Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.

BACKGROUND: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. MATERIALS AND METHODS: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. RESULTS: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. CONCLUSIONS: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.

Accumulated dose implications from systematic dose-rate transients in gated treatments with Viewray MRIdian accelerators.

The combination of magnetic resonance (MR) imaging and linear accelerators (linacs) into MR-Linacs enables continuous MR imaging and advanced gated treatments of patients. Previously, a dose-rate transient (∼8% reduced dose rate during the initial 0.5 s of each beam) was identified for a Viewray MRIdian MR-Linac (Klavsenet al2022Radiation Measurement106759). Here, the dose-rate transient is studied in more detail at four linacs of the same type at different hospitals. The implications of dose-rate transients were examined for gated treatments. The dose-rate transients were investigated using dose-per pulse measurements with organic plastic scintillators in three experiments: (i) A gated treatment with the scintillator placed in a moving target in a dynamic phantom, (ii) a gated treatment with the same dynamic conditions but with the scintillator placed in a stationary target, and (iii) measurements in a water-equivalent material to examine beam quality deviations at a dose-per-pulse basis. Gated treatments (i) compared with non-gated treatments with a static target in the same setup showed a broadening of accumulated dose profiles due to motion (dose smearing). The linac with the largest dose-rate transient had a reduced accumulated dose of up to (3.1 ± 0.65) % in the center of the PTV due to the combined dose smearing and dose-rate transient effect. Dose-rate transients were found to vary between different machines. Two MR-Linacs showed initial dose-rate transients that could not be identified from conventional linearity tests. The source of the transients includes an initial change in photon fluence rate and an initial change in x-ray beam quality. For gated treatments, this caused a reduction of more than 1% dose delivered at the central part of the beam for the studied, cyclic-motion treatment plan. Quality assurance of this effect should be considered when gated treatment with the Viewray MRIdian is implemented clinically.

Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

Copper transformation, speciation, and detoxification in anoxic and suboxic freshwater sediments.

The complex chemistry of copper (Cu) in freshwater sediments at low concentrations is not well understood. We evaluated the transformation processes of Cu added to freshwater sediments under suboxic and anoxic conditions. Freshwater sediments from three sources in Michigan with different characteristics (Spring Creek, River Raisin, and Maple Lake) were spiked with 30 or 60 mg kg-1 Cu and incubated under a nitrogen atmosphere. After 28-d, each treatment subset was amended with organic matter (OM) to promote anoxic conditions and evaluate its effects on Cu speciation. OM addition triggered a shift from suboxic to anoxic conditions, and sequential extractions showed that Cu accordingly shifted from acid-soluble to oxidizable fractions. Extended X-ray absorption fine-structure (EXAFS) spectroscopy revealed that Cu sulfides dominated all anoxic samples except for Spring Creek 30 mg kg-1, where Cu(I) was predominantly complexed to thiol groups of OM. Covellite and chalcopyrite (CuFeS2) were the predominant Cu species in nearly all anoxic samples, as determined by Raman spectroscopy, scanning electron microscopy, and X-ray absorption near-edge structure (XANES) spectroscopy. Copper reduction also occurred under suboxic conditions: for two of three sediments, around 80% had been reduced to Cu(I), while the remaining 20% persisted as Cu(II) complexed to OM. However, in the third coarsest (i.e., Spring Creek), around 50% of the Cu had been reduced, forming Cu(I)-OM complexes, while the remainder was Cu(II)-OM complexes. Toxicity tests showed that survival of H. azteca and D. magna were significantly lower in suboxic treatments. Anoxic sediments triggered a near-complete transformation of Cu to sulfide minerals, reducing its toxicity.

Postmastectomy Radiation Therapy Planning After Immediate Implant-based Reconstruction Using the European Society for Radiotherapy and Oncology-Advisory Committee in Radiation Oncology Practice Consensus Guidelines for Target Volume Delineation.

