Interobserver, intraobserver, and interlaboratory variability in reporting pT4a colon cancer

Abstract Clinical significance of the pT4 category in colon cancer is increasing with several therapeutic implications. The aim of this study was to evaluate variability in diagnosing pT4a colon cancer. Twelve pathologists classified 66 preselected scanned Hematoxylin/Eosin-stained slides with tumor cells at a distance of 25–1500 μm (n = 22), 0–25 μm (n = 22), or on (n = 22) the peritoneal surface. Inter- and intraobserver variability were calculated using Kappa statistics. For interlaboratory variability, pathology reports of pT3 and pT4a colon cancer were extracted from the Dutch Pathology Registry between 2012 and 2015. The proportion of pT4a (pT4a/(pT3+pT4a)) was compared between 33 laboratories. Potential risk of understaging was assessed by determining the average number of blocks taken from pT3 and pT4a N0-2M0 tumors with metachronous peritoneal metastasis. Interobserver variability among 12 pathologists was 0.50 (95%CI 0.41–0.60; moderate agreement). Intraobserver variability (8 pathologists) was 0.71 (substantial agreement). A total of 7745 reports with pT3 or pT4aN0-2M0 colon cancer from 33 laboratories were included for interlaboratory analysis. Median percentage of pT4a was 15.5% (range 3.2–24.6%). After adjustment for case mix, 8 labs diagnosed pT4a significantly less or more frequently than the median lab. Metachronous peritoneal metastases were histologically verified in 170 of 6629 pT3 and in 129 of 1116 pT4a tumors, with a mean number of blocks of 4.03(SD 1.51) and 4.78 (SD 1.76) taken from the primary tumors, respectively (p < 0.001). A substantial variability in diagnosing pT4a colon cancer exists, both at pathologist and laboratory level. Diagnosis of pT4a stage appears to be challenging and there is a need for standardizing assessment of this pathological entity.

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Data Driven Mathematical Model of FOLFIRI Treatment for Colon Cancer

Cancers ◽

10.3390/cancers13112632 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2632

Author(s):

Aparajita Budithi ◽

Sumeyye Su ◽

Arkadz Kirshtein ◽

Leili Shahriyari

Keyword(s):

Mathematical Model ◽

Colon Cancer ◽

Cancer Patients ◽

Immune Cell ◽

Treatment Options ◽

Data Driven ◽

T Helper ◽

Primary Tumors ◽

Cell Fractions

Many colon cancer patients show resistance to their treatments. Therefore, it is important to consider unique characteristic of each tumor to find the best treatment options for each patient. In this study, we develop a data driven mathematical model for interaction between the tumor microenvironment and FOLFIRI drug agents in colon cancer. Patients are divided into five distinct clusters based on their estimated immune cell fractions obtained from their primary tumors’ gene expression data. We then analyze the effects of drugs on cancer cells and immune cells in each group, and we observe different responses to the FOLFIRI drugs between patients in different immune groups. For instance, patients in cluster 3 with the highest T-reg/T-helper ratio respond better to the FOLFIRI treatment, while patients in cluster 2 with the lowest T-reg/T-helper ratio resist the treatment. Moreover, we use ROC curve to validate the model using the tumor status of the patients at their follow up, and the model predicts well for the earlier follow up days.

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Diagnostic validity of different cephalometric analyses for assessment of the sagittal skeletal pattern

Dental Press Journal of Orthodontics ◽

10.1590/2177-6709.23.5.075-081.oar ◽

2018 ◽

Vol 23 (5) ◽

pp. 75-81 ◽

Cited By ~ 4

Author(s):

Maheen Ahmed ◽

Attiya Shaikh ◽

Mubassar Fida

Keyword(s):

