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Dual- or multi-modality combination therapy has become one of the most effective strategies to overcome drug resistance in cancer therapy, and the optimized ratio of the therapeutic agents working on the tumor greatly affects the therapeutic outcomes. However, the absence of a facile method to optimize the ratio of therapeutic agents in nanomedicine has, at least in part, impaired the clinical potential of combination therapy. Herein, a new cucurbit[7]uril (CB[7])-conjugated hyaluronic acid (HA) based nanomedicine was developed, in which both chlorin e6 (Ce6) and oxaliplatin (OX) were co-loaded non-covalently at an optimized ratio via facile host-guest complexation, for optimal, combined photodynamic therapy (PDT)/chemotherapy. To maximize the therapeutic efficacy, a mitochondrial respiration inhibitor, atovaquone (Ato), was also loaded into the nanomedicine to limit consumption of oxygen by the solid tumor, sparing oxygen for more efficient PDT. Additionally, HA on the surface of nanomedicine allowed targeted delivery to cancer cells with over-expressed CD44 receptors (such as CT26 cell lines). Thus, this supramolecular nanomedicine platform with an optimal ratio of photosensitizer and chemotherapeutic agent not only provides an important new tool for enhanced PDT/chemotherapy of solid tumors, but also offers a CB[7]-based host-guest complexation strategy to facilely optimize the ratio of therapeutic agents for multi-modality nanomedicine. Chemotherapy remains the most common modality for cancer treatment in clinical practice. Combination therapy by co-delivery of two or more therapeutic agents has been recognized as one of the most effective strategies to improve therapeutic outcome of cancer treatment. However, the ratio of loaded drugs could not be facilely optimized, which may greatly affect the combination efficiency and overall therapeutic outcome. Herein, we developed a hyaluronic acid based supramolecular nanomedicine with facile method to optimize the ratio of two therapeutic agents for improved therapeutic outcome. This supramolecular nanomedicine not only provides an important new tool for enhanced photodynamic therapy/chemotherapy of solid tumors, but also offers insights in using macrocyclic molecule-based host-guest complexation to facilely optimize the ratio of therapeutic agents in multi-modality nanomedicine. [Display omitted] [ABSTRACT FROM AUTHOR]

We evaluated whether tissue tumor mutational burden (tTMB) and STK11 , KEAP1 , and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR / ALK alterations in the phase III KEYNOTE-042 trial. This retrospective exploratory analysis assessed prevalence of tTMB and STK11 , KEAP1 , and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [ STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [ KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [ KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11 , KEAP1 , or KRAS mutation status. • Pembrolizumab monotherapy is a standard first-line treatment of patients with PD-L1-positive advanced/metastatic NSCLC. • We assessed clinical utility of potential biomarkers among patients receiving pembrolizumab versus chemotherapy. • tTMB ≥175 mutations/exome was associated with improved outcomes among patients receiving pembrolizumab versus chemotherapy. • tTMB has potential clinical utility as a biomarker for pembrolizumab in first-line PD-L1-positive advanced/metastatic NSCLC. • Pembrolizumab improved overall survival versus chemotherapy regardless of STK11 , KEAP1 , or KRAS mutation status. [ABSTRACT FROM AUTHOR]

