Dynamic altruistic cooperation within breast tumors.

BACKGROUND: Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism's survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast cancer cells and its contribution to chemoresistance. METHODS: MicroRNA profiling was performed on circulating tumor cells collected from the blood of treated breast cancer patients. Cancer cell lines ectopically expressing candidate miRNA were used in co-culture experiments and treated with docetaxel. Ecological parameters like relative survival and relative fitness were assessed using flow cytometry. Functional studies and characterization performed in vitro and in vivo include proliferation, iTRAQ-mass spectrometry, RNA sequencing, inhibition by small molecules and antibodies, siRNA knockdown, CRISPR/dCas9 inhibition and fluorescence imaging of promoter reporter-expressing cells. Mathematical modeling based on evolutionary game theory was performed to simulate spatial organization of cancer cells. RESULTS: Opposing cancer processes underlie altruism: an oncogenic process involving secretion of IGFBP2 and CCL28 by the altruists to induce survival benefits in neighboring cells under taxane exposure, and a self-sacrificial tumor suppressive process impeding proliferation of altruists via cell cycle arrest. Both processes are regulated concurrently in the altruists by miR-125b, via differential NF-κB signaling specifically through IKKß. Altruistic cells persist in the tumor despite their self-sacrifice, as they can regenerate epigenetically from non-altruists via a KLF2/PCAF-mediated mechanism. The altruists maintain a sparse spatial organization by inhibiting surrounding cells from adopting the altruistic fate via a lateral inhibition mechanism involving a GAB1-PI3K-AKT-miR-125b signaling circuit. CONCLUSIONS: Our data reveal molecular mechanisms underlying manifestation, persistence and spatial spread of cancer cell altruism. A minor population behave altruistically at a cost to itself producing a collective benefit for the tumor, suggesting tumors to be dynamic social systems governed by the same rules of cooperation in social organisms. Understanding cancer cell altruism may lead to more holistic models of tumor evolution and drug response, as well as therapeutic paradigms that account for social interactions. Cancer cells constitute tractable experimental models for fields beyond oncology, like evolutionary ecology and game theory.

Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

Use of tongue base palpation among oral healthcare providers: Cross-sectional survey.

OBJECTIVES: To assess the use of tongue base palpation during cancer screening exams by Oral Healthcare Providers (OHPs) and explore attitudes about (1) the usefulness of oral cancer screening (OCS) in detecting early, asymptomatic lesions and (2) routine OCS of the general population. STUDY DESIGN: Survey study. SETTING: Private and hospital-based clinical practices of OHPs located in Massachusetts and Connecticut, United States. METHODS: An anonymous, online 9-item survey assessing beliefs and practice patterns about cancer screening exams was distributed to OHPs with practices in Massachusetts and Connecticut from August 2020 to June 2021. Data were analyzed using chi-square tests and Pearson correlations. Statistically significant levels were established at P < .050. RESULTS: One hundred seventy-one responses were analyzed (response rate 17 %). Tongue base palpation was performed as part of a routine cancer screening exam by 55 % of otolaryngologists, 34 % of dentists and 29 % of OMFS (P = .030). Providers who palpated the tongue base were also more likely to use palpation as an exam technique in the tonsils (r = 0.52 [95 % CI 0.40-0.62]; P < .001) among other intra-and extra-oral anatomical subsites. Almost all dentists (92 %) and OMFS (98 %) but only 58 % of otolaryngologists considered OCS useful for detection of early, asymptomatic malignant lesions in the oral cavity (P < .001). CONCLUSIONS: While tongue base palpation can detect oropharyngeal cancers in a pre-symptomatic stage, it is underutilized during routine cancer screening exams. Considering the rising incidence of oropharyngeal cancer, tongue base palpation should be established as a routine part of cancer screening by OHPs.

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Paper-Based MicroRNA Expression Profiling from Plasma and Circulating Tumor Cells.

BACKGROUND: Molecular characterization of circulating tumor cells (CTCs) holds great promise for monitoring metastatic progression and characterizing metastatic disease. However, leukocyte and red blood cell contamination of routinely isolated CTCs makes CTC-specific molecular characterization extremely challenging. METHODS: Here we report the use of a paper-based medium for efficient extraction of microRNAs (miRNAs) from limited amounts of biological samples such as rare CTCs harvested from cancer patient blood. Specifically, we devised a workflow involving the use of Flinders Technology Associates (FTA)® Elute Card with a digital PCR-inspired "partitioning" method to extract and purify miRNAs from plasma and CTCs. RESULTS: We demonstrated the sensitivity of this method to detect miRNA expression from as few as 3 cancer cells spiked into human blood. Using this method, background miRNA expression was excluded from contaminating blood cells, and CTC-specific miRNA expression profiles were derived from breast and colorectal cancer patients. Plasma separated out during purification of CTCs could likewise be processed using the same paper-based method for miRNA detection, thereby maximizing the amount of patient-specific information that can be derived from a single blood draw. CONCLUSIONS: Overall, this paper-based extraction method enables an efficient, cost-effective workflow for maximized recovery of small RNAs from limited biological samples for downstream molecular analyses.

