As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients.
Data from ...advanced GI-NEC patients diagnosed 2000–2009 were retrospectively registered at 12 Nordic hospitals.
The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels.
Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.
•This ESMO Clinical Practice Guideline provides key recommendations for managing anal cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment, ...follow-up and survivorship.•Treatment algorithms for locoregional and advanced anal cancer are provided.•Opportunities for personalised medicine in anal cancer are discussed.•Recommendations were compiled by the authors based on available scientific data and the authors' collective expert opinions.
Melting curves of Ca‐perovskite (pure CaSiO3) were determined by ab initio density functional theory, using two solid‐liquid coexistence methods and two free energy approaches, in the form of ...thermodynamic integration and two‐phase thermodynamics. The melting curves based on the solid‐liquid coexistence methods and thermodynamic integration rise steeply from 2000 K at 14 GPa to 7000 K at 136 GPa. The melting temperature at 136 GPa is 1400 K higher than previous ab initio predictions. The high thermal stability of Ca‐perovskite is linked to its high‐symmetry isometric structure and consistent with experiments, demonstrating that Ca‐perovskite is the most refractory phase in basaltic compositions in the lower mantle pressure range. The steep dT/dp slope of the melting curve also shows that the Ca‐perovskite liquidus field expands relative to those of bridgmanite and silica with increasing pressure, in agreement with experimental evidence from simple and complex systems.
Plain Language Summary
Melting of mantle minerals provides key information for understanding our planet's thermal evolution from the early stage of magma ocean crystallization to the present partial melting that is likely to occur near the core‐mantle boundary. We determined the melting curve of Ca‐perovskite (CaSiO3), the third most abundant mineral in the Earth's lower mantle, in a wide pressure range up to the core‐mantle boundary pressure. Several atomistic simulation methods were used and show that Ca‐perovskite melts about 2000 K higher than bridgmanite at the pressure conditions of lowermost mantle. This agrees with the experimental findings that Ca‐perovskite is the last mineral to disappear when basaltic rocks undergo partial melting in the lower mantle.
Key Points
The Ca‐perovskite (CaSiO3) melting curve determined to 136 GPa by four ab initio atomistic simulation methods
A high melting temperature of about 7000 K at the core‐mantle boundary suggests a wide liquidus field in the system CaO‐MgO‐SiO2
Ca‐perovskite is the first liquidus phase in basaltic compositions in the lowermost mantle
The terrestrial planets accreted from a diverse suite of solar system materials ranging from strongly O-deficient materials similar to enstatite chondrites via ordinary chondrite materials to fully ...oxidised carbonaceous chondrite and cometary materials. Heliocentric zoning with increasingly oxidised planetesimals outwards through the protoplanetary disc is broadly reflected in core fraction and FeOmantle concentration, ranging from 68 wt% core and 0.5 wt% FeOmantle for Mercury to 18 wt% core and 24 wt% FeOmantle for Vesta. Mercury, Venus and Earth grew mostly from materials which were isotopically similar to enstatite chondrites, although Earth and Venus also received more oxidised material. The elevated (Mg + Fe)/Si ratio, compared to chondrites, in the bulk silicate fraction of the terrestrial planets, except for Mercury, may be related to a combination of nebular fractionation associated with forsterite condensation, concentration of olivine-rich chondrules near the mid-plane of the accretion disc and multi-cycle impact erosion of protocrusts. For the extremely reduced Mercury the silicate magma ocean (MO) and a core with 15 wt% Si might have equilibrated with a melt layer of FeS at the core-mantle boundary (CMB). Recent data from the MESSENGER mission combined with experimentally derived phase relations, support estimates of about 0.5 wt% FeO and 10 wt% S in the MO and the current mantle. Core segregation at very high temperatures for the largest planets, Venus and Earth, led to cores with high Si content, even at relatively high oxygen fugacities and FeOmantle contents, because increasing temperature shifts the equilibrium:SiO2MO+2Fecore=2FeOMO+Sicoretowards the products (right side). The hot protocores of Venus and Earth might have started with about 5–7 wt% Si and 2–3 wt% O. Mars and Vesta segregated S-rich cores at high oxygen fugacity and low pressure.
Strong partitioning of Fe and Mg to melt and solids, respectively, caused neutrally buoyant bridgmanite (bm) to crystallise from the MO at 1700–1860 km depth (72–80 GPa), resulting in a separate basal magma ocean (BMO) within Earth, and probably also in Venus. Slow cooling of a thermally insulated BMO and core, accompanied by protracted crystallisation of bm and ferropericlase (fp), would facilitate core-BMO chemical exchange by reversing the equilibrium SiO2MO + 2Fecore = 2FeOMO + Sicore towards the reactants. Transfer of silica crystals and a liquid SiO2 component from the core to the BMO, and liquid FeO and Fe2O3 components from the BMO to the core, would increase the Si/Mg, Mg/Fe and bm/fp ratio of the resulting cumulates. Because the solidus temperature of peridotite is <200–300 K above the present temperature of the outermost core, and the melting interval of late-stage BMO melt enriched in Al, Fe, Ca and Na would be lower than that of peridotite, the BMO might have persisted through the Hadean and possibly also the Archean. Low solid state diffusion rates, especially in bm, would have restricted the core-mantle interaction upon BMO solidification, but limited core-mantle interaction could possibly occur via partially molten ultra-low velocity zones. An outermost stagnant low-density and low-velocity core layer (E′-layer), with reduced Si and elevated O contents relative to the convecting core, appears to trace the core-BMO exchange. The E′-layer is compositionally gradational towards the convecting core at 445 km below the CMB. High thermal conductivity and minimal convective entrainment in the low-viscosity core fluid might have developed and stabilised such a gradational layer since the Hadean or early Archean.
