Summary Background MABp1, an antibody that targets interleukin 1α, has been associated with antitumour activity and relief of debilitating symptoms in patients with advanced colorectal cancer. We ...sought to establish the effect of MABp1 with a new primary endpoint in patients with advanced colorectal cancer. Methods Eligible patients for the double-blind phase of this ongoing, placebo-controlled, randomised, phase 3 trial, had metastatic or unresectable disease, Eastern Cooperative Oncology Group performance status score 1 or 2, systemic inflammation, weight loss, and other disease-related morbidities associated with poor prognosis, and were refractory to oxaliplatin and irinotecan. Patients were randomly assigned 2:1 to receive either MABp1 or placebo. Randomisation codes were obtained from a centrally held list via an interactive web response system. Patients received an intravenous infusion of 7·5 mg/kg MABp1 or placebo given every 2 weeks for 8 weeks. The primary endpoint was assessed in patients who received at least one dose of MABp1 or placebo (modified intention-to-treat population), and was a composite of stable or increased lean body mass and stability or improvement in two of three symptoms (pain, fatigue, or anorexia) at week 8 compared with baseline measurements. This study is registered with ClinicalTrials.gov , number NCT02138422. Findings Patients were enrolled between May 20, 2014, and Sept 2, 2015. The double-blind phase of the study was completed on Nov 3, 2015. Of 333 patients randomly assigned treatment, 207 received at least one dose of MABp1 and 102 at least one dose of placebo. 68 (33%) and 19 (19%) patients, respectively, achieved the primary endpoint (relative risk 1·76, 95% CI 1·12–2·77, p=0·0045). The most common grade 3–4 adverse events in the MABp1 group compared with in the placebo group were anaemia (eight 4% of 207 vs five 5% of 102 patients), increased concentration of alkaline phosphatase (nine 4% vs two 2%), fatigue (six 3% vs seven 7%), and increased concentration of aspartate aminotransferase (six 3% vs two 2%). After 8 weeks, 17 (8%) patients in the MABp1 group and 11 (11%) in the placebo group had died, but no death was judged to be related to treatment. The incidence of serious adverse events was not significantly different in the MABp1 group and placebo groups (47 23% vs 33 32%, p=0·07). Interpretation The primary endpoint was a useful means of measuring clinical performance in patients. MABp1 might represent a new standard in the management of advanced colorectal cancer. Funding XBiotech.
Cancer stroma contains the neural compartment with specific components and action. Neural microenvironment processing includes among others axonogenesis, perineural invasion (PNI), neurosignaling, ...and tumor cell neural/neuroendocrine differentiation. Growing data suggest that tumor-neural crosstalk plays an important function in prostate cancer (PCa) biology. However, the mechanisms involved in PNI and axonogenesis, as well as their patho-clinical correlations in this tumor are unclear.
The present study was carried out on FFPE samples of 73 PCa and 15 benign prostate (BP) cases. Immunohistochemistry with neural markers PGP9.5, TH, and NFP was performed on constructed TMAs and selected tissue sections. The analyzed parameters of tumor innervation included small nerve density (ND) measured on pan-neural marker (PGP9.5) and TH s4tained slides, as well assessment of PNI presence and morphology. The qualitative and topographic aspects were studied. In addition, the expression of neuroendocrine marker chromogranin and NPY was assessed with dedicated indexes. The correlations of the above parameters with basic patho-clinical data such as patients' age, tumor stage, grade, angioinvasion, and ERG status were examined.
The study showed that innervation parameters differed between cancer and BP. The neural network in PCa revealed heterogeneity, and ND PGP9.5 in tumor was significantly lower than in its periphery. The density of sympathetic TH-positive fibers and its proportion to all fibers was lower in cancer than in the periphery and BP samples. Perineural invasion was confirmed in 76% of cases, usually multifocally, occurring more commonly in tumors with a higher grade. NPY expression in PCa cells was common with its intensity often rising towards PNI. ERG+ tumors showed higher ND, more frequent PNI, and a higher stage. Moreover, chromogranin-positive cells were more pronounced in PCa with higher NPY expression.