Objective: To assess the cost-effectiveness of acupuncture in the management of chemotherapy-induced peripheral neuropathy (CIPN) in Hong Kong. Methods: A within trial cost-utility analysis with the primary endpoint for the economic evaluation being the Quality Adjusted Life Year (QALY) and associated Incremental Cost Effectiveness Ratio (ICER) over 14 weeks of treatment. A secondary cost-effectiveness analysis was undertaken with the endpoint being change in pain as measured on the Brief Pain Inventory (BPI). Results: Eighty-seven patients were randomised to acupuncture or usual care. Acupuncture resulted in significant improvements in pain intensity (8- and 14-week mean changes compared to usual care of −1.8 and −1.8, respectively), pain interference (8- and 14-week mean changes compared to usual care of −1.5 and −0.9, respectively) and indicators of quality of life and neurotoxicity-related symptoms. However, in the economic evaluation there was little difference in QALYs between the two arms (mean change 0.209 and 0.200 in the acupuncture and usual care arms, respectively). Also, costs yielded deterministic ICERs of HK$616,965.62, HK$824,083.44 and HK$540,727.56 per QALY gained from the health care provider perspective, the societal perspective and the patient perspective, respectively. These costs are significantly higher than the cost-effectiveness threshold of HK$180,450 that was used for the base case analysis. Conclusion: While acupuncture can improve symptoms and quality of life indicators related to CIPN, it is unlikely to be a cost-effective treatment for CIPN-related pain in health care systems with limited resources. Trial registration number: NCT02553863 (ClinicalTrials.gov) post-results. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the diagnostic accuracy of breast MRI for detecting residual tumor and the tumor size whether it would be affected after neoadjuvant chemotherapy. Methods: Total 109 patients with NAC and 682 patients without NAC were included in this retrospective study. Measurement of the largest diameter of tumors at pathology was chosen as gold standard and compared with preoperative breast MRI. A concordance threshold of ±25% of maximal tumor size was used. The accuracy of MRI was graded as concordant, underestimation, or overestimation rate. Further subgroup analysis with tumor stages, histologic subgroups and intrinsic subtypes was performed. Results: The post-NAC MRI was associated with 92.5% sensitivity, 55.2% specificity, 85.1% positive predictive value, 72.7% negative predictive value, and overall 82.6% accuracy for detecting residual tumor. In determining tumor size, the overall concordance rates of the non-NAC group and the NAC group were 43.5% and 41.3%, respectively (p = 0.678). But the overestimation rate and underestimation rate were 26.6% and 32.1% for NAC group, and 52.9% and 3.5% for the non-NAC group (p<0.001). While in the subgroups analysis, the concordance rate of the NAC group (26.7%) was lower than that of the non-NAC group (82.1%) at T3 stage (p<0.001). There were no statistically significant differences between different tumor histologic subgroups and intrinsic subtypes. Conclusions: The overall accuracy of MRI in predicting tumor size was not affected by NAC; however, it tends to underestimate tumor size after NAC, especially in patients with T3 lesions and above. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility of utilizing back-to-back random-start ovarian stimulation to increase oocyte yield for fertility preservation prior to cancer treatment. Methods: A case series of 15 patients who underwent back-to-back random-start stimulation cycles prior to chemotherapy. Results: Of the 15 back-to-back random-start stimulation cases, 13 had breast cancer and 2 had other cancers. The average age was 38 years (range 30–43) and average AFC was 8 (range 3–14). Fourteen of the 15 women (93%) who underwent two ovarian stimulation cycles completed both of them. The average time to complete back-to-back random-start ovarian stimulation was 33 days (range 13–43 days). The average time between the first cycle completion and the second cycle start in our back-to-back random-start stimulations was 9 days (range 0–14 days). Two of the women underwent back-to-back random-start ovarian stimulation prior to starting neoadjuvant chemotherapy for breast cancer. Eleven of our 15 women at least doubled their oocyte or embryo yield relative to their first cycle. Only 1 of the 15 second cycles was canceled. The mature oocyte rate, fertilization rate, and embryo yield were similar among the first and second cycles. Conclusions: Back-to-back random-start ovarian stimulation may be an effective way to maximize fertility preservation, even in time-limited settings. [ABSTRACT FROM AUTHOR]

Background: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.Methods: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.Findings: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.Interpretation: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.Funding: Merck Sharp & Dohme. [ABSTRACT FROM AUTHOR]

Purpose: After chemotherapy for breast cancer, most women will recover some ovarian function, but the timing and extent of this recovery are poorly understood. We studied post-chemotherapy ovarian recovery in women with and without a history of ovarian suppression during chemotherapy.Methods: Reproductive age breast cancer patients who were seen prior to chemotherapy for fertility preservation consult were consented for follow-up ovarian function assessment (every 3-6 months after chemotherapy) with antral follicle count (AFC) in this prospective cohort study. We restricted our analysis to those with menses present after chemotherapy. Box plots were used to demonstrate the change in follow-up AFC versus time elapsed after chemotherapy. A mixed effects regression model was used to assess differences in AFC.Results: Eighty-eight patients with a history of newly diagnosed breast cancer were included. Forty-five patients (51%) had ovarian suppression with GnRH agonist (GnRHa) during chemotherapy. AFC recovery appeared to plateau at 1 year after completing chemotherapy at a median of 40% of pre-chemotherapy AFC. After adjustment for age, initial AFC, cyclophosphamide exposure, combined hormonal contraceptive (CHC) use, and tamoxifen use, AFC recovered faster and to a greater degree for those women who underwent GnRHa therapy for ovarian protection during chemotherapy (P = 0.032).Conclusions: Women with menses after chemotherapy for breast cancer appear to recover their full potential AFC 1 year after their last chemotherapy dose. Treatment with GnRHa during chemotherapy is associated with a higher degree of AFC recovery. The findings of this study can aid in counseling patients prior to chemotherapy about expectations for ovarian recovery and planning post-treatment fertility preservation care to maximize reproductive potential when pre-treatment fertility preservation care is not possible or has limited oocyte yield. [ABSTRACT FROM AUTHOR]

Background: Malignancy is associated with an increased risk of venous thromboembolism. Inferior vena cava filters are a viable alternative when anticoagulation is infeasible because of the risk of bleeding. Although the current guidelines recommend that all patients with a vena cava filter be treated with anticoagulation treatment when the risk of bleeding is reduced, studies concerning the role of concomitant anticoagulation after vena cava filter insertion in high-risk patients are scarce. Since many cancer patients suffer from a high risk of hemorrhagic complications, we aimed to determine the effect of post-filter anticoagulation on mortality in patients with a malignant solid tumor.Methods: A retrospective cohort study of patients with pulmonary embolism was performed between January 2010 and May 2016. Patients with a solid tumor and vena cava filter inserted because of pulmonary embolism were included. Using Cox proportional hazards model, the prognostic effect of clinical variables was analyzed.Results: A total of 180 patients were analyzed, with 143 patients receiving and 37 patients not receiving post-filter anticoagulation treatment. Mortality was not significantly different between the two groups. The presence of metastatic cancer and that of pancreatobiliary cancer were significant risk factors for mortality. However, post-filter anticoagulation did not show significant effect on mortality regardless of the stage of cancer.Conclusion: In patients with cancer-associated pulmonary embolism, the effect of post-filter anticoagulation on mortality may not be critical, especially in patients with a short life expectancy. [ABSTRACT FROM AUTHOR]

