Survival endpoints in colorectal cancer and the effect of second primary other cancer on disease free survival

<p>Abstract</p> <p>Background</p> <p>In cancer research the selection and definitions of survival endpoints are important and yet they are not used consistently. The aim of this study was to compare different survival endpoints in patients with primary colorectal cancer (CRC) and to understand the effect of second primary other cancer on disease-free survival (DFS) calculations.</p> <p>Methods</p> <p>A population-based cohort of 415 patients with CRC, 332 of whom were treated with curative intention between the years 2000-2003, was analysed. Events such as locoregional recurrence, distant metastases, second primary cancers, death, cause of death and loss to follow-up were recorded. Different survival endpoints, including DFS, overall survival, cancer-specific survival, relapse-free survival, time to treatment failure and time to recurrence were compared and DFS was calculated with and without inclusion of second primary other cancers.</p> <p>Results</p> <p>The events that occurred most often in patients treated with curative intention were non-cancer-related death (n = 74), distant metastases (n = 66) and death from CRC (n = 59). DFS was the survival endpoint with most events (n = 170) followed by overall survival (n = 144) and relapse-free survival (n = 139). Fewer events were seen for time to treatment failure (n = 80), time to recurrence (n = 68) and cancer-specific survival (n = 59). Second primary other cancer occurred in 26 patients and its inclusion as an event in DFS calculations had a detrimental effect on the survival. The DFS for patients with stage I-III disease was 62% after 5 years if second primary other cancer was not included as an event, compared with 58% if it was. However, the difference was larger for stage II (68 vs 60%) than for stage III (49 vs 47%).</p> <p>Conclusions</p> <p>The inclusion of second primary other cancer as an endpoint in DFS analyses significantly alters the DFS for patients with CRC. Researchers and journals must clearly define survival endpoints in all trial protocols and published manuscripts.</p

Highly sensitive and specific protein detection via combined capillary isoelectric focusing and proximity ligation

Detection and quantification of proteins and their post-translational modifications are crucial to decipher functions of complex protein networks in cell biology and medicine. Capillary isoelectric focusing together with antibody-based detection can resolve and identify proteins and their isoforms with modest sample input. However, insufficient sensitivity prevents detection of proteins present at low concentrations and antibody cross-reactivity results in unspecific detection that cannot be distinguished from bona fide protein isoforms. By using DNA-conjugated antibodies enhanced signals can be obtained via rolling circle amplification (RCA). Both sensitivity and specificity can be greatly improved in assays dependent on target recognition by pairs of antibodies using in situ proximity ligation assays (PLA). Here we applied these DNA-assisted RCA techniques in capillary isoelectric focusing to resolve endogenous signaling transducers and isoforms along vascular endothelial growth factor (VEGF) signaling pathways at concentrations too low to be detected in standard assays. We also demonstrate background rejection and enhanced specificity when protein detection depended on binding by pairs of antibodies using in situ PLA, compared to assays where each antibody preparation was used on its own.</p

Highly sensitive and specific protein detection via combined capillary isoelectric focusing and proximity ligation

Detection and quantification of proteins and their post-translational modifications are crucial to decipher functions of complex protein networks in cell biology and medicine. Capillary isoelectric focusing together with antibody-based detection can resolve and identify proteins and their isoforms with modest sample input. However, insufficient sensitivity prevents detection of proteins present at low concentrations and antibody cross-reactivity results in unspecific detection that cannot be distinguished from bona fide protein isoforms. By using DNA-conjugated antibodies enhanced signals can be obtained via rolling circle amplification (RCA). Both sensitivity and specificity can be greatly improved in assays dependent on target recognition by pairs of antibodies using in situ proximity ligation assays (PLA). Here we applied these DNA-assisted RCA techniques in capillary isoelectric focusing to resolve endogenous signaling transducers and isoforms along vascular endothelial growth factor (VEGF) signaling pathways at concentrations too low to be detected in standard assays. We also demonstrate background rejection and enhanced specificity when protein detection depended on binding by pairs of antibodies using in situ PLA, compared to assays where each antibody preparation was used on its own.</p

Viscoelasticplastic-Fracture modeling of asphalt mixtures under monotonic and repeated loads

