Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R.

BACKGROUND: Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis. PATIENTS AND METHODS: PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method. RESULTS: By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%). CONCLUSIONS: PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors.

BACKGROUND: This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples. RESULTS: Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6-9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose-positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent. CONCLUSIONS: The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.

Nonimaging optics in luminescent solar concentration.

Light trapped within luminescent solar concentrators (LSCs) is naturally limited in angular extent by the total internal reflection critical angle, θcrit, and hence the principles of nonimaging optics can be leveraged to increase LSC concentration ratio by appropriately reshaping the edges. Here, we use rigorous ray-tracing simulations to explore the potential of this concept for realistic LSCs with compound parabolic concentrator (CPC)-tapered edges and show that, when applied to a single edge, the concentration ratio is increased by 23% while maintaining >90% of the original LSC optical efficiency. Importantly, we find that CPC-tapering all of the edges enables a significantly greater intensity enhancement up to 35% at >90% of the original optical efficiency, effectively enabling two-dimensional concentration through a cooperative, ray-recycling effect in which rays rejected by one CPC are accepted by another. These results open up a significant opportunity to improve LSC performance at virtually no added manufacturing cost by incorporating nonimaging optics into their design.

Status of PI3K inhibition and biomarker development in cancer therapeutics.

The phosphatidylinositol 3-kinase (PI3K) signalling pathway is integral to diverse cellular functions, including cellular proliferation, differentiation and survival. The 'phosphate and tensin homologue deleted from chromosome 10' (PTEN) tumor suppressor gene plays a critical role as a negative regulator of this pathway. An array of genetic mutations and amplifications has been described affecting key components of this pathway, with implications not only for tumorigenesis but also for resistance to some classic cytotoxics and targeted agents. Emerging preclinical research has significantly advanced our understanding of the PI3K pathway and its complex machinations and interactions. This knowledge has enabled the evolution of rationally designed drugs targeting elements of this pathway. It is important that the development of suitable biomarkers continues in parallel to optimize use of these agents. A new generation of PI3K inhibitors is now entering early clinical trials, with much anticipation that they will add to the growing armamentarium of targeted cancer therapeutics.

Practice guideline on prophylactic cranial irradiation in small-cell lung cancer.

PURPOSE: To develop an evidence-based clinical practice guideline that would address the following questions: (a) What is the role of prophylactic cranial irradiation (PCI) in patients with limited or extensive stage small-cell lung cancer (SCLC) who have achieved complete remission in response to induction therapy (chemotherapy or chemoradiotherapy)? (b) What dose and fractionation schedules of PCI are optimal? (c) Does the use of PCI in patients with SCLC in complete remission affect quality of life? Survival, disease-free survival, quality of life, and adverse effects were the outcomes of interest. METHODS AND MATERIALS: A systematic review of the published literature was undertaken to provide the data for an evidence-based practice guideline. RESULTS: Six randomized controlled trials and one fully published individual patient data meta-analysis were included in the systematic review of the evidence. For patients who have achieved complete response after induction therapy, there is evidence of a disease-free survival benefit (4 of 6 trials) and an overall survival benefit (meta-analysis). There is insufficient evidence to make a definitive recommendation with respect to dose. There is some indication that 30-36 Gy in 2-3 Gy per fraction, or a biologically equivalent dose, may produce a better outcome than a lower dose or less aggressive fractionation regimen. The schedule commonly used in Canada is 25 Gy in 10 fractions over 2 weeks. Data from further research, including a trial currently ongoing that compares 25 Gy in 10 fractions with 36 Gy in 18 fractions, will be required to determine optimal dose of PCI. There is insufficient evidence to make recommendations concerning the optimal timing of PCI in relation to the administration of chemotherapy. Lung DSG members generally felt that it should be given as soon as possible after completion of chemotherapy. There is evidence from trials with data for up to 2 years of follow-up that prophylactic cranial irradiation does not produce significant late neurotoxicity. There is evidence from one trial that prophylactic cranial irradiation does not have a detrimental effect on quality of life in the first 12 months following the completion of therapy. There is insufficient evidence to comment on the long-term effects of prophylactic cranial irradiation on quality of life. CONCLUSION: For adult patients with limited or extensive SCLC who achieve a complete remission with induction therapy, PCI is recommended.

Anatomy and physiology of adipose tissue.

