Summary Background Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of ...nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. Methods In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov , NCT01928394. Findings Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9–16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3–35·4) of 78 patients. Grade 3–4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four 5%), elevated amylase (three 4%), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two 3% each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. Interpretation Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. Funding Bristol-Myers Squibb.
Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences ...the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC.
Mechanized cut-to-length forest operations often rely on the use of brush mats created from harvesting debris (tree limbs, tops, and foliage) to reduce soil disturbances as a result of in-stand ...machine traffic. These brush mats, placed directly on the forest floor within machine operating trails, distribute loads of timber harvesting and extraction machinery to a greater area, thereby reducing peak pressures exerted to the ground and rutting for maintaining technical trafficability of operating trails. Forest biomass has also been promoted as a source of green and renewable energy, to reduce carbon emissions from energy production. However, to maintain sufficient quality of biomass for bioenergy operations (high heating value and low ash content), brush needs to be free of contaminants such as mineral soil. This constraint eliminates the possibility of the dual use of brush, first as a soil protective layer on machine operating trails and afterwards for bioenergy generation. Leaving machine operating trails uncovered will cause machine loads to be fully and directly applied to the soil, thus increasing the likelihood of severe soil disturbance, tree growth impediment and reducing trail trafficability. The main objective of this study was to quantify the effect of varying machine operating trail spacing and width on the amount of brush required for soil protection. This was achieved by creating five model forest stands (four mature and one immature), commonly found in New Brunswick, Canada, and using their characteristics as input in the Biomass Opportunity and Supply Model (BiOS) from FPInnovations. BiOS provided several key biomass related outputs allowing the determination of the amount of biomass available for soil protection, which was the main focus of this research. The simulation results showed that regardless of trail area tested, all four mature forest stands were able to support uniform distribution of 20 kg m−2 brush mats (green mass) throughout their entire trail network during clear-cut operations but not during partial harvests. From the three factors assessed (brush amount, trail width, and trail spacing), trail width had the highest effect on the required brush amount for trail protection, which in turn has a direct impact on the amount of brush that could be used for bioenergy generation.
Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. ...One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.
Fully mechanized timber harvesting systems are well established in forest operations worldwide. In cut-to-length (CTL) systems, forwarders are used for extracting logs from the stand. The ...productivity of a forwarder is related to site- and stand-specific characteristics, technical parameters, organizational aspects, and the individual skills of the operator. The operator’s performance during “loading” considerably affects forwarder productivity, since this element occupies nearly 50% of forwarding cycle time in CTL operations. When positioning the forwarder for loading, different loading angles and loading distances arise. Additionally, different log orientation angles in relation to the machine operating trail can be observed. Therefore, an in-depth analysis of loading conditions was conducted. The goal of this pilot case study was to explore the potential impact of different loading angles and distances, and log orientation angles, on time consumption per loading cycle in order to derive indications for more efficient work practices. Therefore, controlled loading sequences were tested on a physical Rottne-F10-based forwarder simulator with an experienced forest machine operator. Three loading angles (45°, 90° and 135° azimuthal to the machine axis) with five loading distances (3, 4, 5, 6 and 7 m), and three log orientation angles (45°, 90°, 135°), resulted in a total of 45 settings, which were tested in 10 repetitions each. The time required for a loading cycle was captured in a time study, applying the snap-back method. Results showed that all three tested variables had a significant influence on time consumption per loading cycle. Loading at an angle of 135°, and from a close (3 m) or far distance (7 m) led to especially increased cycle times. Loading from 4 to 6 m distance could be detected as an optimal loading range. Additionally, log orientation angles of 45° and 90° led to increased loading efficiency. Even if the validity of the results may be limited due to different conditions and influencing factors in field forwarding operations, these data can contribute to a better understanding of the loading element and, in particular, to productivity determining factors of forwarder work.
Purpose
First-line treatment of patients with recurrent, metastatic prostate cancer involves hormone therapy with or without additional systemic therapies. Prostate-specific membrane antigen (PSMA) ...positron emission tomography (PET)/computed tomography (CT) allows the detection of oligometastatic disease that may be amenable to image-guided radiotherapy. The current study classifies the type and localization of metastases and the clinical outcome of PSMA-PET/CT-guided radiotherapy to selected metastases.
Materials and methods
Between 2011 and 2019, 86 patients with recurrent, oligometastatic prostate carcinoma were identified by PSMA-PET/CT and were treated with image-guided radiotherapy of their metastases. Sites of relapse were characterized, and the primary endpoint overall survival (OS), biochemical progression-free survival (bPFS), and androgen deprivation therapy (ADT)-free survival were tabulated.
Results
In total, 37% of the metastases were bone metastases, 48% were pelvic nodal metastases, and 15% were nodal metastases outside of the pelvis. After PSMA-guided radiotherapy, a biochemical response was detected in 83% of the cohort. A statistically significant decrease in the standard uptake value (SUV) was seen in irradiated metastases. After a median follow-up of 26 months, the 3-year OS and bPFS were 84% and 55%, respectively. The median time of ADT-free survival was 13.5 months. A better clinical outcome was observed for patients receiving concomitant ADT or more than 24 fractions of radiation.
Conclusion
PSMA-guided radiotherapy is a promising therapeutic approach with excellent infield control for men with oligorecurrent prostate carcinoma. However, prospective, randomized trials are necessary to determine if this approach confers a survival advantage.