The primordial bm-dominated cumulates with high Mg/Fe ratios and viscosities may have become convectively aggregated into large refractory domains, remaining neutrally buoyant in the middle to upper parts of the lower mantle and resistant to convective destruction. Late-stage dense BMO cumulates with elevated Fe/Mg ratios relative to the bulk mantle composition might represent a suitable material for 100–200 km thick thermochemical piles at the bottom of the large low S-wave velocity provinces (LLSVPs) under Africa and the Pacific. A degree-2 convection pattern, possibly initiated and stabilised during Earth's early rapid rotation, involving antipodally ascending columns in equatorial positions and an intermediary descending longitudinal belt, might have swept the late-stage, dense bridgmanitic cumulates with high Fe/Mg-ratios, viscosity and bulk modulus towards the root zones of the upwelling columns.
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•Core and mantle compositional estimates for the terrestrial planets are provided•Melting and silicate-metal partitioning led to magma oceans (MO) and cores•Core-mantle separation in Earth and Venus occurred at high temperature and pressure•Mineral-melt density relations led to a separate basal MO (BMO) in Earth and Venus•Cooling of Earth and Venus cores led to core-BMO chemical exchange
Summary
New therapies, including the anti‐cytotoxic T lymphocyte antigen (CTLA)‐4 antibody, ipilimumab, is approved for metastatic melanoma. Prognostic biomarkers need to be identified, because the ...treatment has serious side effects. Serum samples were obtained before and during treatment from 56 patients with metastatic or unresectable malignant melanoma, receiving treatment with ipilimumab in a national Phase IV study (NCT0268196). Expression of a panel of 17 inflammatory‐related markers reflecting different pathways including extracellular matrix remodeling and fibrosis, vascular inflammation and monocyte/macrophage activation were measured at baseline and the second and/or third course of treatment with ipilimumab. Six candidate proteins endostatin, osteoprotegerin (OPG), C‐reactive protein (CRP), pulmonary and activation‐regulated chemokine (PARC), growth differentiation factor 15 (GDF15) and galectin‐3 binding‐protein (Gal3BP) were persistently higher in non‐survivors. In particular, high Gal3BP and endostatin levels were also independently associated with poor 2‐year survival after adjusting for lactate dehydrogenase, M‐stage and number of organs affected. A 1 standard deviation increase in endostatin gave 1·74 times 95% confidence interval (CI) = 1·10–2·78, P = 0·019 and for Gal3BP 1·52 times (95% CI = 1·01–2·29, P = 0·047) higher risk of death in the adjusted model. Endostatin and Gal3BP may represent prognostic biomarkers for patients on ipilimumab treatment in metastatic melanoma and should be further evaluated. Owing to the non‐placebo design, we could only relate our findings to prognosis during ipilimumab treatment.
New therapies including the anti‐CTLA‐4 antibody, ipilimumab is approved for metastatic melanoma. Prognostic biomarkers need to be identified, as the treatment has serious side effects. Endostatin and Gal3BP may represent prognostic biomarkers for patients receiving ipilimumab in metastatic melanoma.
Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody ...targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC.
Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% 95% confidence interval (CI) 7.6% to 22.5%, with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class.
Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.
•Retifanlimab (PD-1 inhibitor) monotherapy demonstrated encouraging results in patients with platinum-refractory SCAC.•Clinically meaningful antitumor activity was reported with ORR of 13.8% and stable disease in 35.1%, for a DCR of 48.9%.•Observed responses in advanced SCAC were durable (median 9.5 months).•Acceptable safety profile consistent with that reported for the PD-(L)1 inhibitor class.•Promising results warrant further investigation of retifanlimab in advanced SCAC as well as earlier stages of disease.
•No difference in QLQ-C30, QLQ-CR29 and LARS results between the EXP and STD group.•Sensory related symptoms more often in the EXP group compared to the STD group.•Neurotoxicity grade 1–2 more often ...in the EXP compared to the STD group.•No difference in grade ≥3 neurotoxicity between the groups.•No difference in any type of toxicity between the EXP and STD group.