In summary, the increasing frequency with which we perform lipectomy prompts us to investigate the risks and benefits to which we may be subjecting our patients. It is hoped that this article has shed some light on the biology and anatomy of adipose tissue so that we can make educated guesses as to the effects of its removal.

Adjuvant chemotherapy for deep muscle-invasive transitional cell bladder carcinoma - a practice guideline.

BACKGROUND AND PURPOSE: To examine the role of adjuvant chemotherapy in the treatment of patients with deep muscle-invasive transitional cell carcinoma (TCC) of the bladder who have undergone cystectomy. MATERIALS AND METHODS: A systematic review of the published literature was combined with a consensus process, involving the interpretation of evidence within the context of conventional practice, to develop an evidence-based practice guideline for use in Ontario. RESULTS: Five randomized controlled trials (RCTs) comparing adjuvant chemotherapy with observation were found that reported data on survival. Sample sizes of the trials were small, and each of the trials evaluated a cisplatin-based chemotherapy regimen; however, none studied less toxic combination chemotherapy regimens such as gemcitabine-cisplatin or dose-intensive methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) with granulocyte-colony stimulating factor (G-CSF). One trial was excluded due to inadequate reporting of outcomes. The remaining four studies failed to demonstrate an overall survival benefit in favor of adjuvant chemotherapy, although three of the four trials showed statistically significant benefits for adjuvant chemotherapy with respect to disease-free survival. CONCLUSIONS: As randomized trials have not proven a benefit in overall survival, adult patients with deep muscle-invasive TCC of the bladder should not be routinely offered adjuvant chemotherapy following cystectomy. Disease-free survival may be improved by adjuvant chemotherapy, but it is unclear whether this improvement compensates for the detrimental effects of chemotherapy. If a patient chooses adjuvant chemotherapy to improve disease-free survival they should be made aware of the lack of proven overall survival benefit, and a cisplatin-based combination chemotherapy regimen such as MVAC or CMV is recommended. RCTs of gemcitabine-cisplatin and dose-intensive MVAC plus G-CSF in the setting of metastatic TCC of the bladder provide indirect evidence that these regimens could offer equivalent benefit to MVAC and CMV but with less toxicity in patients with muscle-invasive disease. The use of these regimens in the adjuvant setting after cystectomy is currently being evaluated in a randomized trial (EORTC trial 30994).

Anatomy of the subcutaneous tissue of the trunk and lower extremity.

Dissections on 8 fresh and 10 embalmed cadavers were used to determine the anatomy of the subcutaneous adipose tissue in the trunk and extremities. These dissections, along with CT scans, confirmed Gray's original description of the subcutaneous tissue consisting of a superficial and deep adipose layer. The superficial adipose layer is contained within organized, compact fascial septa. The deep adipose layer demonstrated regional variations with respect to its fascial framework, but was contained within a relatively loose, less organized, and more widely spaced fascial septa. We observed that the adipose layers are partitioned by a discrete subcutaneous fascia which fuses with the underlying muscle fascia at particular anatomic locations. The deep layer is thus contained by the subcutaneous fascia above and the muscle fascia below to form what we termed the deep adipose compartments. The deep adipose compartments contributed significantly to overall adipose thickness, are bilateral, and are found in the abdomen and paralumbar and gluteal-thigh regions.

Competitive water polo. Upper extremity injuries.

Water polo is a contact sport combining the skills of swimming, swim conditioning, throwing and, occasionally, the elements of wrestling and boxing. As such, the athletes frequently sustain upper extremity injuries involving the shoulder, the elbow, or the hand and fingers; moreover, injuries may result from either overuse or acute trauma. Successful treatment of these injuries requires an understanding of the peculiarities of the game and the likely mechanisms of injury, and the experience to properly recognize when they occur.

PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer.

There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation.

Biomarkers in colorectal cancer.

Systemic therapies available for treatment of colorectal cancer have increased in recent years, leading to improved clinical outcomes. However, a significant proportion of patients fail to derive meaningful benefits, whereas others suffer from unacceptable toxicities. Therefore, not only does the search for novel and effective anticancer agents continue, there is also a pressing need to optimise the use of all treatments in the therapeutic armamentarium. In addition to knowledge gleaned from well-designed and relevant clinical trials, increasing effort is being invested into biomarkers. The identification and implementation of validated biomarkers has the potential to further our understanding of the biology of colorectal cancer and also to greatly improve the efficiency with which cancer treatments are administered.