Rutting and cracking occur simultaneously in asphalt mixtures as observed in the field and in the laboratory. Existing mechanical models have not properly addressed viscoelastic and viscoplastic deformation together with cracking attributable to model deficiencies, parameter calibration, and numerical inefficiency. This study developed viscoelasticplastic-fracture (VEPF) models for the characterization of viscoelasticity by Prony model and viscoplasticity by Perzyna's flow rule with a generalized Drucker-Prager yield surface and a nonassociated plastic potential. Viscofracture damage was modeled by a viscoelastic Griffith criterion and a pseudo J-integral Paris's law for crack initiation and propagation, respectively. The VEPF models were implemented in a finite element program by using a weak form partial differential equation modeling technique without the need for programming user-defined material subroutines. Model parameters were derived from fundamental material properties by using dynamic modulus, strength, and repeated load tests. Simulations indicated that the viscoelastic-viscoplastic-viscofracture characteristics were effectively modeled by the VEPF models for asphalt mixtures at different confinements and temperatures. An asphalt mixture under monotonic compressive loads exhibited a sequenced process including a pure viscoelastic deformation stage, a coupled viscoelastic-viscoplastic deformation stage, a viscoelastic-viscoplastic deformation coupled with a viscofracture initiation and a propagation stage, and then a viscoelastic-viscofracture rupture stage with saturated viscoplastic deformation. The asphalt mixture under repeated loads yielded an increasing viscoplastic strain at an increasing rate during the first half of the haversine load, while the increment of the viscoplastic strain (per load cycle) decreased with load cycles. The finite element program, which is based on a partial differential equation, effectively modeled the coupled viscoelastic-viscoplastic-viscofracture behaviors of the asphalt mixtures

Rectal cancer treatment and outcome in the elderly: an audit based on the Swedish rectal cancer registry 1995–2004

<p>Abstract</p> <p>Background</p> <p>Limited information is available regarding the effect of age on choice of surgical and oncological treatment for rectal cancer. The objective of this study was to assess the influence of age on treatment and outcome of rectal cancer.</p> <p>Methods</p> <p>We utilized data in the Swedish Rectal Cancer Registry (SRCR) from patients treated for rectal cancer in Sweden in 1995–2004.</p> <p>Results</p> <p>A total of 15,104 patients with rectal cancer were identified, 42.4% of whom were 75 years or older. Patients ≥75 years were less likely to have distant metastases than younger patients (14.8% vs. 17.8%, <it>P </it>< 0.001), and underwent abdominal tumor resection less frequently (68.5% vs. 84.4%, <it>P </it>< 0.001). Of 11,725 patients with abdominal tumor resection (anterior resection [AR], abdominoperineal excision [APE], and Hartmann's procedure [HA]), 37.4% were ≥75 years. Curative surgery was registered for 85.0% of patients ≥ 75 years and for 83.9% of patients < 75 years, <it>P </it>= 0.11. Choice of abdominal operation differed significantly between the two age groups for both curative and non-curative surgery, The frequency of APE was similar in both age groups (29.5% vs. 28.6%), but patients ≥75 years were more likely to have HA (16.9% vs. 4.9%) and less likely to have preoperative radiotherapy (34.3vs. 67.2%, <it>P </it>< 0.001). The relative survival rate at five years for all patients treated with curative intent was 73% (70–75%) for patients ≥75 years and 78% (77–79%) for patients < 75 years of age. Local recurrence rate was 9% (8–11%) for older and 8% (7–9%) for younger patients.</p> <p>Conclusion</p> <p>Treatment of rectal cancer is influenced by patient's age. Future studies should include younger and older patients alike to reveal whether or not age-related differences are purposive. Local recurrence following surgery for low tumors and quality of life aspects deserve particular attention.</p

Benefit from preoperative radiotherapy in rectal cancer treatment: disease-free patients' and oncologists' preferences

Preoperative radiotherapy (PRT) in resectable rectal cancer improves local control but increases probability of faecal incontinence and sexual dysfunction. Consensus was reached in 2001 in the Netherlands on a guideline advising PRT to new patients. Purpose was to assess at what benefit oncologists and rectal cancer patients prefer PRT followed by surgery to surgery alone, and how oncologists and patients value various treatment outcomes. Sixty-six disease-free patients and 60 oncologists (surgical, radiation, medical) were interviewed. Minimally desired benefit from PRT (local control) was assessed using the Treatment Tradeoff Method. Importance of survival, local control, faecal incontinence, and sexual dysfunction in determining treatment outcome preferences was assessed using Adaptive Conjoint Analysis. The range of required benefit from PRT varied widely within participant groups. Seventeen percent of patients would choose PRT at a 0% benefit; 11% would not choose PRT for the maximum benefit of 11%. Mean minimally desired benefit excluding these two groups was 4%. For oncologists, the required benefit was 5%. Also, how strongly participants valued treatment outcomes varied widely within groups. Of the four outcomes, participants considered incontinence most often as most important. Relative treatment outcome importance differed between specialties. Patients considered sexual functioning more important than oncologists. Large differences in treatment preferences exist between individual patients and oncologists. Oncologists should adequately inform their patients about the risks and benefits of PRT, and elicit patient preferences regarding treatment outcomes