Purpose Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials. Materials and Methods This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and "as-treated" populations for efficacy and safety endpoints, respectively. Results In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade) with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. Conclusion These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background and objective: An adjusted indirect comparison was conducted to assess efficacy outcomes, particularly overall survival (OS), of osimertinib versus platinum-based doublet chemotherapy in patients with epidermal growth factor receptor-mutated (EGFRm) T790M mutation-positive non-small-cell lung cancer (NSCLC) who had progressed following an EGFR tyrosine kinase inhibitor (TKI). Analysis of treatment effect from two separate trials had the potential to more accurately estimate the magnitude of OS benefit due to absence of confounding due to treatment switching from the control arm to the osimertinib arm of the ongoing randomized control trial, AURA3.Methods: Two non-randomized individual datasets were compared: pooled patients from the AURA extension and AURA2 trials (osimertinib 80 mg, n = 405, with a confirmed T790M mutation using tissue samples), and patients from the control arm of the IMPRESS study (platinum-based doublet chemotherapy, n = 61, with a confirmed T790M mutation using plasma circulating tumour DNA [ctDNA]). A propensity score-based approach was used to account for differences in baseline demographics and disease characteristics.Results: After adjustment for baseline differences between the two groups, osimertinib demonstrated a statistically significant improvement in progression-free survival (PFS) versus platinum-based doublet chemotherapy (hazard ratio [HR] = 0.278, 95% confidence interval [CI] 0.188-0.409, p < 0.0001; median PFS 10.9 vs. 5.3 months). Improvements were also observed for objective response rate (ORR) and disease control rate (DCR) (ORR: 64.3 vs. 33.3%; odds ratio [OR] = 5.31, 95% CI 2.47-11.40, p < 0.001; DCR: 92.1 vs. 75.0%; OR = 4.72, 95% CI 1.92-11.58, p < 0.001). Similar results were obtained for patients who received osimertinib as second-line treatment only. A statistically significant improvement in OS was observed for the osimertinib group (HR = 0.412, 95% CI 0.273-0.622, p < 0.0001). Median OS for osimertinib was not reached.Conclusions: In this indirect comparison, osimertinib showed a statistically significant improvement in efficacy outcomes versus platinum-based doublet chemotherapy in patients with EGFRm T790M NSCLC who had progressed after EGFR-TKI therapy. [ABSTRACT FROM AUTHOR]

Lung cancer has the highest incidence and mortality rate worldwide among all malignancy-associated mortalities, of which non-small cell lung cancer accounts for 80% of all cases. Resistance against epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) develops following 8-12 months of disease progression, and is a critical issue. HCC827 cell lines with resistance to EGFR-TKIs were successfully screened. The half maximal inhibitory concentration values were 1,000-fold higher than the values for the parental HCC827 cell line, thereby demonstrating cross-resistance against the same family of TKIs. The expression of B-cell lymphoma 2 (Bcl2) was markedly increased in the resistant clones, as well as in the patient biopsies. The phosphatase and tensin homolog phosphoinositide 3-kinase signaling axis is a potential mechanism for acquiring resistance, and therefore targeting Bcl2 may be a useful strategy for further investigations. [ABSTRACT FROM AUTHOR]

Study Question: Is random start ovarian stimulation associated with delays in initiation of neoadjuvant chemotherapy for breast cancer?Summary Answer: Among women who complete fertility preservation (FP) consultation, random start ovarian stimulation is unlikely to delay time to initiation of neoadjuvant chemotherapy start.What Is Known Already: Neoadjuvant chemotherapy is now a widely accepted treatment modality for operable breast cancer and random start ovarian stimulation is an increasingly-utilized modality for FP. While conventional ovarian stimulation does not appear to delay starting adjuvant chemotherapy, the relationship between random start ovarian stimulation and neoadjuvant chemotherapy start is not well-understood.Study Design, Size, Duration: Cross-sectional study of all women seen between from January 2011 to April 2017 for FP consultation prior to starting neoadjuvant chemotherapy for breast cancer.Participants/materials, Setting, Methods: A chart-review was performed. Study inclusion criteria were female sex; age 18-45; non-metastatic breast cancer diagnosis; underwent FP consultation; underwent neoadjuvant chemotherapy. Referrals for FP evaluation came from a regional referral base of oncology clinics. Various time-points related to cancer diagnosis, FP or chemotherapy were obtained from medical record review. We compared time-points between those who underwent ovarian stimulation for FP versus those who did not using T-tests and linear modeling.Main Results and the Role Of Chance: A total of 89 women who had FP consultation prior to neoadjuvant chemotherapy were identified. Sixty-seven percent underwent ovarian stimulation prior to cancer treatment and 33% did not. Women who underwent ovarian stimulation were similar in parity and clinical cancer stage to those who did not. Overall, the average time from cancer diagnosis to chemotherapy start was similar between the group that did undergo ovarian stimulation and those who did not (38.1 ± 11.3 versus 39.4 ± 18.5 days, P = 0.672). Those that underwent ovarian stimulation were referred 9.4 ± 6.8 days after diagnosis versus 17.9 ± 15.3 days for those who did not undergo ovarian stimulation (P < 0.001).Limitations Reasons For Caution: Retrospective study with potential for selection bias among those who underwent ovarian stimulation versus those who did not. Reasons for caution include the possibility of unmeasured differences among those who did and did not undergo ovarian stimulation, including: patients' and providers' perceptions of the urgency to start chemotherapy, ongoing oncology work-up and treatment planning, FP decision-making, and the pursuit of second and third opinions. The difference in time from referral to FP consultation may have also influenced patients' decisions about whether to undergo ovarian stimulation.Wider Implications Of the Findings: In this study, FP with random start ovarian stimulation was not associated with a delay cancer treatment in the neoadjuvant setting, so long as there was a prompt FP referral. Patients undergoing neoadjuvant chemotherapy should be informed of these findings to avoid unnecessary anxiety due to concern for delays.Study Funding/competing Interest(s): This study was supported by departmental research funding within the University of California, San Francisco Department of Obstetrics, Gynecology and Reproductive Sciences. There are no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