The RAPIDO trial demonstrated a decrease in disease-related treatment failure (DrTF) and an increase in pathological complete responses (pCR) in locally advanced rectal cancer (LARC) patients receiving total neoadjuvant treatment (TNT) compared to conventional chemoradiotherapy. This study examines health-related quality of life (HRQL), bowel function, and late toxicity in patients in the trial.
Patients were randomized between short-course radiotherapy followed by pre-operative chemotherapy (EXP), or chemoradiotherapy and optional post-operative chemotherapy (STD). The STD group was divided into patients who did (STD+) and did not (STD−) receive post-operative chemotherapy. Three years after surgery patients received HRQL (EORTC QLQ-C30, QLQ-CR29 and QLQ-CIPN20) and LARS questionnaires. Patients who experienced a DrTF event before the toxicity assessments (6, 12, 24, or 36 months) were excluded from analyses.
Of 574 eligible patients, 495 questionnaires were returned (86%) and 453 analyzed (79% completed within time limits). No significant differences were observed between the groups regarding QLQ-C30, QLQ-CR29 or LARS scores. Sensory-related symptoms occurred significantly more often in the EXP group compared to all STD patients, but not compared to STD+ patients. Any toxicity of any grade and grade ≥ 3 toxicity was comparable between the EXP and STD groups at all time-points. Neurotoxicity grade 1–2 occurred significantly more often in the EXP and STD+ group at all time-points compared to the STD− group.
The results demonstrate that TNT for LARC, yielding improved DrTF and pCRs, does not compromise HRQL, bowel functional or results in more grade ≥3 toxicity compared to standard chemoradiotherapy at three years after surgery in DrTF-free patients.
Prediction models are useful tools in the clinical management of colon cancer patients, particularly when estimating the recurrence rate and, thus, the need for adjuvant treatment. However, the most ...used models (MSKCC, ACCENT) are based on several decades-old patient series from clinical trials, likely overestimating the current risk of recurrence, especially in low-risk groups, as outcomes have improved over time. The aim was to develop and validate an updated model for the prediction of recurrence within 5 years after surgery using routinely collected clinicopathologic variables.
A population-based cohort from the Swedish Colorectal Cancer Registry of 16,134 stage I-III colon cancer cases was used. A multivariable model was constructed using Cox proportional hazards regression. Three-quarters of the cases were used for model development and one quarter for internal validation. External validation was performed using 12,769 stage II-III patients from the Norwegian Colorectal Cancer Registry. The model was compared to previous nomograms.
The nomogram consisted of eight variables: sex, sidedness, pT-substages, number of positive and found lymph nodes, emergency surgery, lymphovascular and perineural invasion. The area under the curve (AUC) was 0.78 in the model, 0.76 in internal validation, and 0.70 in external validation. The model calibrated well, especially in low-risk patients, and performed better than existing nomograms in the Swedish registry data. The new nomogram's AUC was equal to that of the MSKCC but the calibration was better.
The nomogram based on recently operated patients from a population registry predicts recurrence risk more accurately than previous nomograms. It performs best in the low-risk groups where the risk-benefit ratio of adjuvant treatment is debatable and the need for an accurate prediction model is the largest.
Background
Colon cancer in older patients represents a major public health issue. As older patients are hardly included in clinical trials, the optimal treatment of these patients remains unclear. ...The present international EURECCA comparison explores possible associations between treatment and survival outcomes in elderly colon cancer patients.
Subjects, Materials, and Methods
National data from Belgium, Denmark, The Netherlands, Norway, and Sweden were obtained, as well as a multicenter surgery cohort from Germany. Patients aged 80 years and older, diagnosed with colon cancer between 2001 and 2010, were included. The study interval was divided into two periods: 2001–2006 and 2007–2010. The proportion of surgical treatment and chemotherapy within a country and its relation to relative survival were calculated for each time frame.
Results
Overall, 50,761 patients were included. At least 94% of patients with stage II and III colon cancer underwent surgical removal of the tumor. For stage II–IV, the proportion of chemotherapy after surgery was highest in Belgium and lowest in The Netherlands and Norway. For stage III, it varied from 24.8% in Belgium and 3.9% in Norway. For stage III, a better adjusted relative survival between 2007 and 2010 was observed in Sweden (adjusted relative excess risk RER 0.64, 95% confidence interval CI: 0.54–0.76) and Norway (adjusted RER 0.81, 95% CI: 0.69–0.96) compared with Belgium.
Conclusion
There is substantial variation in the rate of treatment and survival between countries for patients with colon cancer aged 80 years or older. Despite higher prescription of adjuvant chemotherapy, poorer survival outcomes were observed in Belgium. No clear linear pattern between the proportion of chemotherapy and better adjusted relative survival was observed.
Implications for Practice
With the increasing growth of the older population, clinicians will be treating an increasing number of older patients diagnosed with colon cancer. No clear linear pattern between adjuvant chemotherapy and better adjusted relative survival was observed. Future studies should also include data on surgical quality.
The aim of this international comparison was to compare treatment strategies and relative survival between countries for older patients with colon cancer, using data from population‐based cancer registries across Europe.
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