Reliability And Validity ◽

Class I ◽

Kappa Statistics ◽

Class Iii ◽

Validity And Reliability ◽

Substantial Agreement ◽

Lateral Cephalograms ◽

Skeletal Pattern ◽

Beta Angle ◽

Final Group

Abstract Introduction: Numerous cephalometric analyses have been proposed to diagnose the sagittal discrepancy of the craniofacial structures. Objective: This study aimed at evaluating the reliability and validity of different skeletal analyses for the identification of sagittal skeletal pattern. Methods: A total of 146 subjects (males = 77; females = 69; mean age = 23.6 ± 4.6 years) were included. The ANB angle, Wits appraisal, Beta angle, AB plane angle, Downs angle of convexity and W angle were used to assess the anteroposterior skeletal pattern on lateral cephalograms. The sample was classified into Class I, II and III groups as determined by the diagnostic results of majority of the parameters. The validity and reliability of the aforementioned analyses were determined using Kappa statistics, sensitivity and positive predictive value (PPV). Results: A substantial agreement was present between ANB angle and the diagnosis made by the final group (k = 0.802). In the Class I group, Downs angle of convexity showed the highest sensitivity (0.968), whereas ANB showed the highest PPV (0.910). In the Class II group, ANB angle showed the highest sensitivity (0.928) and PPV (0.951). In the Class III group, the ANB angle, the Wits appraisal and the Beta angle showed the highest sensitivity (0.902), whereas the Downs angle of convexity and the ANB angle showed the highest PPV (1.00). Conclusion: The ANB angle was found to be the most valid and reliable indicator in all sagittal groups. Downs angle of convexity, Wits appraisal and Beta angle may be used as valid indicators to assess the Class III sagittal pattern.

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Observer variability in grading patients with subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.1982.56.5.0628 ◽

1982 ◽

Vol 56 (5) ◽

pp. 628-633 ◽

Cited By ~ 52

Author(s):

Kenneth W. Lindsay ◽

Graham Teasdale ◽

Robin P. Knill-Jones ◽

Lilian Murray

Keyword(s):

Subarachnoid Hemorrhage ◽

Clinical Condition ◽

Systemic Disease ◽

Observer Variation ◽

Observer Agreement ◽

Grading System ◽

Kappa Statistics ◽

Observer Variability ◽

Content Type ◽

Grade 3

✓ The management of individual patients with subarachnoid hemorrhage depends greatly on assessment of the patient's clinical condition. Difficulty in applying current grading systems prompted the authors to conduct studies of observer variability and to attempt to identify sources of inconsistency. Observers graded 15 patients by both the Hunt and Hess and Nishioka systems. Considerable observer variability was found, with up to four different grades being selected for the same patient. Kappa statistics were used to evaluate the data. This method determines observer agreement occurring in excess of chance. Kappa values for each grading system showed observer agreement to be significantly better than chance, yet revealed marked observer variation. Most variation occurred when Grade 3 was selected, irrespective of the system used. In a further study where observers graded clinical summaries, similar variation occurred; therefore, inconsistency was due mainly to difficulty in matching patients with levels described in the grading system, rather than to fluctuation in the patients' clinical condition or difference in the observers' examination technique. Variability was high when patients with systemic disease or vasospasm on angiography were graded with the Hunt and Hess system. The studies show that a simpler and more reliable grading system is required, and emphasize the need for caution when interpreting the results from different published series.

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Coexistence of Different Histotypes of Renal Carcinoma: Our Experience and Literature Review

Urologia Journal ◽

10.1177/039156030907600219 ◽

2009 ◽

Vol 76 (2) ◽

pp. 130-132

Author(s):

M. Esposito ◽

V. Varca ◽

A. Simonato ◽

C. Toncini ◽

G. Carmignani ◽

...

Keyword(s):

Renal Carcinoma ◽

Case Reports ◽

Rare Condition ◽

Renal Tumors ◽

Renal Oncocytoma ◽

Synchronous Tumors ◽

Primary Tumors ◽

Imaging Procedure ◽

Preoperative Ct ◽

Pathology Reports

The coexistence of multiple, synchronous primary tumors of different histology within the same kidney is a rare condition. We report herein a series of five patients with two tumors of different histology involving synchronously the same kidney. Materials and Methods We reviewed the pathology reports of a series of 381 patients who underwent surgery for primary renal tumors at our institution from 2000 to 2007. In the files of all patients with synchronous tumors of different histology, special attention was given to the results of imaging studies. Results Five out of 381 patients (1.37%) had coexistence of two primary tumors of different histology within the same kidney. Four patients had ultrasonography as the first imaging procedure, one patient had ultrasonography as the second imaging procedure; all had preoperative CT of the abdomen. Both lesions were detected by preoperative CT in 4/5 of the cases; in the remaining one, the smaller lesion was not visible, even in retrospect. Conclusions The coexistence of multiple and synchronous primary tumors of different histology within the same kidney has been only rarely described. To the best of our knowledge, in literature there are only case reports with the exception of a case of renal oncocytoma with evolving papillary RCC. We believe that this condition could be more frequent if the radiologist and the anatomopathologist try to find it.