Objective Intraperitoneal chemotherapy (IP ChT) is an emerging modality in the treatment of advanced gastric adenocarcinoma with peritoneal disease. Cytological evaluation of peritoneal fluid specimens from patients undergoing IP ChT is important in clinical management. However, direct intraperitoneal exposure to chemotherapeutic agents induces cytomorphological changes in benign constituents of peritoneal fluid, presenting particular challenges to accurate cytological interpretation. These morphological changes have not been well characterised in the literature. We systematically reviewed the cytomorphological features in immunocytochemically-confirmed positive and negative IP ChT peritoneal fluid samples to elucidate the degree of morphological overlap between malignant and reactive cells. Methods We reviewed 39 peritoneal fluid samples of patients treated with IP ChT, and scored specific cytomorphological parameters of both benign and malignant cells with the aid of relevant immunocytochemical interrogation. Results The present findings show a significant degree of morphological overlap between reactive and malignant cells. Abnormal, 'exploding' mitotic figures, nuclear membrane irregularities, multi-nucleation and cytoplasmic vacuolation were commonly observed in negative fluid specimens. The most helpful feature that favoured malignant cells was the increased nuclear-to-cytoplasmic ratio. A background inflammatory milieu of eosinophils and/or neutrophils was seen in 45-58% of post IP ChT peritoneal fluid specimens. The presence of pseudoparakeratotic cells, a novel observation in post IP ChT fluid specimens is also described. Conclusions The extent of reactive cytomorphological anomalies arising from treatment with IP ChT poses unique diagnostic challenges and may prompt a malignant or 'atypical' diagnosis in benign reactive samples. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OSA) is a common malignant bone tumor of large breed dogs that occurs at predictable anatomic sites. At the time of initial diagnosis, most affected dogs have occult pulmonary metastases. Even with aggressive surgical treatment combined with chemotherapy, the majority of dogs diagnosed with OSA live less than 1 year from the time of diagnosis. The ability to identify canine OSA cases most responsive to treatment is needed. In humans, OSA is also an aggressive tumor that is histologically and molecularly similar to canine OSA. The expression of the tumor suppressor gene product P16 by human OSA tissue has been linked to a favorable response to chemotherapy. Results: We identified an antibody that binds canine P16 and developed a canine OSA tissue microarray in order to test the hypothesis that P16 expression by canine OSA tissue is predictive of clinical outcome following amputation and chemotherapy. Although statistical significance was not reached, a trend was identified between the lack of canine OSA P16 expression and a shorter disease free interval.Conclusions: The identification of a molecular marker for canine OSA is an important goal and the results reported here justify a larger study. [ABSTRACT FROM AUTHOR]

Imaging of cancer with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) has become a standard component of diagnosis and staging in oncology, and is becoming more important as a quantitative monitor of individual response to therapy. In this article we investigate the challenging problem of predicting a patient’s response to neoadjuvant chemotherapy from a single 18F-FDG PET scan taken prior to treatment. We take a “radiomics” approach whereby a large amount of quantitative features is automatically extracted from pretherapy PET images in order to build a comprehensive quantification of the tumor phenotype. While the dominant methodology relies on hand-crafted texture features, we explore the potential of automatically learning low- to high-level features directly from PET scans. We report on a study that compares the performance of two competing radiomics strategies: an approach based on state-of-the-art statistical classifiers using over 100 quantitative imaging descriptors, including texture features as well as standardized uptake values, and a convolutional neural network, 3S-CNN, trained directly from PET scans by taking sets of adjacent intra-tumor slices. Our experimental results, based on a sample of 107 patients with esophageal cancer, provide initial evidence that convolutional neural networks have the potential to extract PET imaging representations that are highly predictive of response to therapy. On this dataset, 3S-CNN achieves an average 80.7% sensitivity and 81.6% specificity in predicting non-responders, and outperforms other competing predictive models. [ABSTRACT FROM AUTHOR]

The article offers information on a clinical trial that compared the efficacy of anaplastic lymphoma kinase (ALK) inhibitor crizotinib to pemetrexed-plus-platinum chemotherapy for the initial treatment of patients with advanced non-small-cell lung cancer (NSCLC). Topics discussed include the rearrangement of the ALK gene in NSCLC, comparison of the adverse events experienced by the patients and advantages of crizotinib in terms of symptom reduction.

