Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial

Cáncer gástrico; Metastásico; PertuzumabCàncer gàstric; Metastàtic; PertuzumabGastric cancers; Metastatic; PertuzumabBackground Dual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB’s end-of study analyses aimed to evaluate the long-term efficacy and safety of pertuzumab plus trastuzumab and chemotherapy for previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer. Methods Eligible patients were randomized 1:1 to pertuzumab/placebo plus trastuzumab and chemotherapy every 3 weeks. Primary endpoint: overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results The intention-to-treat population comprised 388 patients in the pertuzumab arm and 392 in the placebo arm. The safety population comprised 385 and 388 patients, respectively. Median follow-up was ≥ 44.4 months. Median OS was increased by 3.9 months (hazard ratio 0.85 [95% confidence intervals, 0.72–0.99]) and median PFS by 1.3 months (hazard ratio 0.73 [95% confidence intervals, 0.62–0.85]) in the pertuzumab vs. the placebo arm. ORR was numerically higher (57.0% vs. 48.6%) and median DoR 1.8 months longer with pertuzumab treatment. There was a trend for more favorable hazard ratios in certain subgroups related to HER2 amplification/overexpression. Safety was comparable between arms, except for serious and grade 3–5 adverse events, and any-grade diarrhea, which were more frequent with pertuzumab. Conclusions JACOB did not meet its primary endpoint. Nonetheless, the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up.This study was sponsored by F. Hoffmann-La Roche Ltd. The sponsor, F. Hoffmann-La Roche Ltd, contributed to the design of this study. Data collected by the investigators were analyzed by statisticians at F. Hoffmann-La Roche Ltd. Authors employed by the study sponsor contributed to the conduct of the study, collection, management, analysis, and interpretation of the data, and preparation, review, and approval of the manuscript, as well as the decision to submit the manuscript for publication

Role of Capsule and Interleukin-6 in Long-Term Immune Control of Cryptococcus neoformans Infection by Specifically Activated Human Peripheral Blood Mononuclear Cells

Cryptococcus neoformans is a frequent cause of meningoencephalitis in immunosuppressed individuals. To better understand the mechanisms of a protective immune response to C. neoformans, a long-term in vitro model of human immune control of cryptococcal infection was developed. Peripheral blood mononuclear cells (PBMC) prestimulated with heat-killed C. neoformans significantly restricted the growth of C. neoformans after a subsequent live infection compared to that with unstimulated PBMC. Live infection with encapsulated C. neoformans was controlled for as long as 10 days, while infection with acapsular organisms could sometimes be eradicated. During immune control, fungal cells were both intracellular and extracellular within aggregates of mononuclear phagocytes and lymphocytes. Optimal immune control depended on the presence of both CD4(+) and CD8(+) T cells. Immune control of cryptococcal growth was more effective following prestimulation with acapsular compared with encapsulated organisms. Prestimulation with acapsular organisms was associated with a significant and prolonged increase in interleukin-6 (IL-6) production compared with prestimulation with encapsulated C. neoformans. Addition of IL-6 and depletion of CD25(+) T cells prior to prestimulation and infection with encapsulated organisms resulted in reductions in cryptococcal growth that reached borderline statistical significance. Depletion of CD25(+) T cells significantly reduced cryptococcal growth in wells with unstimulated PBMC. The results demonstrate an association between high levels of IL-6 and resistance to infection and, through suppression of IL-6 release, an additional mechanism whereby the cryptococcal capsule subverts a protective immune response. Further work is required to clarify the mechanism of action of IL-6 in this setting and any interaction with regulatory T cells

Immune dysfunction in HIV-seronegative, Cryptococcus gattii meningitis

The pathophysiology of meningitis caused by Cryptococcus gattii in apparently immunocompetent individuals remains unclear. We measured multiple cytokines in CSF from a HIV-seronegative, apparently immunocompetent, Thai patient with C. gattii meningitis, over the first 2 weeks of antifungal therapy. Levels of proinflammatory IFN-gamma, TNF-alpha, and IL-6 were very low compared to patients with HIV-related Cryptococcus neoformans meningitis and of IL-10 very high. While patients with C. gattii meningitis may be a heterogeneous group, these data suggest in this case a maladapted immune response to cryptococcal exposure had allowed progression to clinical cryptococcal diseas

IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis.

