Modal Inferences in Science : A Tale of Two Epistemologies

Recent epistemology of modality has seen a growing trend towards metaphysics-first approaches. Contrastingly, this paper offers a more philosophically modest account of justifying modal claims, focusing on the practices of scientific modal inferences. Two ways of making such inferences are identified and analyzed: actualist- manipulationist modality (AM) and relative modality (RM). In AM, what is observed to be or not to be the case in actuality or under manipulations, allows us to make modal inferences. AM-based inferences are fallible, but the same holds for practically all empirical inquiry. In RM, modal inferences are evaluated relative to what is kept fixed in a system, like a theory or a model. RM-based inferences are more certain but framework-dependent. While elements from both AM and RM can be found in some existing accounts of modality, it is worth highlighting them in their own right and isolating their features for closer scrutiny. This helps to establish their relevant epistemologies that are free from some strong philosophical assumptions often attached to them in the literature. We close by showing how combining these two routes amounts to a view that accounts for a rich variety of modal inferences in science.Peer reviewe

Epistemology of Modality : Between the Rock and the Hard Place

We review some of the major accounts in the current epistemology of modality and identify some shared issues that plague all of them. In order to provide insight into the nature of modal statements in science, philosophy, and beyond, a satisfactory epistemology of modality would need to be suitably applicable to practical and theoretical contexts by limited beings. However, many epistemologies of modality seem to work only when we have access to the kind of knowledge that is at least currently beyond our reach. Or, in the extreme case, it is argued that even if we knew all the relevant information about the respective domain – or even the entire state of the world – there would still remain a special class of modal truths that would be left unaccounted for. Neither picture bodes well for practical applicability, nor for the philosophical justification of these epistemologies. This is especially the case as we hold that one of the main motivations for modal inquiry typically arises in cases of imperfect information and limited cognitive resources. We close by providing a partial remedy to the situation by suggesting an overall framework of relative modality (RM) that can be used to both unify some existing modal epistemologies and, at the same time, make them more metaphysically modest.Peer reviewe

Epistemology of Modality : Between the Rock and the Hard Place

We review some of the major accounts in the current epistemology of modality and identify some shared issues that plague all of them. In order to provide insight into the nature of modal statements in science, philosophy, and beyond, a satisfactory epistemology of modality would need to be suitably applicable to practical and theoretical contexts by limited beings. However, many epistemologies of modality seem to work only when we have access to the kind of knowledge that is at least currently beyond our reach. Or, in the extreme case, it is argued that even if we knew all the relevant information about the respective domain – or even the entire state of the world – there would still remain a special class of modal truths that would be left unaccounted for. Neither picture bodes well for practical applicability, nor for the philosophical justification of these epistemologies. This is especially the case as we hold that one of the main motivations for modal inquiry typically arises in cases of imperfect information and limited cognitive resources. We close by providing a partial remedy to the situation by suggesting an overall framework of relative modality (RM) that can be used to both unify some existing modal epistemologies and, at the same time, make them more metaphysically modest.Peer reviewe

Prognostic and predictive value of ALDH1, SOX2 and SSEA-4 in bladder cancer

Transurethral resection of bladder tumor (TUR-BT) and radical cystectomy (RC) are standard treatment options for bladder cancer (BC). Neoadjuvant chemotherapy (NAC) prior to RC improves outcome of some patients but currently there are no valid biomarkers to identify patients who benefit from NAC. Presence of cancer stem cells (CSC) has been associated with poor outcome and resistance to chemotherapy in various cancers. Here we studied the expression of stem cell markers ALDH1, SOX2 and SSEA-4 with immunohistochemistry in tissue microarray material consisting of 195 BC patients treated with RC and 74 patients treated with TUR-BT followed by NAC and RC. Post-operative follow-up data of up to 22 years was used. Negative to weak cytoplasmic SOX2 staining was associated with lymphovascular invasion and non-organ confined disease. It was also associated with shortened cancer-specific survival, but the finding was not statistically significant. Contrary to previous reports, none of the other tested biomarkers were associated with cancer-specific mortality or clinicopathological characteristics. Neither were they associated with response to NAC. Despite the promising results of previously published studies, our results suggest that CSC markers ALDH1, SOX2 and SSEA-4 have little if any prognostic or predictive value in BC treated with RC.Peer reviewe