AIMS: To evaluate how common radiation therapy techniques perform in the setting of the new European Society for Radiotherapy and Oncology-Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) delineation recommendations for immediate breast reconstruction (IBR). MATERIALS AND METHODS: Seven Danish radiation therapy centres and six international European centres participated in this project. Two breast cancer cases (one left-sided and one right-sided) with a retropectoral implant were chosen for radiation therapy planning using deep-inspiration breath-hold. Target volumes were delineated according to ESTRO-ACROP delineation recommendations. The centres were asked to plan the cases using any radiation therapy technique according to the Danish Breast Cancer Group plan objectives. RESULTS: In total, 35 treatment plans were collected. Half of the submitted plans, for both the left-sided and the right-sided case, used the field-in-field (FiF) technique (nine for each), a quarter used volumetric arc radiation therapy (VMAT; five for right-sided, four for left-sided) and the remaining quarter was a mix of inverse intensity-modulated radiation therapy (IMRT), helicoidal therapy and hybrid (combined open fields and VMAT) techniques. Mean clinical target volume doses were in the range 99-102% of the prescribed dose. The median FiF mean heart dose (MHD) for right-sided radiation therapy was 1 Gy (range 0.8-3.7) and 5.2 Gy for left-sided radiation therapy (range 2.2-6.5). For right-sided radiation therapy, the median VMAT MHD was 3.42 Gy, for IMRT was 2.3 Gy and for helicoidal therapy was 5.1 Gy. For left-sided radiation therapy, the median VMAT MHD was 6.3 Gy, for IMRT was 7.8 Gy and for helicoidal therapy was 7.3 Gy. CONCLUSIONS: Different radiation therapy techniques could be used to plan radiation therapy in the setting of IBR. FiF provided good coverage with acceptable organ at risk doses. The best dose distribution results as a trade-off between the objectives of target volume coverage and high-dose organ at risk inclusion. The radiation therapy technique affects the interplay between these objectives.

Costs and where to find them: identifying unit costs for health economic evaluations of diabetes in France, Germany and Italy.

BACKGROUND: Health economic evaluations require cost data as key inputs. Many countries do not have standardized reference costs so costs used often vary between studies, thereby reducing transparency and transferability. The present review provided a comprehensive overview of cost sources and suggested unit costs for France, Germany and Italy, to support health economic evaluations in these countries, particularly in the field of diabetes. METHODS: A literature review was conducted across multiple databases to identify published unit costs and cost data sources for resource items commonly used in health economic evaluations of antidiabetic therapies. The quality of unit cost reporting was assessed with regard to comprehensiveness of cost reporting and referencing as well as accessibility of cost sources from published cost-effectiveness analyses (CEA) of antidiabetic medications. RESULTS: An overview of cost sources, including tariff and fee schedules as well as published estimates, was developed for France, Germany and Italy, covering primary and specialist outpatient care, emergency care, hospital treatment, pharmacy costs and lost productivity. Based on these sources, unit cost datasets were suggested for each country. The assessment of unit cost reporting showed that only 60% and 40% of CEAs reported unit costs and referenced them for all pharmacy items, respectively. Less than 20% of CEAs obtained all pharmacy costs from publicly available sources. CONCLUSIONS: This review provides a comprehensive account of available costs and cost sources in France, Germany and Italy to support health economists and increase transparency in health economic evaluations in diabetes.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Long-term Data from the Swedish National Environmental Monitoring Program of Pesticides in Surface Waters.

Environmental monitoring is essential for assessing the impact of human activities on the environment. Monitoring data are used to ascertain that environmental standards are met, to inform policy making, to determine trends, and to provide parameterization data for prediction models. The design of monitoring programs depends on what is being monitored, for what purpose, and available resources. Here we describe the strategy and design of the Swedish environmental monitoring program for chemical pesticides in surface waters and provide data generated within this program since 2002 (). We include examples of how the data can be used for toxicity assessments, trend analyses, and comparison between sampling strategies. Our goal is to increase awareness of this dataset and provide detailed information about the data so that it may be incorporated into meta-analytical research, comparison studies, model validation, and other scientific efforts.

Is Peritoneal Tumor Penetration of Prognostic Importance in Gastrointestinal Stromal Tumors?

