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Background Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. Methods We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. Results CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p =0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p =0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65; p =0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p =0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p =0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p =0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p =0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p <0.001). Conclusion The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.

This case discusses a 62-year-old woman with de novo metastatic lung adenocarcinoma (PD-L1 >50% with a KRAS G12C mutation, ALK and EGFR negative) who was on pembrolizumab for 1 year without any significant toxicity, only low-grade dermatitis and hypothyroidism. She was transitioned to pembrolizumab every 6 weeks at 4 mg/kg and began to develop oral sores shortly thereafter. The sores proved refractory to nystatin and mouth rinses containing corticosteroids, and the patient was ultimately diagnosed with autoimmune-triggered lichen planus. Unfortunately, her symptoms also proved refractory to typical treatments for lichen planus and worsened to the point where she began to develop cutaneous lesions and difficulty swallowing. Unfortunately, she also developed a keratoacanthoma that required excision. The pembrolizumab was stopped, and the patient’s symptoms improved with 5 days of systemic prednisone, metronidazole, and triamcinolone oral paste. Her NSCLC remains stable off active treatment for 6 months. This case study is on rare auto-immune toxicity as well as a keratoacanthoma from anti-PD-(L) 1 blockade, accompanied by sustained treatment response after cessation of the offending drug.

Background We compared the health‐related quality of life (HRQOL) in patients undergoing trimodality therapy for resectable stage I‐III esophageal cancer. Methods A total of 96 patients were randomized to standard neoadjuvant cisplatin and 5‐fluorouracil chemotherapy plus radiotherapy (neoadjuvant) followed by surgical resection or adjuvant cisplatin, 5‐fluorouracil, and epirubicin chemotherapy with concurrent extended volume radiotherapy (adjuvant) following surgical resection. Results There was no significant difference in the functional assessment of cancer therapy‐esophageal (FACT‐E) total scores between arms at 1 year (p = 0.759) with 36% versus 41% (neoadjuvant vs. adjuvant), respectively, showing an increase of ≥15 points compared to pre‐treatment (p = 0.638). The HRQOL was significantly inferior at 2 months in the neoadjuvant arm for FACT‐E, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ‐OG25), and EuroQol 5‐D‐3 L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). Half of patients were able to complete the prescribed neoadjuvant arm chemotherapy without modification compared to only 14% in the adjuvant arm (p < 0.001). Chemotherapy related adverse events of grade ≥2 occurred significantly more frequently in the neoadjuvant arm (100% vs. 69%, p < 0.001). Surgery related adverse events of grade ≥2 were similar in both arms (72% vs. 86%, p = 0.107). There were no 30‐day mortalities and 2% vs. 10% 90‐day mortalities (p = 0.204). There were no significant differences in either overall survival (OS) (5‐year: 35% vs. 32%, p = 0.409) or disease‐free survival (DFS) (5‐year: 31% vs. 30%, p = 0.710). Conclusion Trimodality therapy is challenging for patients with resectable esophageal cancer regardless of whether it is given before or after surgery. Newer and less toxic protocols are needed. This randomized trial assessed the health related quality of life in esophageal cancer patients undergoing neoadjuvant versus adjuvant trimodality therapy. Every patient experienced at least one adverse event. The quality of life was worse for patients undergoing neoadjuvant compared to adjuvant chemoradiation with no significant difference in either overall survival or disease‐free survival. More effective therapy is needed.