A phase II study investigating intercalated combinations of eribulin and erlotinib in 21- and 28-day regimens in unselected patients with previously treated advanced non-small-cell lung cancer. Combination treatment demonstrated modest activity; the addition of erlotinib did not appear to improve outcomes in an unselected population. The 28-day regimen is suitable for further investigation.Background This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. Patients and methods Eligible patients were randomized to eribulin mesylate 2.0 mg/m2 on day 1 with erlotinib 150 mg on days 2–16 (21-day regimen) or eribulin mesylate 1.4 mg/m2 on days 1 and 8 with erlotinib 150 mg on days 15–28 (28-day regimen). The primary end point was objective response rate (ORR). Results One hundred and twenty-three patients received ≥1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%–24%] and 17% (95% CI 8%–29%), and disease control rates were 48% (95% CI 35%–61%) and 63% (95% CI 50%–75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. Conclusion Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier NCT01104155. [ABSTRACT FROM AUTHOR]

Patients with non-small-cell lung cancer ( NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor ( EGFR) tyrosine-kinase inhibitors ( TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival ( PFS) data from 27 erlotinib studies ( n = 731), 54 gefitinib studies ( n = 1802) and 20 chemotherapy studies ( n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [ AI] 11.6-13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0-9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3-6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: To evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) as an adjuvant chemotherapy in advanced gastric cancer (AGC) patients with serosal invasion. Methods: Patients who received radical surgery and palliative surgery between January 2002 and December 2010 were retrospectively examined. Patients were divided into two groups, namely, one group that underwent surgery and another group that underwent surgery with HIPEC. All patients who received HIPEC had suspected serosal invasion on an abdominal computed tomography or by the surgeon's assessment during the operation. Results: The prophylactic groups included 83 patients who underwent gastrectomy alone. A total of 29 patients underwent gastrectomy with HIPEC. The 5-year survival rates were 10.7% and 43.9%, respectively. The 5-year mean survival times were 22.66 (17.55–25.78) and 34.81 (24.97–44.66) months (p = 0.029), respectively. There were 52 patients who had a recurrence of carcinomatosis among 133 patients who had resections (52/133, 39.1%). The 3-year disease-free survival rate for carcinomatosis was 28.87% in the group that received surgery alone, whereas it was 66.03% in the group that received HIPEC. There was no significant difference in the rate of complication between the two groups in the prophylactic group (p = 0.542). Thus, curative surgery with HIPEC had a better prognosis for AGC with serosal invasion. The carcinomatosis recurrence time was longer in patients who underwent gastrectomy with HIPEC and received R0 resection. Conclusion: The survival benefit of HIPEC as an adjuvant therapy for gastric cancer patients with serosal invasion should be validated in a large cohort. [Copyright &y& Elsevier]

Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB Array Tools and Pathway Studio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients. [ABSTRACT FROM AUTHOR]

The phase III AVAiL study evaluated the efficacy and safety of the anti-vascular epidermal growth factor agent bevacizumab combined with platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). We report the results of a preplanned analysis of Asian patients enrolled in AVAiL. Patients with recurrent or advanced non-squamous NSCLC were randomized to receive bevacizumab 7.5 mg/kg, bevacizumab 15 mg/kg or placebo, plus cisplatin 80 mg/m and gemcitabine 1250 mg/m for up to six cycles, followed by bevacizumab or placebo until disease progression. An exploratory analysis was undertaken to assess efficacy and safety in an Asian subgroup. Of the 1043 patients enrolled, 105 were Asian and were included in the subgroup analysis. Progression-free survival was 8.5 months (95% CI 7.3-10.8) in the bevacizumab 15-mg/kg group, 8.2 (95% CI 6.6-11.7) in the 7.5-mg/kg group and 6.1 (95% CI 5.1-8.0) in the placebo group. Median overall survival in the 7.5-mg/kg bevacizumab group was prolonged compared with placebo group (HR 0.46; 95% CI 0.22-0.97). Nausea was the most common adverse event, occurring at similar rates (ranging from 69-76%) in all study groups. Hypertension was the most common adverse event of special interest, seen in 29, 55 and 16% of patients in the 7.5-mg/kg and 15-mg/kg bevacizumab and placebo groups, respectively. Study results strongly suggest that bevacizumab at a dose of 7.5 mg/kg improves the duration of overall survival when combined with cisplatin-gemcitabine in Asian patients. Bevacizumab was well tolerated in this patient group. [ABSTRACT FROM AUTHOR]

Background: Genotype B and C are the predominant hepatitis B virus (HBV) strains in Taiwan. We aimed to investigate the role of genotype in HBV-related hepatocellular carcinoma (HCC) after resection. Study Design: From October 2005 to November 2008, 64 patients who underwent liver resection for HBV-related HCC were enrolled. HBV genotypes were determined by molecular method. Patient characteristics, biochemical, tumor, and viral factors were evaluated for their prognostic significance. Results: During a mean follow-up of 26.6 ± 13.2 months, patients infected with genotype C had higher HBV viral load (p = 0.007) and worse disease-free survival rate (p = 0.028) than patients with genotype B. By univariate analysis, genotype C, alanine transaminase >50 U/L, tumor size ≥5 cm, and microvascular invasion were associated with tumor recurrence. Further multivariate analysis demonstrated genotype C remained a significant risk factor (p = 0.034). Conclusions: Genotype C is a strong risk factor for HCC recurrence after resection. More intensive monitoring for recurrence should be considered in patients with genotype C. [ABSTRACT FROM AUTHOR]