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis

CCR5- and CXCR4-Tropic Subtype C Human Immunodeficiency Virus Type 1 Isolates Have a Lower Level of Pathogenic Fitness than Other Dominant Group M Subtypes: Implications for the Epidemic▿ ‡

Human immunodeficiency virus type 1 (HIV-1) subtype C is the dominant subtype globally, due largely to the incidence of subtype C infections in sub-Saharan Africa and east Asia. We compared the relative replicative fitness (ex vivo) of the major (M) group of HIV-1 subtypes A, B, C, D, and CRF01_AE and group O isolates. To estimate pathogenic fitness, pairwise competitions were performed between CCR5-tropic (R5) or CXCR4-tropic (X4) virus isolates in peripheral blood mononuclear cells (PBMC). A general fitness order was observed among 33 HIV-1 isolates; subtype B and D HIV-1 isolates were slightly more fit than the subtype A and dramatically more fit than the 12 subtype C isolates. All group M isolates were more fit (ex vivo) than the group O isolates. To estimate ex vivo transmission fitness, a subset of primary HIV-1 isolates were examined in primary human explants from penile, cervical, and rectal tissues. Only R5 isolates and no X4 HIV-1 isolates could replicate in these tissues, whereas the spread to PM1 cells was dependent on active replication and passive virus transfer. In tissue competition experiments, subtype C isolates could compete with and, in some cases, even win over subtype A and D isolates. However, when the migratory cells from infected tissues were mixed with a susceptible cell line, the subtype C isolates were outcompeted by other subtypes, as observed in experiments with PBMC. These findings suggest that subtype C HIV-1 isolates might have equal transmission fitness but reduced pathogenic fitness relative to other group M HIV-1 isolates

Linjaliikenteen kannattavuuden seuranta : Yritys X

Tämän opinnäytetyön tarkoituksena oli selvittää toimeksiantajayrityksen ajosarjojen kannattavuutta ja asiakkaiden maksutapaprofiilia. Tutkimuksessa tarkastellaan toimeksiantajayrityksen 11:stä ajosarjaa syyskuusta marraskuuhun vuonna 2017. Työn toimeksiantajayritys on Uudenmaan alueella toimiva linja-, tilaus- ja taksiliikennettä harjoittava perheyritys. Liikesalaisuudellisista syistä yritys haluaa pysyä nimettömänä. Samasta syystä tutkimuksessa saadut tulokset ovat salaisia. Työn teoriaosuudessa käsitellään yrityksen kannattavuutta ja sen kehittämistä. Keskeisessä osassa on katetuottolaskenta, jota käytetään myös tehdyssä tutkimuksessa. Tutkimuksessa käytettävä tieto saatiin pääasiassa toimeksiantajayrityksen eri ohjelmista. Apuna käytettiin myös ulkopuolisten yritysten laskelmia, jotka perustuivat toimeksiantajayrityksen kirjanpitoon. Tietojen perusteella tutkittavista ajosarjoista luotiin katetuottotaulukot sekä maksutapaprofiilit. Tutkimuksessa saatiin selville, että osa ajosarjoista oli kannattavia ja osa tappiollisia. Kuitenkin tutkittaessa tappioiden ja tuottojen euromääräisiä tuloksia, voitiin todeta tuottojen kattavan tappioiden kulut, eli toiminta oli kannattavaa. Muuttamalla joidenkin ajosarjojen linjoja, mahdollistettiin toimeksiantajayrityksen kannattavuuden parantaminen. Ajosarjoista yksi lopetettiin kokonaan. Asiakkaiden maksutapaprofiilissa voitiin huomata selvä suosio seutulipuilla. EU:n palvelusopimusasetuksen takia seutuliput tulevat ajan kuluessa loppumaan, joten toimeksiantajayrityksen on tärkeää luoda asiakkaille korvaava lipputuote sen tilalle.The aim of this thesis was to analyze the profitability of a case company’s bus transport lines and to find out which payment method customers use. Eleven routes of the case company were selected for the investigation from September to November 2017. The case company wishes to remain anonymous due to trade secrets. For the same reason conclusions of the investigation are not published. Company profitability and how to develop it forms the theory part of this thesis. Calculating the profit margin is relevant in this context. Data used in the investigation comes mainly from the software the case company uses. Also calculations from other companies based on the case company’s bookkeeping were utilized. Based on the data profit margin tables and customer profiles based on payment method were created. The study concluded that some routes were making a profit and some were operating at a loss. However, when comparing revenues and expenses in euros the revenues covered the losses and the operation remained profitable. This shows that the business is operating at a profit. By changing some of the routes it was possible to improve the company’s profit. One of the eleven routes was terminated. The investigation considering customer’s payment method showed that regional tickets were popular. As regional tickets are going to disappear due to EU regulation it is crucial for the case company to produce some other option for them