A1-adenosine acute withdrawal response and cholecystokinin-8 induced contractures are regulated by Ca(2+)- and ATP-activated K(+) channels.

In isolated guinea-pig ileum (GPI), the A1-adenosine acute withdrawal response is under the control of several neuronal signalling systems, including the µ/κ-opioid and the cannabinoid CB1 systems. It is now well established that after the stimulation of the A1-adenosine system, the indirect activation of both µ/κ-opioid and CB1 systems is prevented by the peptide cholecystokinin-8 (CCk-8). In the present study, we have investigated the involvement of the Ca(2+)/ATP-activated K(+) channels in the regulation of both acute A1-withdrawal and CCk-8-induced contractures in the GPI preparation. Interestingly, we found that: (a) the A1-withdrawal contracture is inhibited by voltage dependent Ca(2+)-activated K(+) channels, Kv, while it is enhanced by the voltage independent Ca(2+)-activated K(+) channels, SKCa; (b) in the presence of CCk-8, the inhibitory effect of the A1 agonist, CPA, on the peptide induced contracture is significantly enhanced by the voltage independent Ca(2+)-activated K(+) channel, SKCa; and (c) the A1-withdrawal contracture precipitated in the presence of CCk-8 is controlled by the ATP-sensitive potassium channels, KATP. Our data suggest, for the first time, that both Ca(2+)- and ATP-activated K(+) channels are involved in the regulation of both A1-withdrawal precipitated and CCk-8 induced contractures.

Efficient cell transfection with melamine-based gemini surfactants.

Gemini surfactants consisting of two melamine scaffolds connected by a n-hexyl linker and functionalized with a 1-propylammonium polar head and a lipophilic chain having variable carbon length (from C8 to C16) were synthesized. These were then used successfully for the transfection of A549, U87 MG, and Bristol 8 cell lines with maxGFP expressing plasmid. The transfection protocol was optimized appropriately (confluence, reagent/pcDNA ratio, compaction time, and transfection time) for each cell line. Under optimized conditions, the C12 and C14 melamine gemini surfactants showed little toxicity and remarkable transfection efficiency, superior to the gold-standard Lipofectamine 2000. These reagents were also able to efficiently transfect primary DRG neurons, which are notoriously difficult to transfect. The presence of serum completely inhibited the transfection capacity of these reagents. Owing to their ready availability, straightforward synthesis, high chemical stability (even in solution), ease of use (no formulation is required), improved transfection ability, and low toxicity, melamine-based gemini surfactants are very promising reagents for cellular DNA transfection.

Identifying the core concepts of pharmacology education: A global initiative.

BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

The role of Popeye domain-containing protein 1 (POPDC1) in the progression of the malignant phenotype.

The Popeye domain-containing protein 1 (POPDC1), a tight junction-associated transmembrane protein with a unique binding site for cAMP, has been shown to act as a tumour suppressor in cancer cells. Through interaction with many downstream effectors and signalling pathways, POPDC1 promotes cell adhesion and inhibits uncontrolled cell proliferation, epithelial-to-mesenchymal transition and metastasis. However, POPDC1 expression is down-regulated in many types of cancer, thereby reducing its tumour-suppressive actions. This review discusses the role of POPDC1 in the progression of the malignant phenotype and highlights the broad range of benefits POPDC1 stabilisation may achieve therapeutically. Cancer stem cells (CSCs) are a key hallmark of malignancies and commonly promote treatment resistance. This article provides a comprehensive overview of CSC signalling mechanisms, many of which have been shown to be regulated by POPDC1 in other cell types, thus suggesting an additional therapeutic benefit for POPDC1-stabilising anti-cancer drugs. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

The path towards herd immunity: Predicting COVID-19 vaccination uptake through results from a stated choice study across six continents.