Ensaio de dissolução de cápsulas de fluconazol: problemas encontrados na determinação por espectrofotometria na região do UV / Fluconazole capsule dissolution test: problems encountered in UV spectrophotometry determination

Entre as classes terapêuticas analisadas no Programa Nacional de Verificação da Qualidade de Medicamentos (PROVEME), o antifúngico fluconazol constava na apresentação de cápsulas de diferentes procedências. Na realização dos ensaios de dissolução conforme as técnicas dos fabricantes, constatou-se que os valores obtidos por espectrofotometria-UV foram superiores aos obtidos nos ensaios de teor e uniformidade de conteúdo, cuja determinação foi por CLAE-UV. Considerando este fato, foi objetivo deste trabalho realizar o ensaio de dissolução destas amostras pelos respectivos métodos dos fabricantes e o quantitativo do ensaio por espectrofotometria no UV e por CLAE-UV, a fim de avaliar as possíveis interferências dos excipientes nestas determinações. Os valores obtidos por espectrofotometria foram superiores aos obtidos por CLAE, confirmando a interferência dos excipientes. Concluiu-se que a metodologia a ser empregada na análise de fármacos deve ser criteriosamente selecionada, a fim de evitar resultados não condizentes com a real formulação do produto.

Among the therapeutic classes analyzed in the Programa Nacional de Verificação da Qualidade de Medicamentos (PROVEME) consisted the antifungal fluconazole in the dosage form of capsules from different origins. In dissolution tests, according to manufacturers techniques, it was found that the values obtained by UV-spectrophotometry were higher than those obtained from tests of content and content uniformity, whose determination was by HPLC-UV. Considering this fact, the objective of this study was to perform the dissolution test of these samples by the respective manufacturers methods and the quantitative assay by UV-spectrophotometry and HPLC-UV, to evaluate possible interferences of excipients in these determinations. The values obtained by spectrophotometry were higher than those obtained by HPLC, confirming the excipients interference. It was concluded that the methodology to be employed in drug analysis should be carefully selected in order to avoid results not commensurate with the real product formulation.

Enzyme-linked immunosorbent assay to evaluate the immunogenicity of a polyvalent Klebsiella capsular polysaccharide vaccine in humans.

A highly sensitive enzyme-linked immunosorbent assay was developed for Klebsiella capsular polysaccharide (CPS) and used to evaluate the immunoglobulin G (IgG) antibody response to a 24-valent CPS vaccine in seven adult volunteers. The median rise in titer to all vaccine antigens in samples from the volunteers was significant (twofold or greater). Significant IgG responses to 11 immunologically related serotypes not included in the vaccine were also noted. The mean cross-reacting IgG titer of 127.2 was only slightly lower than the mean titer of 175.7 to the serotypes in the vaccine (P less than 0.05). The mean 29.9-fold increase in titer to the serotypes in the vaccine was significantly higher than the mean 13.5-fold increase in titer to the additional antigens (P less than 0.001). The difference was partly because of the significantly lower (P less than 0.01) natural antibody titers in the preimmune sera to the serotypes in the vaccine, compared with those to serotypes not included in the vaccine. The selection of vaccine serotypes was based on the frequency of serotype isolation from cases of Klebsiella bacteremia. The above findings, which show low levels of natural antibody to these serotypes, support the hypothesis that anti-CPS antibody is protective against bacteremic disease.

Enzyme-linked immunosorbent assay for detection of antibodies to Pseudomonas aeruginosa exoproteins.

Enzyme-linked immunosorbent assays were developed with four purified Pseudomonas aeruginosa extracellular proteins (exotoxin A, elastase, alkaline protease, and phospholipase C) to determine antibody levels in sera from healthy subjects and the serological response in patients colonized or infected with Pseudomonas aeruginosa. Five of 39 burn patients with wounds colonized by Pseudomonas aeruginosa had elevated antibody titers to alkaline protease. Response to the other antigens was found in only a few patients. Pseudomonas aeruginosa infections (septicemia, osteitis, pneumonia etc.) resulted in increased antibody levels to exotoxin A or phospholipase C in 15 of 22 patients. These findings suggest that repeated determinations of antibodies to Pseudomonas aeruginosa exotoxin A and phospholipase C might be used to monitor therapy in certain patients with osteitis and other deep Pseudomonas infections.