Oral spleen tyrosine kinase/Janus Kinase inhibitor gusacitinib for the treatment of chronic hand eczema: Results of a randomized phase 2 study.

BACKGROUND: Gusacitinib is an oral inhibitor of Janus and Spleen tyrosine kinases. METHODS: The efficacy and safety of gusacitinib were evaluated in a double-blind, placebo-controlled, multicenter, phase 2 study in 97 chronic hand eczema patients randomized (1:1:1) to placebo or gusacitinib (40 or 80 mg) for 12 weeks (part A). Then, in part B (through week 32), the patients received gusacitinib. RESULTS: At week 16, patients receiving 80 mg gusacitinib showed a 69.5% (P <.005) decrease in the modified total lesion-symptom score versus 49.0% for 40 mg (P =.132), and 33.5% for placebo. Considerable improvement in Physician's Global Assessment was seen in 31.3% of patients receiving 80 mg versus 6.3% of placebo (P <.05). A 73.3% decrease in the hand eczema severity index versus placebo (21.7%) occurred in patients receiving 80 mg (P <.001). Patients receiving 80 mg experienced a considerable decrease in hand pain (P <.05). As early as week 2, considerable reductions over placebo in modified total lesion-symptom score (P <.005), Physician's Global Assessment (P =.04), and hand eczema severity index (P <.01) were observed (80 mg gusacitinib). Adverse events included upper respiratory infection, headache, nausea, and nasopharyngitis. CONCLUSIONS: Gusacitinib showed rapid improvement in chronic hand eczema patients and was well tolerated, warranting further investigations.

Single agent VS-6766 or VS-6766 plus defactinib in KRAS-mutant non-small-cell lung cancer: the RAMP-202 phase II trial.

KRAS mutations occur in approximately 30% of lung adenocarcinomas, mainly in codon 12 (83% of cases), p.G12C being the prevalent one (40%), followed by p.G12V and p.G12D (22 and 16%, respectively). Treatment options for advanced KRAS mutant non-small-cell lung cancer (KRAS-MT NSCLC) are limited to chemotherapy and immune checkpoint inhibitors (CPIs). However, clinical trials exploring specific targeted agents are expected to change the treatment landscape of this disease. Here, we describe the design and scientific rationale of the randomized, phase II, open label, RAMP-202 study, which will evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib in advanced KRAS-MT NSCLC patients after failure of prior platinum-based chemotherapy and CPI.

The alteration of KRAS gene occurs in approximately 30% of lung cancers. According to international guidelines, treatment options for patients with advanced KRAS mutant lung cancer are now limited to chemotherapy and immunotherapy. However, clinical trials are exploring how specific targeted agents are expected to change the treatment landscape of this disease. Here, we describe the design and scientific rationale of the RAMP-202 study, which will evaluate the efficacy and safety of two new biological agents for patients with KRAS mutant lung cancer. The enrolled patients were those who had failure of prior platinum-based chemotherapy and immunotherapy. Clinical Trial Registration: NCT04620330 (ClinicalTrials.gov).

Sequential Treatment of Extreme Maxillary Hypoplasia: A Historical Patient Report of an Edentulous Adult Patient With Ankyloglossia.

INTRODUCTION: The management of multiple dimensions in orthognathic surgery often requires careful planning. Too large discrepancies could require a sequential procedure to make alignment of the archs possible. REPORT OF CASE: The authors report a case of a 30-year-old partially edentulous man with severe maxillary hypoplasia caused by an untreated ankyloglossia. The transverse deficiency was estimated at more than 15 mm and the sagittal discrepancy shows a negative overjet of 11.5 mm. These wide deficits needed a 2-step surgery and the use of computed-aided design/computed-aided manufacturing. The first step was a palatal expansion by a fan-shaped Le Fort I osteotomy. The second step treated sagittal discrepancy and re-expanded the maxilla.At the end, the sagittal dimension got normal and the maxilla have been widened to almost 7 mm. CONCLUSION: Custom-made surgery is very useful for uncommon cases, in particular for toothless patients. It facilitates complex operations and allows precise results.

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (TH2/TH22/TH17/TH1) and epidermal differentiation. OBJECTIVE: We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. METHODS: Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. RESULTS: ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including TH2 (IL4 receptor [IL4R], IL13, CCL13/monocyte chemoattractant protein 4, CCL17/thymus and activation-regulated chemokine, CCL18/pulmonary and activation-regulated chemokine, CCL22/macrophage-derived chemokine, and CCL26/eotaxin-3), TH17/TH22 (lipocalins, PI3/elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and TH1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. CONCLUSION: The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.

Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens.

PURPOSE: Antiandrogens inhibit the androgen receptor and have an important role in the treatment of prostate cancer. This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of prostate cancer. MATERIALS AND METHODS: We searched PubMed® for clinical trials with the search terms antiandrogens and prostate cancer combined with drug names for antiandrogens. This article represents a collaboration of clinical investigators who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with prostate cancer. RESULTS: Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, which were designed to target the androgen receptor, were developed primarily for use in combination with castration to provide combined androgen blockade. Modest clinical benefits were observed with the combination of first generation antiandrogens and castration vs castration alone. With increased knowledge of androgen receptor structure and its biological functions a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August 2012. Apalutamide was recently approved while darolutamide is not yet approved in the United States. These next generation antiandrogens are being actively tested in earlier disease states such as nonmetastatic prostate cancer. Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a broader spectrum of patients with prostate cancer. CONCLUSIONS: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater knowledge about the structural and functional biology of the androgen receptor in prostate cancer will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate cancer may further improve the survival and quality of life of patients with current local and/or systemic treatment modalities.

Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. METHODS: ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55-69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50-74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years' follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. FINDINGS: With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83-1·99) after 9 years (1·64 [1·58-1·69] including France), 1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). INTERPRETATION: In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. FUNDING: Each centre had its own funding responsibility.

Prostate-cancer mortality at 11 years of follow-up.

BACKGROUND: Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS: The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS: After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS: Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).

Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. OBJECTIVE: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2-4 yr). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 25589 men aged 55-59 yr, 16898 men aged 60-64 yr, and 12936 men aged 65-69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2-4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60-61 yr. RESULTS AND LIMITATIONS: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2-1.5% for men with PSA <1.0 ng/ml to 13.3-13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60-61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60-61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68-70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76-78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice. CONCLUSIONS: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55-69 yr is a strong indicator to delay or stop further screening. PATIENT SUMMARY: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.

Screening and prostate-cancer mortality in a randomized European study.

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. METHODS: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). CONCLUSIONS: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

Phase I study of oral irinotecan as a single-agent and given sequentially with capecitabine.

PURPOSE: To assess the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of orally administered irinotecan in the semi-solid matrix (SSM) formulation, both as a single agent and in sequential combination with capecitabine, in patients with advanced solid tumors. PATIENTS AND METHODS: Forty-three patients were treated with irinotecan given as a single oral daily dose on days 1-5 every three weeks. An additional forty patients were treated with sequential oral irinotecan given daily on days 1-5 followed by capecitabine given orally as a divided dose twice daily on days 6-14 of each three week cycle. RESULTS: The MTD of single-agent oral irinotecan was estimated to be 60 mg/m(2)/day, and DLT included diarrhea, nausea, and neutropenia. In an initial group of patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, the MTD of sequential oral irinotecan/capecitabine was estimated to be 40/1600 mg/m(2)/day with DLT of delayed diarrhea. In a subsequent group of patients with ECOG PS of 0 or 1, the MTD for the sequential combination was 50/2000 mg/m(2)/day. The most common adverse events were fatigue, diarrhea, nausea/vomiting and dehydration. Pharmacokinetic (PK) evaluation showed that oral irinotecan was rapidly absorbed and effectively converted to the active metabolite, SN-38, achieving approximately 50% of the SN-38 systemic exposure resulting from an equivalent IV dose. CONCLUSIONS: Oral irinotecan can be safely administered as a single agent or in sequential combination with capecitabine. The efficacy of oral irinotecan should be explored further as a potentially convenient alternative to IV chemotherapy.

PCA: prostate cancer, patient-centred approach or both?