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Occasional Diagnosis of Synchronous Renal Cell Carcinoma during Staging of Other Primary Tumors

Tumori Journal ◽

10.1177/030089169608200516 ◽

1996 ◽

Vol 82 (5) ◽

pp. 488-490 ◽

Cited By ~ 4

Author(s):

Lino Piccinini ◽

Gabriele Luppi ◽

Alessandra Zoboli ◽

Pietro Torricelli

Keyword(s):

Renal Cell ◽

Cell Cancer ◽

Diagnostic Techniques ◽

Neoplastic Disease ◽

Resonance Imaging ◽

Primary Tumors ◽

Therapeutic Implications ◽

Diagnostic Report ◽

Primary Neoplasms ◽

Initial Staging

Synchronous renal cell cancer (RCC) associated with primary neoplasms of other organs or tissues represents a rare diagnostic report during life. Recently, the widespread use of new diagnostic techniques (echography, computed tomography and magnetic resonance imaging) has permitted diagnosis of clinically silent RCC. We report 6 RCC cases occasionally diagnosed during initial staging of a primary cancer of other organs: 1 rhinopharyngeal carcinoma, 1 gastric cancer, 1 Waldenstrom's disease, 1 non-Hodgkin's lymphoma, 2 breast cancer. RCC was clinically silent in all patients. The diagnostic problems related to a report of a renal mass in patients with neoplastic disease at other sites and the consequent therapeutic implications are discussed.

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Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2004.08.066 ◽

2004 ◽

Vol 22 (18) ◽

pp. 3758-3765 ◽

Cited By ~ 17

Author(s):

Carlo Aschele ◽

Domizia Debernardis ◽

Sara Lonardi ◽

Roberto Bandelloni ◽

Stefania Casazza ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Protein Expression ◽

Regional Lymph Node ◽

Survival Rates ◽

Distant Metastases ◽

Patient Characteristics ◽

Rank Test ◽

Primary Tumors ◽

Major Predictor

Purpose To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors. Patients and Methods DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin–modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases. Results Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P = .04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16. Conclusion Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.

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Impact of interobserver variability in delineating clinical target volumes (CTV) for head and neck intensity modulated radiation therapy (IMRT): Potential for a geographical miss

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e17013 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e17013-e17013

Author(s):

S. Chilukuri ◽

S. Surana ◽

P. P. Mohanty ◽

R. Kuppuswamy

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Imaging Techniques ◽

Target Volume ◽

High Dose ◽

Observer Variability ◽

Median Dose ◽

Median Percentage ◽

Inter Observer Variability

e17013 Background: Despite modern day imaging techniques and guidelines for delineation of the clinical target volume, there remains significant inter-observer variability in delineating the CTV. With the use of IMRT, the target volume receives a significant tumoricidal dose while the regions just outside the target receive unpredictable doses. In this report, the dose to the region just outside the planning target volume (PTV) (defined as volume of uncertainty [VOU]), presumed to represent the regions subject to maximum inter-observer variability, was studied. Methods: The IMRT plans of 12 patients with head and neck cancer were used to determine the dose just outside the high-risk CTV by growing volumes around CTV with 3 mm, 5 mm, and 7 mm margins. These volumes were edited at regions close to skin/air and bone. PTVs were subsequently grown using the same margins as used in the original plans. With the Boolean operations, each of these volumes was subtracted from the existing PTV to generate the volumes of uncertainty (VOU) in 3 dimensions. The dose to these VOUs was analyzed. D95, D90 and median dose which are the doses received by 95%, 90%, and 50% of the target volume respectively were studied. Results: The median prescribed dose was 68 Gy (60 Gy-72 Gy). The median percentage D95 for 3mm, 5mm and 7mm VOU was 82.5% ± 4.95, 77.25% ± 5.53, and 69% ± 6.93, respectively. The median percentage D90 for these VOU's was 87.7% ± 3.53, 83.2% ± 4.61, and 79% ± 4.5, respectively. The median dose to each of these VOU”s was 96% ± 1.6, 94.5% ± 1.95, and 92.5% ± 1.85 respectively. Conclusions: This study documents that the volumes of uncertainty surrounding the PTV, which could contain subclinical disease, in fact receive a significant amount of RT dose. Hence, despite a large amount of evidence for inter-observer variability in target delineation for head and neck cancer,the majority of locoregional recurrences are within the high dose region and not marginal failures. No significant financial relationships to disclose.