Immunological tumor status may predict response to neoadjuvant chemotherapy and outcome after radical cystectomy in bladder cancer

Bladder cancer (BC) is the ninth most common cancer worldwide. Radical cystectomy (RC) with neoadjuvant chemotherapy (NAC) is recommended for muscle-invasive BC. The challenge of the neoadjuvant approach relates to challenges in selection of patients to chemotherapy that are likely to respond to the treatment. To date, there are no validated molecular markers or baseline clinical characteristics to identify these patients. Different inflammatory markers, including tumor associated macrophages with their plastic pro-tumorigenic and anti-tumorigenic functions, have extensively been under interests as potential prognostic and predictive biomarkers in different cancer types. In this immunohistochemical study we evaluated the predictive roles of three immunological markers, CD68, MAC387, and CLEVER-1, in response to NAC and outcome of BC. 41% of the patients had a complete response (pT0N0) to NAC. Basic clinicopathological variables did not predict response to NAC. In contrast, MAC387(+) cells and CLEVER-1(+) macrophages associated with poor NAC response, while CLEVER-1(+) vessels associated with more favourable response to NAC. Higher counts of CLEVER-1+ macrophages associated with poorer overall survival and CD68(+) macrophages seem to have an independent prognostic value in BC patients treated with NAC. Our findings point out that CD68, MAC387, and CLEVER-1 may be useful prognostic and predictive markers in BC.Peer reviewe

Prediction of neo-adjuvant chemotherapy response in bladder cancer : the impact of clinical parameters and routine biomarkers

Purpose To investigate the role of clinical parameters and immunohistochemical (IHC) biomarkers in their feasibility to predict the effect of neo-adjuvant chemotherapy (NAC) in patients with muscle-invasive urothelial bladder cancer (MIBC). Materials and methods The first 76 consecutive patients with MIBC treated with NAC and radical cystectomy in two University hospitals in Finland between 2008 and 2013 were chosen for this study. After excluding patients with non-urothelial cancer, less than two cycles of chemotherapy, no tissue material for IHC analysis or non-muscle-invasive bladder cancer in re-review, 59 patients were included in the final analysis. A tissue microarray block was constructed from the transurethral resection samples and IHC stainings of Ki-67, p53, Her-2 and EGFR were made. The correlations between histological features in transurethral resection samples and immune-histochemical stainings were calculated. The associations of clinicopathological parameters and IHC stainings with NAC response were evaluated. Factors affecting survival were estimated. Results The complete response rate after NAC was 44%. A higher number of chemotherapy cycles was associated with better response to neo-adjuvant chemotherapy. No response to neo-adjuvant chemotherapy and female gender was associated with decreased cancer-specific survival. The IHC stainings used failed to show an association with neo-adjuvant chemotherapy response and overall or cancer specific survival. Conclusions Patients who do not respond to neo-adjuvant chemotherapy do significantly worse than responders. This study could not find clinical tools to distinguish responders from non-responders. Further studies preferably with larger cohorts addressing this issue are warranted to improve the selection of patients for neo-adjuvant chemotherapy.Peer reviewe

Virtsarakkosyöpä

English summaryPeer reviewe

Prognostic and predictive value of ALDH1, SOX2 and SSEA-4 in bladder cancer

Transurethral resection of bladder tumor (TUR-BT) and radical cystectomy (RC) are standard treatment options for bladder cancer (BC). Neoadjuvant chemotherapy (NAC) prior to RC improves outcome of some patients but currently there are no valid biomarkers to identify patients who benefit from NAC. Presence of cancer stem cells (CSC) has been associated with poor outcome and resistance to chemotherapy in various cancers. Here we studied the expression of stem cell markers ALDH1, SOX2 and SSEA-4 with immunohistochemistry in tissue microarray material consisting of 195 BC patients treated with RC and 74 patients treated with TUR-BT followed by NAC and RC. Post-operative follow-up data of up to 22 years was used. Negative to weak cytoplasmic SOX2 staining was associated with lymphovascular invasion and non-organ confined disease. It was also associated with shortened cancer-specific survival, but the finding was not statistically significant. Contrary to previous reports, none of the other tested biomarkers were associated with cancer-specific mortality or clinicopathological characteristics. Neither were they associated with response to NAC. Despite the promising results of previously published studies, our results suggest that CSC markers ALDH1, SOX2 and SSEA-4 have little if any prognostic or predictive value in BC treated with RC

