, 44%, and 31%, respectively, by removing the highest 5% of emitting vehicles, whereas CO emission factor would be reduced by 50%. The emission distributions of the 93 HDDTs measured were even more skewed: approximately half of the NO(x) and CO fleet-average emission factors and more than 60% of PM2.5, UFP, and BC fleet-average emission factors would be reduced by eliminating the highest-emitting 5% HDDTs. Furthermore, high emissions of BC, PM2.5, and NO(x) tended to cluster among the same vehicles.
Subject(s)
Environmental Monitoring/methods , Vehicle Emissions/analysis , Air Pollutants/analysis , Los Angeles , Motor Vehicles , Particle Size , Particulate MatterABSTRACT
Background: Gemcitabine and nab-paclitaxel (GA) is a first-line treatment for patients with metastatic pancreatic cancer (mPDAC). The traditional dosing schedule of GA is days 1, 8, and 15 of a 28-day cycle. Frequently, older adults are given a modified dosing schedule using 2 doses per cycle because of toxicity. We retrospectively analyzed treatment patterns and outcomes of older adults with mPDAC given these 2 dosing schedules. Methods: Patients 65 years or older with mPDAC treated with GA in a nationwide real-world database between January 1, 2014, and May 31, 2019, were included. Demographic, disease, and treatment information were collected. Patients were grouped by dosing at treatment initiation (traditional vs modified dosing schedules). Endpoints were time on treatment (TOT) and overall survival (OS) in patients receiving at least 2 cycles. All statistical tests were 2-sided. Results: 1317 patients were included (traditional dosing schedule: n = 842; modified dosing schedule: n = 475). Median age at diagnosis was 72 and 73 years for traditional and modified dosing schedules, respectively (P < .001), but sex, race, and performance status were not statistically significantly different. The median TOT and OS were better for the traditional vs modified dosing schedule (unadjusted median TOT, first-line = 4.18 vs 3.26 mo, P =.04; OS = 9.44 vs 7.63 mo, P =.003). Conclusion: In this real-world cohort, treatment of older mPDAC patients with a modified dosing schedule of GA resulted in shorter TOT and worse OS vs a traditional dosing schedule. With the caveats of potential confounding that exist in a nonrandomized retrospective database, these results suggest that dose intensity may be important, and prospective studies are necessary to ensure we treat our patients most effectively.
Subject(s)
Albumins/administration & dosage , Antineoplastic Agents/administration & dosage , Deoxycytidine/analogs & derivatives , Paclitaxel/administration & dosage , Pancreatic Neoplasms/drug therapy , Aged , Aged, 80 and over , Databases as Topic , Deoxycytidine/administration & dosage , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , Male , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Racial Groups , Retrospective Studies , Sex Factors , Treatment Outcome , GemcitabineABSTRACT
[This corrects the article DOI: 10.3389/fonc.2018.00652.].
ABSTRACT
BACKGROUND: Quinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC. PATIENTS AND METHODS: Using a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m2 twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP). RESULTS: Ten patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients. CONCLUSION: Capecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Capecitabine/administration & dosage , Colorectal Neoplasms/drug therapy , Quinacrine/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine/adverse effects , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Drug Administration Schedule , Drug Resistance, Neoplasm , Humans , Male , Maximum Tolerated Dose , Middle Aged , Progression-Free Survival , Quinacrine/adverse effectsABSTRACT
We have observed a wide area of air pollutant impact downwind of a freeway during pre-sunrise hours in both winter and summer seasons. In contrast, previous studies have shown much sharper air pollutant gradients downwind of freeways, with levels above background concentrations extending only 300 m downwind of roadways during the day and up to 500 m at night. In this study, real-time air pollutant concentrations were measured along a 3 600 m transect normal to an elevated freeway 1-2 hours before sunrise using an electric vehicle mobile platform equipped with fast-response instruments. In winter pre-sunrise hours, the peak ultrafine particle (UFP) concentration (~95 000 cm-3) occurred immediately downwind of the freeway. However, downwind UFP concentrations as high as ~ 40 000 cm-3 extended at least 1 200 m from the freeway, and did not reach background levels (~15 000 cm-3) until a distance of about 2 600 m. UFP concentrations were also elevated over background levels up to 600 m upwind of the freeway. Other pollutants, such as NO and particle-bound polycyclic aromatic hydrocarbons, exhibited similar long-distance downwind concentration gradients. In contrast, air pollutant concentrations measured on the same route after sunrise, in the morning and afternoon, exhibited the typical daytime downwind decrease to background levels within ~300 m as found in earlier studies. Although pre-sunrise traffic volumes on the freeway were much lower than daytime congestion peaks, downwind UFP concentrations were significantly higher during pre-sunrise hours than during the daytime; UFP and NO concentrations were also strongly correlated with traffic counts on the freeway. We associate these elevated pre-sunrise concentrations over a wide area with a nocturnal surface temperature inversion, low wind speeds, and high relative humidity. Observation of a wide air pollutant impact area downwind of a major roadway prior to sunrise has important exposure assessment implications since it demonstrates extensive roadway impacts on residential areas during pre-sunrise hours, when most people are at home.