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Detection of metastases in breast cancer: Is whole body PET/MR better than PET/CT?

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.15 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 15-15

Author(s):

Eleonora Teplinsky ◽

Akshat Pujara ◽

Francisco J. Esteva ◽

Linda Moy ◽

Amy Melsaether ◽

...

Keyword(s):

Breast Cancer ◽

Treatment Response ◽

Metastatic Lesion ◽

Lesion Detection ◽

Whole Body ◽

Reference Standard ◽

Therapeutic Implications ◽

Metastatic Setting ◽

Pet Ct ◽

Pathology Reports

15 Background: Whole body PET/CT is commonly utilized in breast cancer (BC) patients (pts). Limitations include assessment of treatment response in bone metastases (mets), high physiologic uptake in brain and liver, and cumulative radiation exposure. The site of mets can have prognostic and therapeutic implications. PET/MR, an exciting new hybrid technology, delivers less radiation than PET/CT. Our aim was to compare the differences in metastatic lesion detection using PET/CT & PET/MR in all BC subtypes. Methods: After a single 18-FDG injection, pts had whole body PET/CT for staging and assessment of treatment response. They were transported to another NYU facility & then underwent whole body PET/MR. PET/MR & PET/CT images were each read by a radiologist blinded to prior exams or reports. Number of mets (up to 6) per organ was recorded. 2 experienced radiologists unblinded to imaging and pathology reports served as the “reference standard”. Results: Forty-eight BC pts underwent PET/CT & PET/MR (28 in metastatic setting, 5 for staging & 15 to rule out recurrence). Median age: 55; range 32-79 with 31 ER+/HER2-, 8 ER+/HER2+, 2 ER-/HER2+, 6 ER-/HER2+, 1 unknown. 20 pts had no distant mets on scan. In the remaining 28 pts, the reference standard detected 9 liver, 18 bone, 7 lung/pleura, 5 brain & 10 lymph node (LN) metastases; some patients had ≥1 metastatic site. PET/CT had more false positives (FP) and false negatives (FN) in the detection of mets (Table). PET/MR had 1 FP in the liver. PET/MR accurately detected 2 bone (ER+/HER2-), 3 liver (ER+/HER2-), 2 LN (1 ER+/HER2+; 1 ER+/HER2-) and 5 brain lesions (1 ER+/HER2-; 3 ER-/HER2+; 1 ER+/HER2+) in 10 unique pts that were not identified on PET/CT. 1 liver (ER+/HER2-) and 2 brain mets (ER-/HER2+) identified on PET/MR were previously unknown. Conclusions: Our preliminary data suggest that PET/MR outperformed PET/CT in detecting mets in the liver, brain, LN & possibly bone. Prospective studies of PET/MR are warranted to determine whether early detection of mets, including occult brain mets in HER2+ pts, impacts survival.[Table: see text]

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Down expression of activin A receptor type 2A in relation to metastatic potential and prognosis of patients with colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.712 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 712-712

Author(s):

Changhua Zhuo ◽

Dan Hu ◽

Xiandong Lin ◽

Ying Chen ◽

Xiongwei Zheng ◽

...