BACKGROUND: Peritoneal tumor penetration (PP) strongly affects prognosis in gastrointestinal carcinomas. In gastrointestinal stromal tumor (GIST), its significance in the absence of tumor rupture has not been subjected to detailed analysis. METHODS: Patients undergoing complete resection for non-metastatic GIST from 2000 to 2017 were identified in the regional sarcoma database at Oslo University Hospital. Patients with extraperitoneal tumors (esophagus, rectum) or ruptured tumors were excluded from the study. Rupture was defined according to the Oslo criteria, and PP was assessed via routine histopathologic examination by sarcoma pathologists. RESULTS: The study enrolled 341 patients. The median follow-up period was 51 months (range 0-175) months. In 82 (24%) of the 341 patients, PP was recorded. There were 32 recurrences, 9 in patients with PP and 23 in patients without PP. Despite statistically significant associations between PP and established risk factors (size, mitotic index, non-gastric location), the 5-year recurrence-free survival rate did not differ between the patients with PP (86%) and those without PP (90%) (hazard ratio 1.25; 95% confidence interval 0.58-2.70; P = 0.577). Adjuvant imatinib was administered to 53 of 97 patients in the high-risk category. The recurrence rates did not differ between the PP-positive and PP-negative patients in either group. CONCLUSIONS: In GIST, PP without tumor rupture appears not to influence prognosis. This lack of prognostic significance may reflect unexplored differences between epithelial and mesenchymal malignancies.

Relationship between R1 resection, tumour rupture and recurrence in resected gastrointestinal stromal tumour.

BACKGROUND: According to guidelines, adjuvant treatment or re-excision should be considered after R1 resection of gastrointestinal stromal tumours (GISTs). However, the prognostic significance of R1 resection is uncertain and tumour rupture confounds its assessment. Here, the impact of positive margins was examined and related to rupture in a population-based cohort. METHODS: Patients undergoing surgery for non-metastatic GIST since 2000 were identified in the sarcoma database of Oslo University Hospital. Margins were coded according to the residual tumour (R) classification and tumour rupture defined according to the Oslo criteria. RESULTS: Among 410 patients, there were 47 who underwent R1 resection and 52 had tumour rupture. The relative risk of R1 resection with rupture was 3·55 (95 per cent c.i. 2·09 to 6·03; P < 0·001). In patients without rupture, there was no difference in estimated 5-year recurrence-free survival after R0 versus R1 resection (87·6 versus 93 per cent; hazard ratio (HR) 0·71, 95 per cent c.i. 0·17 to 2·98; P = 0·638); nor was there any difference among patients with rupture (37 versus 31 per cent; HR 1·31, 0·68 to 2·54; P = 0·420). In multivariable analysis, tumour rupture but not R1 resection was independently associated with recurrence. Twenty-four patients at very low, low or intermediate risk did not receive adjuvant imatinib after R1 resection and remained recurrence-free. CONCLUSION: Positive resection margins are strongly associated with tumour rupture. R1 resection does not independently influence prognosis. Adjuvant imatinib may not be justified after R1 resection in the absence of tumour rupture or other high-risk features.

Beyond total mesorectal excision in locally advanced rectal cancer with organ or pelvic side-wall involvement.

BACKGROUND: In locally advanced rectal cancer (LARC), beyond total mesorectal excision (bTME) is often necessary to obtain complete resection (R0). The aim of this study was to identify prognostic determinants and compare morbidity and survival in LARC cases requiring bTME or TME surgery. METHOD: Single centre cohort study of LARC cases where all patients received neoadjuvant radiotherapy (n = 332). Data was registered prospectively in an institutional database linked to the National Registry. RESULTS: bTME surgery was performed in 224 patients, 171 with resections of adjacent organs (bTME-o group) and 53 with pelvic side-wall resections (bTME-pw group). TME surgery was performed in 108 patients. Six deaths occurred within 100 days and severe morbidity was registered in 23.8% of the whole cohort and in 25.4% of the bTME groups. The R0 rates were 93.5%, 84.2%, and 75.5% in the TME, bTME-o, and bTME-pw groups, respectively. Five-year disease free survival (DFS) was 67.3% (TME group), 54.5% (bTME-o group) and 48.7% (bTME-pw group), and five-year overall survival (OS) 78.7%, 69.0% and 60.4% respectively. Patients with involved resection margins (R1), high pT-stage, pN-positivity or poor response to neoadjuvant therapy were associated with inferior DFS and OS. CONCLUSION: In organ-threatening or infiltrating LARC, bTME surgery can be performed with low mortality and acceptable morbidity to obtain a good long-term outcome. Patients with pelvic side-wall infiltration were identified as a subgroup with increased risk of R1 resection and inferior long-term outcome.