What's known on the subject? and What does the study add? Several studies have explored patient-specific expectations of prostate cancer management, while others have investigated physicians' perceptions. However, the opinions of both groups have seldom been compared in one study. Therefore, the present study compares the results of two surveys, one among physicians and one among patients, on patient-physician communication and patients' expectations of prostate cancer management. The present review aims to highlight the differences and similarities in opinion on prostate cancer management between physicians and patients. It reflects the most important results of two surveys on patient-specific expectations in prostate cancer management, done among European prostate cancer specialists and patients with prostate cancer. These results are compared with published data. In addition, the authors' opinion on the survey results and on optimal prostate cancer management is included. To evaluate differences and similarities in opinions on and expectations of prostate cancer management between physicians and patients. Two surveys on patient-specific opinions and expectations in prostate cancer management were done in 2011 among European prostate cancer specialists and patients with prostate cancer. Survey results were complemented with existing published data and with the authors' opinion. Most specialists spent 15-29 min on delivering the diagnosis, and about the same amount of time on explaining treatment options. This time was considered insufficient by 35% and 48% of patients, respectively. There was a large discrepancy between physicians' and patients' opinions about the type of provided prognostic and therapeutic information, indicating that patients may not have completely understood this information. Shared decision-making was preferred by both patients and specialists. Treatment efficacy was the most important factor determining treatment choice for both groups, while the physician's opinion or experience also had a great impact on patients' treatment choice. Patient-support groups have an important role in providing relevant information and in exchanging experiences between patients. The supportive role of partners/relatives was more appreciated when discussing treatment options than during diagnosis. Although patients' expectations are generally matched by their caring physician(s), physicians can still improve quality of care by taking adequate time for their patients, by using terminology that is easily understood by patients and by encouraging shared decision-making. A multidisciplinary team may be an important part of the treatment paradigm, with the individual patient's needs and preferences as the centre of care.

Synergic effect of graphene oxide and boron nitride on the mechanical properties of polyimide composite films.

The addition of two-dimensional (2D) materials into polymers can improve their mechanical properties. In particular, graphene oxide (GO) and hexagonal boron nitride (h-BN) are expected to be potential nanoplatelet additives for polymers. Interactions between such nanoplatelets and polymers are effective in improving the above properties. However, no report has investigated the effect of using two types of nanoplatelets that have good interaction with polymers. In this study, we fabricated polyimide (PI) films that contain two types of nanoplatelets, amine-functionalized h-BN (BNNH2 ) and GO. We have elucidated that the critical ratio and the content of BNNH2 and GO within PI govern the films' mechanical properties. When the BNNH2 /GO weight ratio was 52 : 1 and their content was 1 wt% in the PI film, the tensile modulus and tensile strength were increased by 155.2 MPa and 4.2 GPa compared with the pristine PI film.

Prostate cancer from the horizon of the patient.

The democratization of civil society and the development of modern medicine changed the sacrosanct doctor-patient relationship to a doctor-partner dialogue. Values and respect were lost in the process where common courtesy and empathy in trust were replaced by patient rights. LAUNCH OF EUROPA UOMO: Europa Uomo, the European prostate cancer coalition, represents 22 national, autonomous patient support groups. Its aim includes increasing the awareness of prostate diseases, support individualized treatment as a balance between optimal medical treatment and personalized care delivered by a multiprofessional team. We expect our information/education from dedicated professional societies while in return we share care for properly informed members as well as a fast, unbiased and cheap distribution of information/innovation across the European continent. THE ROLE OF A PATIENT GROUP: Our advocacy role is focused on quality of life, tailored treatment, knowledge of risk factors, support for research and last but not least active partnerships. We believe that we can play a modest but basic role in common actions to overcome inequalities in treatment and care in Europe. Our responsibilities range from defining patient obligations to facilitating translational research and saving scarce health resources. THE HORIZON OF THE PATIENT: Our hope is to plead for a treatment policy on the man first and then on his cancer and to improve treatment outcomes by multiprofessional collaboration and the development of expert Prostate Units. FUTURE EXPECTATIONS: A transparent, open communication line between the multiprofessional team and the patient is mandatory. The existing uncertainties should be discussed with common sense but always leave a factor of hope in survival or quality of life.

ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.

Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.

ASN004, A 5T4-targeting scFv-Fc Antibody-Drug Conjugate with High Drug-to-Antibody Ratio, Induces Complete and Durable Tumor Regressions in Preclinical Models.