Abstract: Through incorporating into Martin’s drug scheduling model a toxicity metabolism term, our modified model takes into account the body’s ability of recovering from the effect of the drug and successively overcomes two unreasonable problems in Martin’s model. Since different drugs have different toxicity metabolism processes, we propose two renewed drug scheduling models with different toxicity metabolism according to kinetics of enzyme-catalyzed chemical reactions. For exploring multiple efficient drug scheduling policies, we use our adaptive elitist-population based genetic algorithm (AEGA) to solve the renewed models, and discuss the situation of multiple optimal solutions under different parameter settings. The simulation results obtained by the renewed models match well with the clinical treatment experience, and can provide much more drug scheduling polices for the doctor to choose depending on the particular conditions of the patients. [Copyright &y& Elsevier]

This correspondence introduces a multidrug cancer chemotherapy model to simulate the possible response of the tumor cells under drug administration. We formulate the model as an optimal control problem. The algorithm in this correspondence optimizes the multidrug cancer chemotherapy schedule. The objective is to minimize the tumor size under a set of constraints. We combine the adaptive elitist genetic algorithm with a local search algorithm called iterative dynamic programming (IDP) to form a new memetic algorithm (MA-IDP) for solving the problem. MA-IDP has been shown to be very efficient in solving the multidrug scheduling optimization problem. [ABSTRACT FROM AUTHOR]

The article discusses the case of a 59-year old man in Guangzhou, China who was infected with a Novel Avian Influenza A (H5N) Virus. His symptoms included fever an chills, vomiting, cough and shortness of breath. Details of his diagnosis and treatments were included. The case illustrates similarities between a Novel H% and other influenza A (H5N1) viruses.

An 11-year-old Yorkshire Terrier dog presented with progressive ataxia and paraparesis of 1 month duration. The abnormality was localized to the T13-L2 segment by neurologic examination and CT. MRI showed a space-occupying lesion compressing the spinal cord and adjacent osteolysis of the L1 vertebra. A diagnosis of poorly differentiated carcinoma with high malignancy was reached by histopathology of the biopsy samples. Metronomic chemotherapy was applied, but the patient was euthanized at 133 days after first presentation. Samples of the lumbar mass, pulmonary nodules, and lymph nodes were obtained during necropsy and evaluated with histopathology and immunohistochemistry (IHC). Undifferentiated carcinoma suspicious of transitional cell carcinoma was confirmed, but the exact origin of the tumor was undetermined. This is the first case report of an extradural primary carcinoma of unknown primary in the canine spinal cord and paravertebral region. [ABSTRACT FROM AUTHOR]

Simple Summary: In patients with completely resected stage III pN2 non-small cell lung cancer (NSCLC), adjuvant chemotherapy of 4–6 cycles was recommended prior to post-operative radiotherapy (PORT). However, some were given concurrently or early-sequentially with PORT. The objectives of this study were to verify the benefit of adjuvant sequential chemotherapy and radiotherapy (SCRT) relative to that of concurrent chemoradiotherapy (CCRT) in an Asian population and to identify the optimal timing of initiation of PORT as part of adjuvant SCRT. A longer interval (>104 days and <180 days) between the initiation of adjuvant chemotherapy and PORT was associated with improved OS compared with CCRT. No locoregional recurrence-free survival (LRFS) difference related to the interval between the initiation of adjuvant chemotherapy and PORT was observed. In older patients (aged >60 years), the benefit of delayed PORT initiation was more significant. We suggest that PORT should be postponed in the completed-resected pN2 elderly patients. (1) Purpose: To investigate the effects of the time interval between initiation of adjuvant chemotherapy and radiotherapy on survival outcomes in patients with completely resected stage IIIA pN2 non-small-cell lung cancer (NSCLC); (2) Methods: Data on 2515 patients with completely resected stage IIIA pN2 NSCLC in 2007–2017 were extracted from the Taiwan Cancer Registry Database. The survival outcomes in patients who underwent concurrent chemoradiotherapy (CCRT) and sequential chemotherapy and radiotherapy (SCRT) with either a short (SCRT1) or long (SCRT2) interval between treatments were estimated using Kaplan–Meier, Cox regression, and propensity score matching (PSM); (3) Results: Multivariate analyses of OS showed that SCRT2 (hazard ratio [HR] 0.64, p = 0.017) was associated with improved overall survival (OS). After PSM, the median OS periods were 64 and 75 months in the SCRT1 and SCRT2 groups, respectively, which differed significantly from that of 58 months in the CCRT group (p = 0.003). In elderly patients, SCRT2 significantly improved survival relative to CCRT before PSM (p = 0.024) and after PSM (p = 0.002); (4) Conclusions: A longer interval between initiation of adjuvant chemotherapy and postoperative radiotherapy (PORT; SCRT2) improved OS relative to CCRT; the benefits were greater in elderly patients (age >60 years). [ABSTRACT FROM AUTHOR]