Prediction of neo-adjuvant chemotherapy response in bladder cancer: the impact of clinical parameters and routine biomarkers

PurposeTo investigate the role of clinical parameters and immunohistochemical (IHC) biomarkers in their feasibility to predict the effect of neo-adjuvant chemotherapy (NAC) in patients with muscle-invasive urothelial bladder cancer (MIBC).Materials and methodsThe first 76 consecutive patients with MIBC treated with NAC and radical cystectomy in two University hospitals in Finland between 2008 and 2013 were chosen for this study. After excluding patients with non-urothelial cancer, less than two cycles of chemotherapy, no tissue material for IHC analysis or non-muscle-invasive bladder cancer in re-review, 59 patients were included in the final analysis. A tissue microarray block was constructed from the transurethral resection samples and IHC stainings of Ki-67, p53, Her-2 and EGFR were made. The correlations between histological features in transurethral resection samples and immune-histochemical stainings were calculated. The associations of clinicopathological parameters and IHC stainings with NAC response were evaluated. Factors affecting survival were estimated.ResultsThe complete response rate after NAC was 44%. A higher number of chemotherapy cycles was associated with better response to neo-adjuvant chemotherapy. No response to neo-adjuvant chemotherapy and female gender was associated with decreased cancer-specific survival. The IHC stainings used failed to show an association with neo-adjuvant chemotherapy response and overall or cancer specific survival.ConclusionsPatients who do not respond to neo-adjuvant chemotherapy do significantly worse than responders. This study could not find clinical tools to distinguish responders from non-responders. Further studies preferably with larger cohorts addressing this issue are warranted to improve the selection of patients for neo-adjuvant chemotherapy.</p

11C-acetate PET/MRI in bladder cancer staging and treatment response evaluation to neoadjuvant chemotherapy : a prospective multicenter study (ACEBIB trial)

Abstract Background To evaluate the accuracy of 11C-acetate Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in bladder cancer (BC) staging and monitoring response to neoadjuvant chemotherapy (NAC). Methods Eighteen patients were prospectively enrolled. Fifteen treatment naive patients underwent 11C-acetate PET/MRI before transurethral resection of bladder tumor (TUR-BT) for primary tumor evaluation. Five patients with muscle invasive BC were imaged after NAC and prior to radical cystectomy (RC) with extended pelvic lymph node dissection (ePLND) for NAC treatment response evaluation. Two patients were part of both cohorts. 11C-acetate PET/MRI findings were correlated with histopathology. Accuracy for lymph node detection was evaluated on patient and the ePLND template (10 regions) levels. Results The sensitivity, specificity and accuracy of 11C-acetate PET/MRI for the detection of muscle invasive BC was 1.00, 0.69 and 0.73 while the area under the receiver operating characteristic curve (95% confidence interval) was 0.85 (0.55–1.0), respectively. All five NAC patients underwent chemotherapy as planned and 11C-acetate PET/MRI correctly staged three patients, overstaged one and understaged one patient compared with RC and ePLND findings. A total of 175 lymph node were removed, median of 35 (range, 27–43) per patient in five patients who had RC and ePLND while 12 (7%) harboured metastases. Sensitivity, specificity, accuracy and AUC for N-staging were 0.20, 0.96, 0.80 and 0.58 on the ePLND template (10 regions) level. Conclusions 11C-acetate PET/MRI is feasible for staging of BC although sensitivity for the detection of nodal metastases is low. Monitoring response to NAC shows promise and warrants evaluation in larger studies. Trial registration ClinicalTrials.gov Identifier: NCT01918592 , registered August 8 201