Despite unprecedented progress in developing COVID-19 vaccines, global vaccination levels needed to reach herd immunity remain a distant target, while new variants keep emerging. Obtaining near universal vaccine uptake relies on understanding and addressing vaccine resistance. Simple questions about vaccine acceptance however ignore that the vaccines being offered vary across countries and even population subgroups, and differ in terms of efficacy and side effects. By using advanced discrete choice models estimated on stated choice data collected in 18 countries/territories across six continents, we show a substantial influence of vaccine characteristics. Uptake increases if more efficacious vaccines (95% vs 60%) are offered (mean across study areas = 3.9%, range of 0.6%-8.1%) or if vaccines offer at least 12 months of protection (mean across study areas = 2.4%, range of 0.2%-5.8%), while an increase in severe side effects (from 0.001% to 0.01%) leads to reduced uptake (mean = -1.3%, range of -0.2% to -3.9%). Additionally, a large share of individuals (mean = 55.2%, range of 28%-75.8%) would delay vaccination by 3 months to obtain a more efficacious (95% vs 60%) vaccine, where this increases further if the low efficacy vaccine has a higher risk (0.01% instead of 0.001%) of severe side effects (mean = 65.9%, range of 41.4%-86.5%). Our work highlights that careful consideration of which vaccines to offer can be beneficial. In support of this, we provide an interactive tool to predict uptake in a country as a function of the vaccines being deployed, and also depending on the levels of infectiousness and severity of circulating variants of COVID-19.

Second-line combination chemotherapy with vinorelbine and capecitabine in patients with advanced breast cancer previously treated with anthracyclines and/or taxanes.

OBJECTIVE: This phase II study was designed to evaluate the effects of vinorelbine (VRL) and capecitabine (CAP) as second-line combination chemotherapy in patients with advanced breast cancer (ABC) previously treated with anthracyclines and/or taxanes. METHODS: Treatment consisted of VRL 25 mg/m(2) administered on days 1 and 8 of a 21-day treatment cycle, along with oral CAP 825 mg/m(2) twice daily for 14 days, followed by 7 days of rest. RESULTS: 50 patients were enrolled and 48/50 (96.0%) patients were assessable for response. The median time to progression (TTP) and overall survival (OS) of the patients were 5.0 (95% confidence interval, CI, 2.1-7.9 months) and 12.0 months (95% CI, 8.0-16.0 months), respectively. The objective response rate was 26.0% (95% CI, 13.8-38.2%) with 1 confirmed complete response and 12 partial responses. The most frequent hematological adverse event was neutropenia of grade 3 and 4 in 5 (10.4%) and 2 patients (4.2%), respectively. Grade 3 stomatitis, asthenia, and diarrhea were observed in 1 (2.1%), 2 (4.2%) and 3 (6.3%) patients, respectively. CONCLUSION: The combination of VRL and CAP is feasible as second-line chemotherapy in patients with ABC previously treated with anthracyclines and/or taxanes, with efficacy being comparable to other available combination regimens.

Developing a new undergraduate pharmacology core curriculum: The British Pharmacological Society Delphi Method.

The British Pharmacological Society (BPS) developed a new core curriculum for undergraduate pharmacology degrees. To do this, a modification of the Delphi Process was used. Initially, a pharmacology educator workshop was hosted to explore the core attributes expected of pharmacology graduates. We then developed these discussions into knowledge, skills, and attitudes statements and sent them, in the form of a questionnaire, to our Expert Group, which included pharmacology professionals from across academia and industry. In an iterative process, the Expert Group were asked to rank each statement according to how much they agreed it was a core graduate attribute. Where there was disagreement, statements were modified according to feedback. After three rounds of questionnaires, we had a draft core curriculum which was then finalized through a discussion workshop with the education community. In this workshop, practical aspects of curriculum implementation were discussed and the potential for the Society to develop resources to support it considered. The revised core curriculum is freely available on the Society website: https://www.bps.ac.uk/media-library-assets/library/undergraduate-pharmacology-core-curriculum. Several examples exist of the curriculum making an impact within and beyond the United Kingdom, where it has been utilized in a quality assurance context, as a tool for curriculum review and also to guide building new programs. Through a series of further expert workshops, the BPS Education and Training committee is currently developing more granular learning outcomes to accompany the core curriculum alongside recommended resources to enable delivery. In addition, this expanded curriculum is also being reviewed and updated to ensure it is fully inclusive and represents the diversity of pharmacology educators and learners worldwide.

cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A.

cAMP is a key mediator of a number of molecules that induce growth cone chemotaxis, including netrin-1 and myelin-associated glycoprotein (MAG). Endogenous neuronal cAMP levels decline during development, and concomitantly axonal growth cones switch their response to cAMP-dependent guidance cues from attraction to repulsion. The mechanisms by which cAMP regulates these polarized growth cone responses are unknown. We report that embryonic growth cone attraction to gradients of cAMP, netrin-1, or MAG is mediated by Epac. Conversely, the repulsion conferred by MAG or netrin-1 on adult growth cones is mediated by protein kinase A (PKA). Furthermore, fluorescence resonance energy transfer reveals that netrin-1 distinctly activates Epac in embryonic growth cones but PKA in postnatal neurons. Our results suggest that cAMP mediates growth cone attraction or repulsion by distinctly activating Epac or PKA, respectively. Moreover, we propose that the developmental switch in growth cone response to gradients of cAMP-dependent guidance cues from attraction to repulsion is the result of a switch from Epac- to PKA-mediated signaling pathways.