Heritable genomic variation and natural selection have long been acknowledged as striking parallels between evolution and cancer. The logical conclusion, that cancer really is a form of speciation, has seldom been expounded directly. My purpose is to reexamine the \"cancer as species\" thesis in the light of current attitudes to asexual speciation, and modern analyses of species definitions. The chief obstacles to accepting this thesis have been the asexual nature of cancer cell reproduction, the instability of the malignant genotype and phenotype, and our conditioning that speciation is an extremely rare and imperceptibly gradualistic process. However, these are not absolute barriers to the acceptance of cancers as bona fide species. Furthermore, although ongoing clonal evolution of extant cancers also results in a series of secondary speciation events, the initial emergence of a cancer requires a level of taxonomic reclassification even beyond the concept of speciation (i.e., phylogenation), and which is almost certain to provide a rich source of novel drug targets. The implications of the \"cancer as species\" idea may be as important for biology as for oncology, providing as it does an endless supply of observable if accelerated examples of a phenomenon once regarded as rare. From the perspective of cancer treatment, speciation guarantees the existence of causal molecular mechanisms which may have been neglected as exploitable targets for rational therapy; in particular, the mediators of metazoan life seem to have substantial overlap with components commonly deranged in cancer cells. However, the intractability of the drug resistance problem, residing as it does in the inherent plasticity of the genome, is traceable back to, and inseparable from, the very origins and nature of life.

Capecitabine monotherapy as palliation for advanced colorectal cancer (CRC) is generally well tolerated. Adding erlotinib, an EGFR-tyrosine kinase inhibitor, might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone (Arm 1) or capecitabine with erlotinib (Arm 2). Median time-to-progression (TTP) in Arm 1 was 7.9 months versus 9.2 in Arm 2. In -wild type (WT) patients TTP was 8.4 and 11.7 months in Arms 1 and 2, respectively. In -mutated patients TTP was 7.4 and 1.9 months in Arms 1 and 2, respectively (p = 0.023). Arm 2 -WT patients, left-sided primaries, had an overall survival of 16.0 versus 12.1 months in right-sided primaries. Adding erlotinib to capecitabine increased TTP by 3.2 months in -WT patients. This study suggests that erlotinib harms patients with -mutated advanced CRC while it may provide benefit to those with -WT CRC. Further study of EGFR-tyrosine kinase inhibitors in patients with left-sided -WT CRC is warranted.

The high and accelerating price of new anticancer drugs is giving rise to increased concern. However, monetary price is not the only way to value chemotherapy. Toxic effects can also be seen as a form of payment in which “units” of wellbeing are exchanged for “units” of efficacy. Although this trading analogy is not perfect, a proposal can be made that toxicity is a type of price, and that one of its functions is to signal valuation, similar to the crucial signalling function of monetary price in the real economy. This price function of toxicity, to the extent where there is transparency about the real amounts of toxicity, can have two important and helpful consequences: acting as a brake on the increasing monetary price of new drugs, via a damping effect on demand; and assisting individual patients in the informed contemplation of chemotherapy decisions. However, there are two problems that currently impede the effective dissemination of this highly desirable toxicity information. First, a prediction of toxicity in individual patients is difficult. Second, the vast database of real toxic effects in community practice is rarely made available for public scrutiny. Both of these problems, which together constitute a form of hidden cost, are potentially resolvable at least to some extent. In the absence of accurate information on toxic effects, it is easy for monetary price to progressively diverge from true value. We believe that improved transparency with respect to toxic effects, and better toxicity prediction, offer a better and more genuinely market-orientated solution to the issue of price distortions than the bureaucratic imposition of price controls.

Thymidylate synthase (TS) is a target for several anticancer drugs. We previously showed that an antisense oligodeoxynucleotide (ODN) directed against TS mRNA down‐regulated TS protein and enhanced cytotoxicity of TS‐targeting drugs [including 5‐fluorodeoxyuridine (5‐FUdR)] in HeLa cells. Patient tumours with increased TS expression are resistant to TS‐targeting drugs. It was hypothesized that TS mRNA and consequently TS protein could be down‐regulated in 5‐FUdR‐resistant cells that overexpress TS, sensitizing them to 5‐FUdR cytotoxicity. In this study we assessed the capacity of an anti‐TS antisense ODN to circumvent resistance dependent on TS overexpression. Variant HeLa clones exhibiting 2 – 20 fold resistance to 5‐FUdR were selected by exposing cultured cells to drug. Clones FUdR‐5a, −25b, and −50a expressed TS protein levels 10 fold, 10 fold, and 17 fold higher (respectively) than parental cells. Cells were treated with antisense ODN 83 (a 2′‐methoxy‐ethoxylated, phosphorothioated 20‐mer, complementary to a portion of the 3′‐untranslated region of TS mRNA), or ODN 32 (a control ODN with the same base composition as ODN 83, but in randomized order). Twenty‐four and 48 h following transfection (50 – 100 nM ODN, plus polycationic liposome), TS mRNA levels (by RT – PCR) and protein levels (by radiolabelled 5‐FUdR‐monophosphate binding) were decreased by at least 60% in ODN 83‐treated cells compared with control ODN 32‐treated cells. ODN 83 enhanced the cytotoxicity of 5‐FUdR by up to 85% in both parental and 5‐FUdR‐resistant cell lines. Antisense ODN can be used to down‐regulate TS and attenuate drug resistance in TS‐overexpressing cells. British Journal of Pharmacology (2001) 134, 1437–1446; doi:10.1038/sj.bjp.0704394