Simple Summary: Acute Myeloid Leukemia is an aggressive disease with poor outcomes. New targeted therapies that can boost the effects of currently used chemotherapy medications without added toxicity are needed. Targeting an overactive kinase, called the protein Kinase CK2 in AML, helps leukemia cells undergo cell death and helps certain chemotherapy drugs work better. Here, we present evidence that CX-4945, a CK2 inhibitor drug, effectively kills leukemia cells in mouse models and shows the mechanism of action responsible for these effects. Leukemia cells are more sensitive to a decrease in CK2 kinase levels than normal cells. Our results show that inhibiting CK2 kinase makes AML cells more susceptible to anthracycline-induced cell death. Anthracyclines like daunorubicin and doxorubicin are widely used to treat leukemia in children and adults. A rational combination of protein kinase CK2 inhibitors with the standard of care chemotherapy may help treat AML more effectively. Protein Kinase CK2 (Casein Kinase 2 or CK2) is a constitutively active serine-threonine kinase overactive in human malignancies. Increased expression and activity of CK2 in Acute Myeloid Leukemia (AML) is associated with a poor outcome. CK2 promotes AML cell survival by impinging on multiple oncogenic signaling pathways. The selective small-molecule CK2 inhibitor CX-4945 has shown in vitro cytotoxicity in AML. Here, we report that CX-4945 has a strong in vivo therapeutic effect in preclinical models of AML. The analysis of genome-wide DNA-binding and gene expression in CX-4945 treated AML cells shows that one mechanism, by which CK2 inhibition exerts a therapeutic effect in AML, involves the revival of IKAROS tumor suppressor function. CK2 phosphorylates IKAROS and disrupts IKAROS' transcriptional activity by impairing DNA-binding and association with chromatin modifiers. Here, we demonstrate that CK2 inhibition decreases IKAROS phosphorylation and restores IKAROS binding to DNA. Further functional experiments show that IKAROS negatively regulates the transcription of anti-apoptotic genes, including BCL-XL (B cell Lymphoma like–2 like 1, BCL2L1). CX-4945 restitutes the IKAROS-mediated repression of BCL-XL in vivo and sensitizes AML cells to apoptosis. Using CX-4945, alongside the cytotoxic chemotherapeutic drug daunorubicin, augments BCL-XL suppression and AML cell apoptosis. Overall, these results establish the in vivo therapeutic efficacy of CX-4945 in AML preclinical models and determine the role of CK2 and IKAROS in regulating apoptosis in AML. Furthermore, our study provides functional and mechanistic bases for the addition of CK2 inhibitors to AML therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of ovarian clear cell carcinoma was poor due to chemoresistance; therefore, immunotherapy, such as the glypican-3 (GPC3) peptide vaccine, gained attraction, as it prolonged survival. There were some super responders; however, response rates were limited because of the lack of predictive biomarkers for the efficacy of treatment. The purpose of this study was to explore circulating biomarkers using pre-treatment serum samples from a GPC3 peptide vaccine clinical trial in order to predict response to vaccine therapy. We identified serum miR-375-3p, miR-193a-5p, and miR-1228-5p as predictive biomarkers of response to GPC3 peptide vaccine therapy. These miRNAs were not overexpressed in tumor tissues, and functional annotation analysis suggested that these miRNAs were associated with interferon-related pathways. Therefore, these biomarkers may reflect the immune activity of patients and may have broader applications in all immune-related therapies, including tumor vaccines. Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy; however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: As lung cancer has the highest incidence rate compared to any other type of cancer, there have been extensive research studies aiming at finding a better treatment for curing this disease. One of the many approaches is by improving the delivery of anticancer drugs towards cancer cells using advanced technologies. In this review, we focused on docetaxel as one of the most commonly used drugs for lung cancer treatment and discussed the properties of the drug and the application of nanotechnology in delivering this drug to improve its efficacy and specificity while reducing its side effects. Docetaxel (DCX) is a highly effective chemotherapeutic drug used in the treatment of different types of cancer, including non-small cell lung cancer (NSCLC). The drug is known to have low oral bioavailability due to its low aqueous solubility, poor membrane permeability and susceptibility to hepatic first-pass metabolism. To mitigate these problems, DCX is administered via the intravenous route. Currently, DCX is commercially available as a single vial that contains polysorbate 80 and ethanol to solubilize the poorly soluble drug. However, this formulation causes short- and long-term side effects, including hypersensitivity, febrile neutropenia, fatigue, fluid retention, and peripheral neuropathy. DCX is also a substrate to the drug efflux pump P-glycoprotein (P-gp) that would reduce its concentration within the vicinity of the cells and lead to the development of drug resistance. Hence, the incorporation of DCX into various nanocarrier systems has garnered a significant amount of attention in recent years to overcome these drawbacks. The surfaces of these drug-delivery systems indeed can be functionalized by modification with different ligands for smart targeting towards cancerous cells. This article provides an overview of the latest nanotechnological approaches and the delivery systems that were developed for passive and active delivery of DCX via different routes of administration for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer–related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC. [ABSTRACT FROM AUTHOR]

