Circulating Mutant DNA to Assess Tumor Dynamics
Nature Medicine, 2008 · paper · Biomedicine
Applies a highly sensitive assay to measure circulating tumor DNA in 162 plasma samples from 18 colorectal cancer patients undergoing surgery or chemotherapy. The measurements reliably tracked tumor dynamics, and the authors suggest the approach could extend to other cancers.
4 findings
Substance Text gives the day-0 ctDNA range as "ranging from 1.3 to 23,000 mutant templates per sample (median 99", but the largest day-0 value in Table 1 is "20,144 ± 5,504" and the smallest is "1 ± 0.3".
- p. 3 Results, ctDNA dynamics, first paragraph
ranging from 1.3 to 23,000 mutant templates per sample (median 99
- p. 14 Table 1, subject 17 APC, Pre-surgery day 0
20,144 ± 5,504
- p. 14 Table 1, subject 13 APC, Pre-surgery day 0
1 ± 0.3
- p. 3 Results, ctDNA dynamics, first paragraph
ranging from 1.3 to 23,000 mutant templates per sample
Only the authors can say what is right here.
Judge's note: Read all 33 day-0 gene rows of Table 1 on the page images. Sixteen values lie below 99, so the 17th of 33 (the median) is 99, matching the text; the text therefore summarises these tabulated means. The maximum is 20,144 (subject 17 APC), with 17,482 next; neither rounds to 23,000. The lower bound 1.3 against the printed 1 may be table rounding, or 1.3 may be mean plus SD. No statement in the article explains 23,000; only the authors can say which figure is right.
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Substance CEA paragraph says "first post-operative follow-up visit on days 24–48", whereas the Results ("first follow-up visit, 13–56 d after surgery") and the Table 1 headers for both ctDNA and CEA ("Post-operative follow-up days 13–56") give 13–56.
- p. 4 Results, Comparison with carcinoembryonic antigen
first post-operative follow-up visit on days 24–48
- p. 3 Results, ctDNA dynamics, third paragraph
13–56 d after surgery, in 20 instances
- p. 13 Table 1 column header (ctDNA and CEA)
Post-operative follow-up days 13–56
- p. 13 Table 1, CEA column header
days 13–56
Only the authors can say what is right here.
Judge's note: Both passages checked on the page 3 and page 4 images, and the Table 1 headers on pages 13 and 14. No statement in the article defines a narrower window or a subset for the CEA analysis in Fig. 3b. The authors must say which range applies.
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Substance "This difference in sensitivity between the two assays (ctDNA versus CEA) was statistically significant; 56% versus 100%, respectively" assigns 56% to ctDNA and 100% to CEA; the paper's data give ctDNA 18/18 (100%) and CEA 10/18 (56%).
- p. 4 Results, Comparison with carcinoembryonic antigen, first paragraph
(ctDNA versus CEA) was statistically significant; 56% versus 100%, respectively
- p. 4 Discussion, first paragraph
ctDNA was detectable in all subjects before surgery
Judge's note: Page 4 image confirms the wording. The preceding sentence says only ten of eighteen subjects had CEA above 5 ng/ml. In Table 1 the day-0 CEA exceeds 5 in subjects 1, 2, 3, 5, 6, 7, 11, 15, 17 and 18, which is 10 of 18. The Discussion says "ctDNA was detectable in all subjects before surgery". With "respectively" the percentages are attached in reversed order; the evident fix is "100% versus 56%".
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Wording Figure 4 legend names the middle-panel quantity two ways, "tumor volume as assessed by imaging" and "0.0 cm for tumor diameter", while the panel axis reads "Total tumor burden (cm)"; the Results also say "tumor volume" for a quantity plotted in cm.
- p. 11 Figure 4 legend
tumor volume as assessed by imaging
- p. 11 Figure 4 legend
0.0 cm for tumor diameter
- p. 11 Figure 4 middle panels, y-axis
Total tumor burden (cm)
Only the authors can say what is right here.
Judge's note: Viewed the page 11 image. The middle-panel y-axes read "Total tumor burden (cm)" and the legend uses both "tumor volume" and "tumor diameter" for the same panel. The Methods say "we used cross-sectional measurements in centimeters to estimate tumor burden", so the plotted quantity is a linear measure, not a volume. The Results text for subject 8 also says "tumor volume ... decreased only slightly (Fig. 4)". Nothing in the article reconciles the three terms. The data are not affected; this is inconsistent terminology, and the authors should choose the term.