Purpose
Chemotherapy-induced alopecia (CIA) is a distressing side effect for women with breast cancer undergoing chemotherapy. Scalp cooling is a method aiming to prevent CIA, but its efficacy is not ...well defined. Randomized trials until recently and at the time this trial was designed have been lacking.
Methods
Patients undergoing (neo)adjuvant chemotherapy for early breast cancer (EBC) were randomized to scalp cooling (CAP) or observation (NoCAP). All patients received 18–24 weeks of anthracycline- and/or taxane-based chemotherapy. The primary endpoint was patient-reported rate of alopecia according to a modified version of the Dean Scale. Hair preservation was defined as hair loss ≤ grade 2 (≤ 50%). Secondary endpoints were rate of alopecia determined by medical staff, rate of wig/scarf use, tolerability as well as quality of life (QoL).
Results
Seventy-nine patients were randomized. Hair preservation was observed in 39.3% of patients in the CAP arm versus 0% in the NoCAP arm (
p
< 0.001). Wig/scarf use was significantly less frequent in the CAP group (40.7% vs 95.5% outside home before cycle 3,
p
< 0.001). The drop-out rate was 31.7% and 34.2% in the CAP and NoCAP arm, respectively. Main reasons for drop-out were hair loss, adverse events (CAP), and randomization into control arm. We observed no differences in efficacy between anthracycline-based and non-anthracycline-based regimens. QoL did not differ between the study arms.
Conclusions
This trial adds to the evidence that scalp cooling effectively prevents CIA in a meaningful number of patients. This option should be made available for patients undergoing (neo)adjuvant chemotherapy for EBC.
The impact of machines on forest soils is regularly assessed and quantified using absolute bulk density, which is most frequently obtained by soil cores. However, to allow for repeated measurements ...at the exact same locations, non-destructive devices are increasingly being used to determine soil bulk density and moisture content in field studies. An example of such a device is a nuclear moisture and density gauge (NMDG), originally designed as a control measurement for soil bulk density and moisture content in geotechnical applications. Unlike road construction or foundation projects that use mineral soil or gravel, forest soils have complex structures and the presence of organic matter, which can skew moisture and density readings from a NMDG. To gain further knowledge in this respect, we performed controlled tests in a sandbox to quantify the influence of varying amounts of saturated organic matter (3, 5, 10, and 15%) mixed with mineral soil in different layers (0–5, 0–10, 0–20 and 0–40 cm) on the accuracy of soil moisture content obtained by a NMDG and soil theta probe at varying depths. Main results illustrated that the presence of saturated organic matter per se was not problematic but moisture content overestimations and related underestimation of dry bulk density occurred when the tested measurement depth was below the created organic layer. Since forest soils often exhibit higher organic matter contents in the upper horizon, correction factors are suggested to minimize the moisture content variations between NMDG and reference method. With the use of correction factors, NMDG can present a non-destructive, fast, and accurate method of measuring soil moisture and bulk density in forestry applications.
Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation ...of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and induce therapy resistance in cancer cells. Among anti-apoptotic Bcl-2 proteins, we found solely Bcl-xL strongly upregulated in human CRC specimens. In order to study protein function in the context of tumor initiation and progression in vivo, we generated a mouse model lacking Bcl-xL in intestinal epithelial cells (Bcl-xL(IEC-KO)). If challenged in an inflammation-driven tumor model, Bcl-xL(IEC-KO) mice showed a significantly reduced tumor burden with lower tumor numbers per animal and decreased tumor sizes. Analysis of cell death events by immunohistochemistry and immunoblotting revealed a striking increase of apoptosis in Bcl-xL-negative tumors. qRT-PCR and immunohistochemistry excluded changes in proliferative capacity and immune cell infiltration as reasons for the reduced tumor load and thereby identify apoptosis as key mechanism. Human CRC tissue was cultured ex vivo and treated with the small molecule compound ABT-737, which inhibits Bcl-xL and Bcl-2. Under ABT-737 treatment, the amount of apoptotic tumor cells significantly increased compared with controls, whereas proliferation levels remained unaltered. In summary, our findings identify Bcl-xL as a driver in colorectal tumorigenesis and cancer progression, making it a valuable target for clinical application.
On a broader scale, T cell density and localization in colorectal cancer liver metastases have prognostic and predictive implications. As T cell distribution at higher resolutions has not been fully ...investigated, a detailed resolution analysis of T cell distribution was performed. Patient tissues were divided into 10 µm distance classes between the tumor border and adjacent normal liver. Thereby, distinct density patterns of T cell localization in relation to the malignant tissue could be detected. At a distance of 20 to 30 µm to the tumor, a decrease of CD3 T cells is common. Within this area, cytotoxic Granzyme B and CD8
+
T cells were found to be significantly reduced as well as CD163 macrophages were increased and identified to be in close contact with T cells. Our data suggests a physical or functional border within this region. Survival analysis revealed improved overall survival in patients with high T cells numbers at the direct tumor border. Interestingly, the decreased T cells in the 20 to 30 µm region were also found to be significantly associated with improved survival. Consequently, the detailed localization of T cells, despite blockade, could be associated with improved clinical outcome. The high-resolution analysis represents new insights into relevant heterogenous T cell distributions especially related to clinical responses. As the paradoxical observation of localization-dependent prognostic relevance of T cell densities is only detectable by detailed spatial analyses, this investigation of spatial profiles at higher resolutions is suggested as a new biomarker for survival and response to therapies.
PDF