Testosterone replacement in prostate cancer survivors with hypogonadal symptoms.

OBJECTIVE: To describe the clinical outcomes of prostate cancer survivors who were treated with high-dose testosterone-replacement therapy (TRT) for the relief of hypogonadal symptoms. PATIENTS AND METHODS: We reviewed the records of 96 patients who received TRT after initial management for prostate cancer from 2000 to 2007. RESULTS: In all, 41 men had prostate-specific antigen (PSA) progression (PSA Working Group) while on TRT, but only seven had radiographic progression of disease. Fifty-six men discontinued TRT due to increasing PSA levels, and 59% of these men had significant reductions in PSA level with no additional intervention. In all, 31 men remain on TRT with no PSA or radiological progression at a median of 36.7 months; nine men stopped TRT for reasons other than progression. Characteristics associated with continuing TRT were radical prostatectomy as primary management, a low PSA level when starting TRT, and concurrent use of dutasteride. Hypogonadal symptoms were alleviated in most cases. CONCLUSIONS: While most men in this series had increasing PSA levels during TRT, stopping TRT typically resulted in PSA declines. A subset of men were able to remain on TRT for several years without disease progression.

A phase II study of irinotecan and capecitabine for patients with unresectable liver-only metastases from colorectal cancer.

OBJECTIVE: To assess the resectability rate of patients with initially unresectable liver-only metastases from colorectal cancer (CRC) after treatment with irinotecan/capecitabine. METHODS: Patients received irinotecan (240 mg/m(2)) as a 30 min intravenous infusion on day 1 and capecitabine (1000 mg/m(2)) orally bid for 14 days beginning on day 2. Treatment was repeated every 3 weeks. The protocol encouraged two to four cycles of irinotecan/capecitabine after recovery from surgery. RESULTS: Between May 2004 and February 2007, 48 patients entered in the study. Forty-seven (97.9%) of the 48 patients were assessable for response. The overall response rate before surgery was 56.3% (95% CI, 42.3-70.3%) in the treated population, including 2 non-confirmed complete response (CR), 18 partial responses (PR) and 7 non-confirmed PR. Twenty-three (47.9%) of 29 patients with tumor shrinkage proceeded to surgical intervention. Twenty of the 23 patients had a complete resection (S-CR). With a median follow-up time of 32 months (range, 24-38 months), the overall median time to progression and overall survival for all patients were 16.7 months (95% CI, 10.0-23.4 months) and 27.5 months (95% CI, 23.6-31.4 months) for all patients. The 1- 2- and 3-year overall survival estimates were 79.2% (95% CI, 67.7-90.7%), 60.4% (95% CI, 46.6-74.3%) and 29.2% (95% CI, 16.3-42.0%), respectively. Grade 3 diarrhea occurred in eight (17.0%) patients. The most common Grade 3/4 hematological adverse event was neutropenia in 8.5% of the patients. There were no treatment-related deaths during this study. CONCLUSIONS: Irinotecan/capecitabine appears to be a safe and very effective regimen in selected patients with unresectable liver metastases from CRC, but who are treated with a curative intent.

Multimarker circulating DNA assay for assessing blood of prostate cancer patients.