The analysis showed an irregular axonal network in prostate cancer with higher neural density (panneural and adrenergic) in the surroundings and the invasive front. ND and PNI interrelated with NPY expression, neuroendocrine differentiation, and ERG status. The above findings support new evidence for the presence of autocrine and paracrine interactions in prostate cancer neural microenvironment.
Transient or constant impaired immunity is often associated with neoplastic disease or oncological treatment. Among the most common pathogens found in patients with HIV or patients undergoing ...chemotherapy are protozoans of the Cryptosporidium genus, which cause diarrhea in humans and animals. The present study determined the frequency of Cryptosporidium spp. infections in patients with colorectal cancer (N = 108; 42 women; 66 men; median age, 65 years), before beginning oncological treatment, compared to a control group (N = 125; 56 women, 69 men; median age, 63 years) without colorectal cancer or a history of oncological disease. We also assessed whether Cryptosporidium spp. infections were associated with age, gender, cancer stage (based on Astler-Coller or TNM classification), histological grade, or cancer location. Patients were treated at the Pomeranian Medical University, in 2009-2014. The presence of Cryptosporidium spp. antigen was determined in stool samples, analyzed with a commercial immunoenzymatic test. Cryptosporidium spp. infections occurred significantly more often (p = 0.015) in patients (13%) compared to controls (4%). The patient group showed no significant relationship between Cryptosporidium spp. infection and sex, age, tumor location, cancer grade, or stage. A multivariate logistic regression analysis adjusted for age and sex that included all subjects (patient + control groups, n = 233) showed that the odds of a Cryptosporidium spp. infection were more than three-fold higher in patients than in controls, and more than six-fold higher among men than among women.
1) Cryptosporidium spp. infections occurred significantly more frequently in patients with colorectal cancer (before oncological treatment) compared to controls, independent of age and sex. 2) Cryptosporidium spp. infections were not associated with the colorectal cancer stage, grade, or location or with patient age. 3) Male gender was significantly related to the frequency of Cryptosporidium spp. infections, independent of age and the presence of colorectal cancer.
We investigated the status of estrogen receptor alpha (ERα), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) in primary tumor and in the corresponding brain metastases in a ...consecutive series of breast cancer patients. Additionally, we studied factors potentially influencing conversion and evaluated its association with survival.
The study group included 120 breast cancer patients. ERα, PR, and HER2 status in primary tumors and in matched brain metastases was determined centrally by immunohistochemistry and/or fluorescence in situ hybridization.
Using the Allred score of ≥ 3 as a threshold, conversion of ERα and PR in brain metastases occurred in 29% of cases for both receptors, mostly from positive to negative. Conversion of HER2 occurred in 14% of patients and was more balanced either way. Time to brain relapse and the use of chemotherapy or trastuzumab did not influence conversion, whereas endocrine therapy induced conversion of ERα (P = 0.021) and PR (P = 0.001), mainly towards their loss. Receptor conversion had no significant impact on survival.
Receptor conversion, particularly loss of hormone receptors, is a common event in brain metastases from breast cancer, and endocrine therapy may increase its incidence. Receptor conversion does not significantly affect survival.