Thymidylate synthase (TS) catalyses the only de novo pathway to produce thymidylate for DNA replication and repair and is an important target for cancer chemotherapy. Preexisting or acquired drug resistance in tumor cells limits clinical efficacy of TS-targeting drugs. Cells selected for higher TS protein activity have decreased sensitivity to TS-targeting chemotherapeutic agents (5-FUdR and raltitrexed). New therapeutic strategies are required to overcome treatment resistance. Among these, upregulation of drug resistance mediators in normal, nontarget cells and/or antisense downregulation of those mediators (alone or in combination with protein-targeting drugs) are candidate strategies. We have targeted human TS mRNA with antisense oligodeoxynucleotides (AS ODNs), complementary to the translation start site (TSS), the coding region, and the 3′ untranslated region. We report here that, in response to treatment with a novel TSS-targeting AS ODN 791, TS gene transcription in a human cervical carcinoma cell line (HeLa) was unexpectedly increased by 70%. Interestingly, the increased TS gene transcription and nuclear TS RNA did not elevate levels of total cellular TS mRNA, but did increase TS protein activity by 35% and TS protein level by 150%. Increased TS protein activity and level did not alter proliferation rate or sensitivity to TS-targeting drugs (5-FUdR or raltitrexed). To assess concentration-dependent effects of TS on sensitivity to TS-targeting drugs, incremental increases of TS protein levels were generated by transfection of a mammalian TS expression vector. Increases in TS protein of less than approximately 400% did not significantly affect sensitivity to TS-targeting drugs, while greater TS protein levels did. These data indicate that AS ODNs targeting TS mRNA can upregulate TS expression and activity in a manner dependent on the sequence being targeted, and that there exists a threshold increase (greater than approximately 400-700% in HeLa cells), required to initiate resistance to TS-targeting drugs.

Thymidylate synthase (TS) catalyzes de novo production of thymidylate for DNA synthesis and cell proliferation. As such, TS has been a target of antitumor chemotherapy for many years. Our laboratory has identified several antisense oligodeoxynucleotides (ODNs) that downregulate TS mRNA and protein, inhibit cell proliferation, and sensitize cells to TS-directed chemotherapeutic drugs. Based on our observation that targeting distinct regions of the TS mRNA with a variety of antisense molecules resulted in differential effects on TS mRNA levels, it was hypothesized that use of multiple ODNs targeting distinct noncontiguous regions would result in synergistic or antagonistic interactions. In this study, we report that some combinations of TS antisense ODNs were more effective at reducing TS mRNA abundance and inhibiting cell proliferation than the individual ODNs used alone. However, in contrast to the effects on cell proliferation, the enhanced sensitivity to anti-TS chemotherapeutic drugs (i.e., raltitrexed and 5-fluorodeoxyuridine) that is achieved by treatment with individual ODNs was not further augmented by combined ODN treatment. This suggests that ODNs targeting TS mRNA inhibit an alternative function of TS mRNA or protein, distinct from thymidylate production. The results are evidence that the novel use of multiple antisense ODNs that target different regions of the same mRNA represents a general strategy to improve antisense effectiveness.