Cracking in asphalt materials

This chapter provides a comprehensive review of both laboratory characterization and modelling of bulk material fracture in asphalt mixtures. For the purpose of organization, this chapter is divided into a section on laboratory tests and a section on models. The laboratory characterization section is further subdivided on the basis of predominant loading conditions (monotonic vs. cyclic). The section on constitutive models is subdivided into two sections, the first one containing fracture mechanics based models for crack initiation and propagation that do not include material degradation due to cyclic loading conditions. The second section discusses phenomenological models that have been developed for crack growth through the use of dissipated energy and damage accumulation concepts. These latter models have the capability to simulate degradation of material capacity upon exceeding a threshold number of loading cycles.Peer ReviewedPostprint (author's final draft

In situ breast cancer incidence patterns in Iceland and differences in ductal carcinoma in situ treatment compared to Sweden

Funding We thank the Icelandic Cancer Society, the Icelandic Oncologists Research fund and Göngum Saman, a nonprofit organization, for financial support. Publisher Copyright: © 2020, The Author(s).The purpose was to review the incidence of in situ carcinoma in Iceland after initiating population-based mammography screening in 1987 and to compare management of ductal carcinoma in situ (DCIS) between Iceland and the Uppsala–Örebro region (UÖR) in Central Sweden. The Icelandic Cancer Registry provided data on in situ breast carcinomas for women between 1957 and 2017. Clinical data for women with DCIS between 2008 and 2014 was extracted from hospital records and compared to women diagnosed in UÖR. In Iceland, in situ carcinoma incidence increased from 7 to 30 per 100 000 women per year, following the introduction of organised mammography screening. The proportion of in situ carcinoma of all breast carcinomas increased from 4 to 12%. More than one third (35%) of women diagnosed with DCIS in Iceland were older than 70 years versus 18% in UÖR. In Iceland, 49% of all DCIS women underwent mastectomy compared to 40% in UÖR. The incidence of in situ carcinoma in Iceland increased four-fold after the uptake of population-based mammography screening causing considerable risk of overtreatment. Differences in treatment of DCIS were seen between Iceland and UÖR, revealing the importance of quality registration for monitoring patterns of management.Peer reviewe

Tumor location and patient characteristics of colon and rectal adenocarcinomas in relation to survival and TNM classes

<p>Abstract</p> <p>Background</p> <p>Old age at diagnosis is associated with poor survival in colorectal cancer (CRC) for unknown reasons. Recent data show that colonoscopy is efficient in preventing left-sided cancers only. We examine the association of Tumor Node Metastasis (TNM) classes with diagnostic age and patient characteristics.</p> <p>Methods</p> <p>The Swedish Family-Cancer Database has data on TNM classes on 6,105 CRC adenocarcinoma patients. Ordinal logistic regression analysis was performed to model tumor characteristics according to age at diagnosis, tumor localization, gender, socioeconomic status, medical region and family history. The results were compared to results from survival analysis.</p> <p>Results</p> <p>The only parameters systematically associated with TNM classes were age and tumor localization. Young age at diagnosis was a risk factor for aggressive CRC, according to stage, N and M with odds ratios (ORs) ranging from 1.80 to 1.93 for diagnosis before age 50 years compared to diagnosis at 80+ years. All tumor characteristics, particularly T, were worse for colon compared to rectal tumors. Right-sided tumors showed worse characteristics for all classifiers but M. The survival analysis on patients diagnosed since 2000 showed a hazard ratio of 0.55 for diagnosis before age 50 years compared to diagnosis at over 80 years and a modestly better prognosis for left-sided compared to right-sided tumors.</p> <p>Conclusions</p> <p>The results showed systematically more aggressive tumors in young compared to old patients. The poorer survival of old patients in colon cancer was not related to the available tumor characteristics. However, these partially agreed with the limited colonoscopic success with right-sided tumors.</p