ABSTRACT
Background: The prognosis of patients with metastatic colorectal cancer (mCRC) is poor, especially after failure of initial systemic therapy. The VELOUR study showed modestly prolonged overall survival (OS) with ziv-aflibercept plus 5-fluorouracil, leucovorin, and irinotecan (zFOLFIRI) vs. placebo+FOLFIRI after progression on 5-fluoruracil, leucovorin, and oxaliplatin (FOLFOX) ± bevacizumab. The utility of zFOLFIRI after bevacizumab+FOLFIRI is unknown and not recommended in NCCN guidelines. We explored whether zFOLFIRI may be active beyond progression on bevacizumab+FOLFIRI. Methods: We undertook a retrospective analysis of patients treated in routine clinical practice. A chart review was conducted for a cohort (N = 19) of advanced cancer patients (18 mCRC) who received zFOLFIRI from 2014 to 2018 at Fox Chase Cancer Center (FCCC). Analysis included time on zFOLFIRI, PFS, OS, CEA trends and adverse events. A second mCRC cohort (N = 26) from the Flatiron Health EHR-derived database treated with zFOLFIRI after prior bevacizumab+FOLFOX and bevacizumab+FOLFIRI was analyzed for time-on-treatment and overall survival. Results: Median age of mCRC cohort at zFOLFIRI treatment was 54 (FCCC; N = 18) and 62 (Flatiron Health-cohort; N = 26). Of 18 FCCC mCRC patients, 1 patient had prior bevacizumab+FOLFOX and ramucirumab+irinotecan prior to zFOLFIRI for 8.5 months. Of 17 FCCC mCRC patients with prior bevacizumab+FOLFIRI who received zFOLFIRI, 13 had mutant-KRAS, 3 WT-KRAS, and one BRAF-V600E. The patient with BRAF-V600E mutation achieved stable disease on zFOLFIRI after multiple BRAF-targeted therapies. One patient (WT-KRAS mCRC) remained on zFOLFIRI for 14 months. Of 14 patients with mutated-KRAS, 8 remained on zFOLFIRI for >5 months including 3 for >15 months. The rate-of-change in CEA measures on zFOLFIRI was significantly different (p = 0.004) between rapid progressors and those with PFS>4 months. For mCRC patients treated with zFOLFIRI in the 3rd line or greater (N = 18), median PFS was 7.1 months (214 days) and median OS was 13.8 months (416 days). Median time-on-treatment with zFOLFIRI in the Flatiron Health cohort was 4.4 months, median OS was 7.8 months, and longest time-on-treatment with zFOLFIRI was 266 days. Conclusions: In these small real-world cohorts, clinical meaningful stable disease and overall survival on zFOLFIRI beyond progression on bevacizumab+FOLFIRI was observed in patients with mCRC. Further exploration of this approach is warranted.
ABSTRACT
The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden. Mol Cancer Ther; 17(6); 1147-55. ©2018 AACR.
Subject(s)
Antineoplastic Agents/therapeutic use , Matrix Metalloproteinase Inhibitors/therapeutic use , Molecular Targeted Therapy , Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Clinical Trials as Topic , Disease Progression , Disease Susceptibility , Humans , Matrix Metalloproteinase Inhibitors/pharmacology , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Neoplasms/metabolism , Neoplasms/mortality , Neoplasms/pathology , Treatment OutcomeABSTRACT
Immunotherapy has revolutionized the field of oncology. By inhibiting the cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed death-1 (PD-1) immune checkpoint pathways, multiple studies have demonstrated greatly improved survival in locally advanced and metastatic cancers including melanoma, renal, lung, gastric, and hepatocellular carcinoma. Trials in other malignancies are ongoing, and undoubtedly the number of drugs in this space will grow beyond the six currently approved by the Food and Drug Administration. However, by altering the immune response to fight cancer, a new class of side effects has emerged known as immune-related adverse events (irAEs). These adverse events are due to overactivation of the immune system in almost any organ of the body, and can occur at any point along a patient's treatment course. irAEs such as endocrinopathies (thyroiditis), colitis, and pneumonitis may occur more commonly. However, other organs such as the liver, heart, or brain may also be affected by immune overactivation and any of these side effects may become life threatening. This review presents an approach to promptly recognize and manage these toxicities, to hopefully minimize morbidity and mortality from irAEs.