Genotype and risk of tumour rupture in gastrointestinal stromal tumour.

BACKGROUND: Tumour rupture is a strong predictor of poor outcome in gastrointestinal stromal tumours (GISTs) of the stomach and small intestine. The objective was to determine whether tumour genotype was associated with risk of rupture. METHODS: Rupture was classified according to the definition proposed by the Oslo Sarcoma Group. Since January 2000, data were registered retrospectively for all patients at Oslo University Hospital undergoing surgery for localized GIST of the stomach or small intestine. Tumour genotype was analysed by Sanger sequencing. RESULTS: Two hundred and nine patients with mutation data available were identified. Tumour rupture occurred in 37 patients. Among the 155 patients with KIT exon 11 mutations, an increased risk of rupture was observed with a deletion or insertion-deletion (25 of 86, 29 per cent) compared with substitutions (5 of 50, 10 per cent) or duplications/insertions (2 of 19, 11 per cent) (P = 0·014). Notably, rupture occurred in 17 of 46 tumours (37 per cent) with deletions involving codons 557 and 558 (del557/558) versus 15 of 109 (13·8 per cent) with other exon 11 mutations (P = 0·002). This association was confined to gastric tumours: 12 of 34 (35 per cent) with del557/558 ruptured versus six of 77 (8 per cent) with other exon 11 mutations (P = 0·001). In multivariable logistic regression analysis, del557/558 and tumour size were associated with an increased likelihood of tumour rupture, but mitotic count was not. CONCLUSION: Gastric GISTs with KIT exon 11 deletions involving codons 557 and 558 are at increased risk of tumour rupture. This high-risk feature can be identified in the diagnostic evaluation and should be included in the assessment when neoadjuvant imatinib treatment is considered.

Ligand activation induces different conformational changes in CXCR3 receptor isoforms as evidenced by plasmon waveguide resonance (PWR).

The chemokine receptor CXCR3 plays important roles in angiogenesis, inflammation and cancer. Activation studies and biological functions of CXCR3 are complex due to the presence of spliced isoforms. CXCR3-A is known as a pro-tumor receptor whereas CXCR3-B exhibits anti-tumor properties. Here, we focused on the conformational change of CXCR3-A and CXCR3-B after agonist or antagonist binding using Plasmon Waveguide Resonance (PWR). Agonist stimulation induced an anisotropic response with very distinct conformational changes for the two isoforms. The CXCR3 agonist bound CXCR3-A with higher affinity than CXCR3-B. Using various concentrations of SCH546738, a CXCR3 specific inhibitor, we demonstrated that low SCH546738 concentrations (≤1 nM) efficiently inhibited CXCR3-A but not CXCR3-B's conformational change and activation. This was confirmed by both, biophysical and biological methods. Taken together, our study demonstrates differences in the behavior of CXCR3-A and CXCR3-B upon ligand activation and antagonist inhibition which may be of relevance for further studies aimed at specifically inhibiting the CXCR3A isoform.

Deep Pelvic Surgical Site Infection After Radiotherapy and Surgery for Locally Advanced Rectal Cancer.