Camptothecin (CPT) and cisplatin (Pt) have shown synergistic effects on a variety of cancers during preclinical and clinical studies. However, the ratio of the two drugs often could not be precisely regulated in different delivery systems, which hinders the desired synergistic effect. In addition, the low delivery efficiency of the two drugs to the tumor further impedes the ideal therapeutic outcomes. Herein, we report that a platelet-mimicking supramolecular nanomedicine (SN) could precisely control of the ratio of CPT and Pt with a high tumor accumulation rate for cascade amplification of synergistic chemotherapy. The SN was fabricated via the host–guest interaction between cucurbit[7]uril conjugated hyaluronic acid (HA-CB[7]) and adamantane (ADA) respectively functionalized CPT- and Pt-based prodrugs. The ratio of CPT and Pt in the SN could be facilely regulated by simply controlling the loading ratio, based on the strong binding affinity between CB[7] and ADA, and SN60 with 60% CPT and 40% Pt showed the highest synergistic effects on 4T1 cells. To improve the tumor accumulation efficiency of SN, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a tumor vasculature-disruptive agent) was loaded into the optimized SN and then coated with platelet membrane to yield platelet-mimicking supramolecular nanomedicine (D@SN-P). D@SN-P could first passively accumulate in tumors owing to the enhanced permeability and retention (EPR) effect after intravenous administration. The initially release of DMXAA from D@SN-P could induce tumor vascular disruption, and the resultant epithelial collagen exposure around the disrupted tumor vasculature provided a target for further recruitment of platelet-mimicking SN, leading to cascade amplification of tumor accumulation with synergistic chemotherapy. Hence, this platelet-mimicking supramolecular nanomedicine presents a universal supramolecular strategy to finely regulate the ratio of loaded pro-drugs, and improve the accumulation efficiency to amplify chemotherapy via platelet-mimics. This work developed a platelet-mimicking supramolecular nanomedicine (D@SN-P) with a precisely regulated prodrugs for cascade amplification of synergistic chemotherapy. The resultant D@SN-P possessed an optimized ratio of ADA conjugated CPT- and Pt-based prodrugs via facile host–guest complexation between CB[7] and ADA to maximize the synergistic chemotherapy. D@SN-P could passively accumulate in tumors owing to the enhanced permeability and retention effect after intravenous administration. And initially release of DMXAA from D@SN-P would induce tumor vascular disruption, followed by epithelial collagen exposure arround the disrupted tumor vasculature, which then would provide a target for the specific binding of the platelets (including platelet-mimicking SN), leading to cascade amplification of synergistic chemotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients and methods: Patients with advanced NSCLC previously treated with ≥ 1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m² in Japan, 75 mg/m² at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. Results: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P=0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P=0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. Conclusion: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. [ABSTRACT FROM AUTHOR]

Breast cancer is highly heterogenous with temporal and spatial heterogeneity making it necessary for rebiopsy. DS-8201a, a new potential therapy for human epidermal growth factor receptor 2 (HER2) low expression breast cancer, had been proved that it could overcome heterogenous HER2 expression in a preclinical setting. In January 2014, a 23-year-old woman was presented with a lump in the right breast with bone metastasis, diagnosed as infiltrating ductal carcinoma, estrogen receptor (ER)+, progesterone receptor (PR)+, HER2 immunohistochemistry (IHC) 2+, and fluorescence in situ hybridization negative. The patient received a series of therapies including surgery, radiotherapy, endocrine therapy, target therapy, and chemotherapy. The longest progression-free survival was 17 months after surgery. Biopsy of liver metastasis in February 2020 showed triple negative (HER2−, ER−, PR−), which was quite different from the initial diagnosis in 2014, so retesting was performed and the results showed ER−, PR+ by 10%, HER2 IHC score of 1+, indicating heterogeneity of HER2 expression. In May 2020, DS-8201a treatment was initiated and continued for 10 cycles until November 2020. Remarkable relief in symptoms was observed after the first dose. A reduction in the metastatic lesion size (liver and brain) and improved liver function was observed during the therapy. This case indicated the heterogeneity of breast cancer, and impressive efficacy of DS-8201a in a heavily treated patient with HER2-low and HER2 heterogeneity. [ABSTRACT FROM AUTHOR]

Purpose: To identify dosimetric parameters that correlate with acute hematologic toxicity (HT) in patients with squamous cell carcinoma of the anal canal treated with definitive chemoradiotherapy (CRT). Methods and Materials: We analyzed 33 patients receiving CRT. Pelvic bone (PBM) was contoured for each patient and divided into subsites: ilium, lower pelvis (LP), and lumbosacral spine (LSS). The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. Endpoints included grade ≥3 HT (HT3+) and hematologic event (HE), defined as any grade ≥2 HT with a modification in chemotherapy dose. Normal tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT and dosimetric/clinical parameters. Results: Nine patients experienced HT3+ and 15 patients experienced HE. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.175, n = 1, and TD50 = 32 Gy. With this model, mean PBM doses of 25 Gy, 27.5 Gy, and 31 Gy result in a 10%, 20%, and 40% risk of HT3+, respectively. Compared with patients with mean PBM dose of <30 Gy, patients with mean PBM dose ≥30 Gy had a 14-fold increase in the odds of developing HT3+ (p = 0.005). Several low-dose radiation parameters (i.e., PBM-V10) were associated with the development of HT3+ and HE. No association was found with the ilium, LP, or clinical factors. Conclusions: LKB modeling confirms the expectation that PBM acts like a parallel organ, implying that the mean dose to the organ is a useful predictor for toxicity. Low-dose radiation to the PBM was also associated with clinically significant HT. Keeping the mean PBM dose <22.5 Gy and <25 Gy is associated with a 5% and 10% risk of HT, respectively. [Copyright &y& Elsevier]