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Cell Migration ◽

Mrna Expression ◽

Tissue Microarray ◽

Validation Cohort ◽

Activin A ◽

Receptor Type ◽

Primary Tumors

712 Background: The ACVR2A (activin A receptor type 2A) is a membrane receptor in TGF-β signal pathway, which is involved in the regulation of cell proliferation, migration and apoptosis. The expression profiles and biological functions of ACVR2A in colon cancer is largely unknown so far. Methods: ACVR2A expression was investigated using GSE39582 database and two validation cohorts. The in vitro study of the cell proliferation and migration of human colon cell lines was also performed. Results: In GSE39582 database (n = 497), lower mRNA expression of ACVR2A was identified as an inferior prognostic factor by linear regression analysis. In one validation cohort of 15 stage IV patients, the mRNA expression of ACVR2A was significantly reduced in metastatic lesions and primary tumors compared with adjacent normal controls (P = 0.001). In another validation cohort of tissue microarray (TMA) cohort consisting 193 cases, reduced ACVR2A expression was correlated with advanced N stage (P = 0.001) and positive lymphovascular invasion (P = 0.005). Strong correlations between lower ACVR2A mRNA or protein expression and worse survival were also observed in GSE39582 database and TMA validation cohort (all P< 0.05). Moreover, our in vitro studies showed a remarkable increase of cell migration in cell ACVR2A knockdown cells. Conclusions: Taken together, our findings indicate that loss of ACVR2A has an important role in cancer progression and distant metastasis, and may serve as a prognostic marker in patients with colon cancer. Keywords: Activin a receptor type 2A (ACVR2A), Colon Cancer, tissue microarray, Metastasis, Cell proliferation, Cell migration

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Discordance rate of PD-L1 expression between primary and metastatic lesions in urothelial carcinoma (UC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.493 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 493-493

Author(s):

Earle Frederick Burgess ◽

Caroline Naso ◽

Shannon Doherty ◽

Renato Guerrieri ◽

Chad Livasy ◽

...

Keyword(s):

Immune Cell ◽

Checkpoint Inhibitors ◽

Correlation Coefficients ◽

High Expression ◽

Kappa Statistics ◽

Primary Tumors ◽

Metastatic Lesions ◽

Dynamic Expression ◽

Tumor Environment ◽

Metastatic Process

493 Background: Immune checkpoint inhibitors (ICI) targeting PD-1 or PD-L1 are effective in select patients with advanced UC. High PD-L1 expression enriches for response to ICIs; however, the predictive value of PD-L1 expression is limited, which may be due in part to dynamic expression of PD-L1 in the tumor environment. We sought to characterize PD-L1 expression in primary UC and paired metastatic lesions to gain insight into the potential temporal discordance of tumor PD-L1 expression during the metastatic process. Methods: Immunohistochemical (IHC) staining for PD-L1 using the SP-142 antibody was performed on primary tumors and matched metastatic specimens in 83 patients with advanced UC. IHC staining was scored for the percentage of cells positive ( < 5%, ≥5%) in tumor cell (TC) and immune cell (IC) compartments. Correlation of PD-L1 expression in TCs and ICs was estimated using Spearman’s correlation coefficients (ρ). Cohen’s kappa statistics (κ) were utilized to assess the agreement in PD-L1 expression between groups. Results: High (≥5%) PD-L1 expression in primary and metastatic biopsies, respectively, was observed in 6.1% and 14.6% of TCs and in 7.8% and 11.7% of ICs. High co-expression of PD-L1 in both TC and IC compartments was infrequent in primary and metastatic lesions (3.6% and 2.6%, respectively). PD-L1 expression in TCs was positively correlated with PD-L1 expression in ICs in primary tumors (ρ = 0.47) and in metastatic lesions (ρ = 0.27). TC PD-L1 expression in primary tumors was correlated with TC PD-L1 expression in paired metastatic lesions (ρ = 0.44) but there was minimal agreement in high expression rates between primary and metastatic lesions in the TC compartment (κ = 0.147). IC PD-L1 expression in primary tumors was not correlated with IC PD-L1 expression in paired metastatic lesions (ρ = 0.05) and there was poor agreement in high expression rates between primary and metastatic lesions in the IC compartment (κ = 0.086). Conclusions: High PD-L1 IC expression is temporally discordant between primary and metastatic UC lesions. Future studies of PD-1/PD-L1 targeted therapies in patients with metastatic UC should utilize recent biopsies of metastatic lesions to define PD-L1 expression when feasible.

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