The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors but shows very limited expression in normal adult tissues. ASN004 is a 5T4-targeted antibody-drug conjugate (ADC) that incorporates a novel single-chain Fv-Fc antibody and Dolaflexin drug-linker technology, with an Auristatin F hydroxypropylamide payload drug-to-antibody ratio of approximately 10-12. The pharmacology, toxicology, and pharmacokinetic properties of ASN004 and its components were investigated in vitro and in vivo ASN004 showed high affinity for the 5T4 antigen and was selectively bound to and internalized into 5T4-expressing tumor cells, and potent cytotoxicity was demonstrated for a diverse panel of solid tumor cell lines. ASN004 induced complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a wide range of 5T4 expression levels. A single dose of ASN004, as low as 1 mg/kg i.v., achieved complete tumor regression leading to tumor-free survivors in the A431 cervical cancer model. In head-to-head studies, superior activity of ASN004 was demonstrated against trastuzumab-DM1, in a low-5T4/high-HER2 expressing gastric tumor model, and 10-fold greater potency was found for ASN004 against the 5T4-targeted ADC PF-06263507 in a lung tumor model. In marmoset monkeys, ASN004 was well tolerated at doses up to 1.5 mg/kg Q3W i.v., and showed dose-dependent exposure, linear pharmacokinetics, and markedly low exposure of free payload drug. Taken together, these findings identify ASN004 as a promising new ADC therapeutic for clinical evaluation in a broad range of solid tumor types.

Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. RESULTS: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. CONCLUSION: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Prostate cancer treatment in Europe at the end of 1990s.

BACKGROUND: There is wide variation in prostate cancer incidence and survival across Europe. In many countries incidence is rising sharply in relation to the introduction of prostate-specific antigen assay, and there is concern that patients may not be treated appropriately. We therefore aimed to characterize treatment for prostate cancer across Europe. METHODS: We performed a high resolution population-based study, collecting information on the treatment of 3 486 prostate cancer cases diagnosed in 1995-1999 in 11 cancer registries from six European countries. RESULTS: Overall, about one in three patients received radical treatment (prostatectomy 23% or radiotherapy 14%); about 60% of younger patients (<70 years) received radical treatment, while a similar proportion of older patients (> or =70 years) received palliation (transurethral prostatectomy or hormone treatment only). A considerable proportion (61%) of patients with apparently high-risk disease were treated radically within a year of diagnosis, with large variation between regions: >70% in Calvados, Haut-Rhin, Tarn and Eindhoven and <50% in Slovakia and Cracow. Overall 34% of patients with apparently low-risk disease received radical treatment, varying from 17% and 22% in Bas-Rhin and Granada, to 52% and 56% in Calvados and Eindhoven. CONCLUSIONS: Our data indicate wide variation in the treatment for prostate cancer even among patients with apparently similar disease, and further suggest a non-negligible proportion may be receiving inappropriate radical treatment for apparently low-risk disease. Current guidelines indicate active surveillance should become the main means of managing low-risk disease.

Cancer survivorship: an integral part of Europe's research agenda.

Cancer survivorship has traditionally received little prioritisation and attention. For a long time, the treatment of cancer has been the main focus of healthcare providers' efforts. It is time to increase the amount of attention given to patients' long-term well-being and their ability to return to a productive and good life. This article describes the current state of knowledge and identifies research areas in need of development to enable interventions for improved survivorship for all cancer patients in Europe. The article is summed up with 11 points in need of further focus.

A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer.

BACKGROUND: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. OBJECTIVE: To determine whether PSA screening decreases PCa mortality for up to 16yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. DESIGN, SETTING, AND PARTICIPANTS: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182160 men, followed up until 2014 (maximum of 16yr), with a predefined core age group of 162389 men (55-69yr), selected from population registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. RESULTS AND LIMITATIONS: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p<0.001) at 16yr. The difference in absolute PCa mortality increased from 0.14% at 13yr to 0.18% at 16yr. The number of men needed to be invited for screening to prevent one PCa death was 570 at 16yr compared with 742 at 13yr. The number needed to diagnose was reduced to 18 from 26 at 13yr. Men with PCa detected during the first round had a higher prevalence of PSA >20ng/ml (9.9% compared with 4.1% in the second round, p<0.001) and higher PCa mortality (hazard ratio=1.86, p<0.001) than those detected subsequently. CONCLUSIONS: Findings corroborate earlier results that PSA screening significantly reduces PCa mortality, showing larger absolute benefit with longer follow-up and a reduction in excess incidence. Repeated screening may be important to reduce PCa mortality on a population level. PATIENT SUMMARY: In this report, we looked at the outcomes from prostate cancer in a large European population. We found that repeated screening reduces the risk of dying from prostate cancer.