BACKGROUND: High morbidity, increased mortality, and impaired long-term oncologic outcome have been reported after deep surgical site infection (SSI) in rectal cancer surgery. The rate, risk factors and consequences of deep SSI after (chemo)radiotherapy [(C)RT], and surgery for locally advanced rectal cancer (LARC) in a tertiary university hospital single centre cohort of 540 patients are presented. METHODS: Patients with LARC, operated between January 1, 2007 and December 31, 2015, were identified in the institutional prospective database. All patients had tumours threatening the mesorectal fascia or invading adjacent organs, with a high rate of T4 tumours (60 %), and all received (C)RT. Risk factors for deep SSI were calculated by multivariable logistic regression analysis. Morbidity data were assessed. Overall survival (OS) and disease-free survival (DFS) between patients with or without deep SSI were estimated. RESULTS: Of 540 patients, 104 (19 %) experienced a deep SSI, with the highest rate in the abdominoperineal resection (APR) group with 25 %. APR, good response to (C)RT (low tumour regression grade), age, and operative blood loss were identified as significant (P < 0.05) risk factors for deep SSI in multivariable analysis. No difference was found in OS (P = 0.995) or DFS (P = 0.568). Hospital stay increased with 5 days (P < 0.001), and complete wound healing at the 3-month follow-up decreased from 86 to 45 % (P < 0.001) after deep SSI. CONCLUSIONS: Deep SSI is a frequent and major complication after rectal surgery for LARC, with high morbidity, increased hospital stay and protracted wound healing. Interestingly, deep SSI did not influence long-term oncologic outcome.

Definition and clinical significance of tumour rupture in gastrointestinal stromal tumours of the small intestine.

BACKGROUND: Tumour rupture is a risk factor for recurrence of gastrointestinal stromal tumour (GIST). In this study, patterns of recurrence after potential tumour seeding were investigated, and a new definition of tumour rupture, based on major and minor defects of tumour integrity, is proposed. METHODS: Patients undergoing surgery for non-metastatic small intestinal GIST from 2000 to 2012 were included in the study. Tumour spillage, tumour fracture or piecemeal resection, bowel perforation at the tumour site, blood-tinged ascites, microscopic tumour infiltration into an adjacent organ, and surgical biopsy were defined as major defects of tumour integrity. Peritoneal tumour penetration, iatrogenic peritoneal laceration and microscopically involved margins were defined as minor defects. RESULTS: Seventy-two patients were identified. Median follow-up was 58 (range 7-122) months. Radical surgery was performed in 71 patients. A major defect was recorded in 20 patients, and a minor defect in 21. The 5-year recurrence rate was 64, 29 and 31 per cent in patients with major, minor and no defect respectively (P = 0·001). The hazard ratio (HR) for major defect versus no defect was 3·55 (95 per cent c.i. 1·51 to 8·35). Peritoneal recurrence rates for major, minor and no defect were 52, 25 and 19 per cent respectively (P = 0·002), and the HR for major defect versus no defect was 4·98 (1·69 to 14·68). On multivariable analysis, mitotic index, major defect of tumour integrity, tumour size and age were independently associated with risk of recurrence. CONCLUSION: Recurrence rates were increased after major, but not minor tumour ruptures.

Oxaliplatin-containing Preoperative Therapy in Locally Advanced Rectal Cancer: Local Response, Toxicity and Long-term Outcome.

AIMS: This non-randomised study was undertaken to examine oxaliplatin as possibly an intensifying component of sequential neoadjuvant therapy in locally advanced rectal cancer for improved local and metastatic outcome. MATERIALS AND METHODS: Ninety-seven patients (57 T2-3 cases, 40 T4 cases) received two cycles of the Nordic FLOX regimen (oxaliplatin 85 mg/m(2) day 1 and bolus 5-fluorouracil 500 mg/m(2) and folinic acid 100 mg days 1 and 2) before long-course chemoradiotherapy with concomitant oxaliplatin and capecitabine, followed by pelvic surgery. Treatment toxicity, local tumour response and long-term outcome were recorded. RESULTS: Good histologic tumour regression was obtained in 72% of patients. Implementing protocol-specific dose adjustments, tolerance was acceptable and 95% of patients received the total prescribed radiation dose. Estimated 5 year progression-free and overall survival were 61% and 83%, respectively. T4 stage was associated with an inferior local response rate, which again was highly associated with impaired long-term outcome. CONCLUSIONS: In this cohort of rectal cancer patients dominated by T4 and advanced T3 cases given sequential oxaliplatin-containing preoperative therapy with acceptable toxicity, high tumour response rates and overall survival were obtained, consistent with both local and systemic effects. However, tumour response and long-term outcome remained inferior for a significant number of T4 cases, suggesting that the T4 entity is biologically heterogeneous with subgroups of patients eligible for further individualisation of therapy.