BACKGROUND: Prostate cancer (PCa) detection using serum-based prostate specific antigen (PSA) is limited by frequent false-positive and -negative results. Genetic aberrations such as allelic imbalance (AI) and epigenetic changes such as promoter hypermethylation have been detected in circulating DNA of cancer patients. We hypothesized that circulating multimarker DNA assays detecting both genetic and epigenetic markers in serum would be useful in assessing PCa patients. METHODS: We assayed blood from healthy male donors (n = 40) and 83 patients with American Joint Cancer Committee (AJCC) stage I-IV PCa. DNA was assayed for AI of 6 genome microsatellites. We assessed methylation of RASSF1, RARB2, and GSTP1 using a methylation-specific PCR assay and analyzed the sensitivity of each assay for the detection of genetic or epigenetic changes in circulating DNA. The relation between circulating tumor-related DNA detection and prognostic factors was investigated. RESULTS: The proportion of patients demonstrating AI for > or =1 marker was 47% (38 of 81 patients). Methylation biomarkers were detected in 24 of 83 patients (28%). By combining 2 DNA assays, the number of PCa patients positive for > or =1 methylated or LOH marker increased (52 of 83; 63%). The combined assays detected PCa in 15 of 24 patients (63%) with normal PSA concentrations. The combination of the DNA assays detected the presence of PCa regardless of AJCC stage or PSA concentration. Combination of the DNA and PSA assays gave 89% sensitivity. CONCLUSIONS: This pilot study demonstrates that the combined circulating DNA multimarker assay identifies patients with PCa and may yield information independent of AJCC stage or PSA concentration.

Gemcitabine plus cisplatin chemotherapy with concurrent para-toluenesulfonamide local injection therapy for peripherally advanced nonsmall cell lung cancer larger than 3 cm in the greatest dimension.

Para-toluenesulfonamide (PTS), active ingredient being PTS, is a new anticancer drug applied through local intratumoral injection. The aim of this phase II clinical trial was to investigate the response and toxicity of standard gemcitabine (GEM) plus cisplatin (CIS) chemotherapy with concurrent intratumoral injection of PTS in peripherally advanced nonsmall cell lung cancer. Patients received 1250 mg/m of GEM on day 1, 8, and 75 mg/m of CIS on day 1, every 21 days for four cycles. PTS was injected intratumorally through percutaneous injection under computed tomography guidance on days 5, 12, 15, and 18 of cycle 1, and repeated on days 5 and 12 of cycle 2 if a less than 50% necrotic area was achieved after the first cycle according to the computed tomography scan. Twelve (46.2%) patients had metastatic disease, whereas 14 (53.8%) patients had stage IIIB disease. All 26 patients were assessable for response. Overall response rate by intention-to-treat was 53.8% (95% confidence interval: 34.6-73.0%). Median progression-free survival and overall survival were 6.5 months (95% confidence interval: 3.8-10.2 months) and 14.5 months (10.0-18.0 months), respectively. One-year and 2-year survivals were 57.7 and 22.4%, respectively. The grade 3-4 hematologic adverse events were neutropenia in six patients (23.1%), anemia in three (11.5%), and thrombocytopenia in four patients (15.4%). Nonhematologic toxicities were generally mild and usually not dose-limiting. Although grade 1-2 emesis occurred in nine patients (34.6%), only one had grade 3 vomiting. Grade 1-2 cough, local pain, and peripheral neurotoxocity developed in 12 (46.2%), three (11.5%), and five (19.2%) patients, respectively. There were no treatment-related deaths. GEM/CIS chemotherapy with concurrent PTS local injection therapy is a well-tolerated modality with potential activity in previously untreated peripheral advanced nonsmall cell lung cancer patients.

A phase II study of intra-arterial chemotherapy of 5-fluorouracil, cisplatin, and mitomycin C for advanced nonresectable gastric cancer.

The best choice of chemotherapy regimen for patients with advanced gastric cancer (AGC) is still a matter of controversy and requires further investigation. This study was performed to evaluate the efficacy and safety of intra-arterial infusion chemotherapy of 5-fluorouracil 1000 mg/m, cisplatin 50 mg/m, and mitomycin C 10 mg/m (FCM) repeated every 6 weeks, as first-line treatment for AGC. Forty-seven (95.9%) of the 49 patients were assessable for response. Four cases of complete response and 28 cases of partial response were confirmed, giving an overall response rate of 65.3% [95% confidence interval (CI): 52.0-78.6%]. The median time to progression and overall survival for all patients was 8.3 months (95% CI: 6.8-9.8 months) and 14.5 months (95% CI: 12.0-17.0 months). The estimate of overall survival at 12 and 24 months was 55.1% (95% CI: 41.2-69.0%) and 18.4% (95% CI: 7.5-29.2%), respectively. Most patients experienced neutropenia during their course of therapy with 21.3% of patients (n = 10) for grade 3/4 neutropenia. Grade 3 stomatitis, lethargy, and palmar-plantar erythema were observed in two (4.3%), eight (17.0%), and one (2.1%) patients, respectively. Yet, no grade 4 nonhematological toxicity was observed. Intra-arterial infusion chemotherapy of 5-fluorouracil 1000 mg/m, cisplatin 50 mg/m, and mitomycin C 10 mg/m is a tolerated treatment modality with promising activity in patients with previously untreated AGC.