Numerous different molecules of prostate-specific membrane antigen (PSMA) ligands are used to detect prostate cancer (PCa); most approaches utilize gallium PET and a few reports describe the role of ...SPECT/CT. 99mTcTc-PSMA-T4 is a new radiopharmaceutical designed for the diagnosis of patients with PCa. We conducted a single site, prospective, preliminary case series study that included 31 patients with PCa; all had undergone clinical, biochemical or imaging examination and exhibited clear or suspicious active disease or clinical/biochemical recurrence of PCa. Whole-body (WB) SPECT/CT after i.v. administration of 99mTcTc-PSMA-T4 was utilized; acquisition images were obtained at three time points. The clinical value of the images was assessed in regard to the evaluation of tumor extent in patients with confirmed PC that qualified for initial therapy and the evaluation of tumor recurrence; both provided encouraging results. The late acquisition of WB-SPECT resulted in better lesions delineation. The results of the analysis of the sensitivity/specificity were: 92%/100% in cases of primary cancer, 83%/100% in terms of pelvic lymph nodes disease, 100%/95% in other lymph nodes and soft tissue involvement, respectively, and bone mets were both 100%. An oncotropic SPECT 99mTcTc-PSMA-T4 can help in selecting a rational therapeutic strategy for a patient with an initial diagnosis of PCa by assessing the extent of cancer and also after complex radical or palliative therapy in case of biochemical recurrence for re-staging.
The phenomenon called legislative inflation is extensively used in public debate across jurisdictions - including new democracies attempting to overcome communist legal heritage. Typically, the ...phrase refers to the quantitative aspect - growth in the number, volume and frequency of amendments of primary and secondary legislation exceeding the natural demands of the technological progress and growing complexity of business relations. This paper attempts to provide a bird's eye view of legislative inflation in Poland after the 1989 democratic breakthrough. As Poland is an example of successful democratic and market transition of the nineties, substantial redrafting of the legal framework during EU accession and populist right-wing governance, the results seem relevant beyond the domestic context. Documented patterns suggest that the search for driving forces behind the legislative inflation should shift from the parliament towards cabinet ministers and the bureaucratic apparatus under their supervision, the pace of legal text production justifies the search for a theoretical conceptualisation of how the law could govern societies unwilling and unable to familiarise themselves with its flow and to examine the impact of legal text production on society and the economy it seems useful to shift from the data on the text itself towards its actual impact.
The COVID-19 pandemic transformed our understanding of the state’s role during a public health crisis and introduced an array of unprecedented policy tools: ever-stricter travel restrictions, ...lockdowns and closures of whole branches of the economy. Evidence-based policymaking seems to be the gold standard of such high-stakes policy interventions. This article presents an empirical investigation into the regulatory impact assessments accompanying sixty-four executive acts (regulations) introducing anti-pandemic restrictions in Poland over the first year of the pandemic. To this end, the study utilises the so-called scorecard methodology, which is popular in regulatory impact assessment research. This methodology highlights the shallowness of these documents and the accompanying processes, with an absence not only of a sound evidence base behind specific anti-pandemic measures or estimates of their economic impacts, but even of the comparative data on restrictions introduced in other European Union/Organisation for Economic Co-operation and Development (OECD) countries. Overall, the collected data support the hypothesis that the ad hoc pandemic management process crowded out the law-making process through tools such as regulatory impact assessments and consultations. In other words, the genuine decision-making occurred elsewhere (with the exact process being largely invisible to public opinion and scholars) and drafting legal texts simply codified these decisions, with the law-making process becoming mere window-dressing.
We still do not know whether the presently used protocol of the first-line palliative treatment of disseminated colorectal cancer (FOLFOX/FOLFIRI protocol) allows maximization of therapeutic response ...and minimization of side effects. No-one has verified whether continuation of the first-line chemotherapy despite the lack of progression is reflected by improved prognosis or significant risk of toxicity. This issue is of vital importance in the case of developing countries where targeted therapies are not available due to financial shortages. We have identified three potential strategies of the palliative therapy of disseminated colorectal cancer: 1) discontinuation of chemotherapy after a fixed number of cycles with its restart on progression (stop-and-go strategy), 2) intermittent protocol of chemotherapy, and 3) continuation of chemotherapy with discontinuation of the most toxic agent. None of the studies proved the superiority of the most commonly used standard, i.e. 12 cycles of the FOLFOX or FOLFIRI regimen. Although longer duration of this treatment may be associated with higher response rates and longer progression-free survival, these improvements frequently prove insignificant on statistical analysis.
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