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9 minor (typos and the like; most checked by the judge only)
Wording "A sharp drop in the ctDNA level by the day of discharge ... was observed in all subjects who underwent complete resections", yet Table 1 shows subject 16 going from 5 ± 1.7 to 3.5 ± 0.9 (APC) and from 2 ± 0.6 to 1.6 ± 0.2 (TP53), and subject 10 KRAS from 3 ± 1.0 to 2.4 ± 0.5.
- p. 3 Results, ctDNA dynamics, first paragraph
was observed in all subjects who underwent complete resections
- p. 14 Table 1, subject 16 (complete resection), day 0 and days 2–10
3.5 ± 0.9
- p. 13 Table 1, subject 10 surgery 1 KRAS, days 2–10
2.4 ± 0.5
Judge's note: Verified the Table 1 values on the page images. These falls are 20–30% at counts near the detection limit and lie within the printed SDs. The same sentence gives a 10th percentile of 58.9%, which partly concedes that not every drop was sharp, and "sharp" is subjective. This is a wording overstatement only.
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Wording For subject 8 during chemotherapy, "ctDNA decreased by more than 99.9%", but Fig. 4a and Table 1 show about 1,420 fragments before Chemotherapy 1 and roughly 4 at the first point after it, a fall of about 99.7%.
- p. 3 Results, ctDNA dynamics, last paragraph
ctDNA decreased by more than 99.9%
- p. 13 Figure 4a, top panel (PIK3CA), points before and after Chemotherapy 1
PIK3CA
- p. 13 Table 1, subject 8 surgery 1 PIK3CA, follow-up days 13–56
1,420 ± 408
- p. 3 Results, ctDNA dynamics, last paragraph
ctDNA decreased by more than 99.9%, whereas tumor volume
Only the authors can say what is right here.
Judge's note: Viewed Fig. 4a on page 11. The pre-chemotherapy point at about day 25 is about 1,400 (Table 1 follow-up value 1,420 ± 408). The first point after the Chemotherapy 1 band, at about day 88, sits at about 4 on the log axis, clearly above the red line at 1. A fall of more than 99.9% is reached only from the post-surgical peak of 6,459, or by counting the later value of about 0.9 after Surgery 2. The post-chemotherapy value is read from a log plot, so this is a query about which baseline and nadir were used. The "decreased only slightly" remark on tumour burden (about 10 cm to about 6 cm in the middle panel) is a subjective description.
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Wording Methods: "We quantified post-operative changes in ctDNA as a mean percentage decrease after surgery, with its standard error", but the Results give only medians with 10th–90th percentile ranges (e.g. "99.0% median decrease in ctDNA (range between 10th and 90th percentiles, 58.9–99.8%").
- p. 6 Methods, Statistical analyses
We quantified post-operative changes in ctDNA as a mean percentage decrease after surgery, with its standard error
- p. 3 Results, ctDNA dynamics, first paragraph
99.0% median decrease in ctDNA (range between 10th and 90th percentiles, 58.9–99.8%
- p. 6 Methods, Statistical analyses
as a mean percentage decrease after surgery, with its standard error
Judge's note: Checked the Statistical analyses crop on page 6 and the Results on pages 3 and 4. No mean percentage decrease, standard error or confidence interval is printed in the article. The means may have been used only inside the t-tests, so this is a description mismatch and not an error in the data.
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Wording Text says "Subjects 8 and 11 had more than one surgical procedure during the study", but Table 1 also lists two surgeries (surgery numbers 1 and 2) for subject 10; separately, Table 1 spells the procedure "Hepatic metastectomy" throughout (usual spelling: metastasectomy).
- p. 13 Table 1, Surgical procedure column
Hepatic metastectomy
- p. 3 ctDNA dynamics
Subjects 8 and 11 had more than one surgical procedure during the study
- p. 13 Table 1, subject 10
Hepatic metastectomy with RFA
Only the authors can say what is right here.
Judge's note: Viewed the Table 1 images for pages 13 and 14. Subject 10 has surgery 1 (right hemicolectomy with hepatic metastectomy, complete) and surgery 2 (hepatic metastectomy with RFA, complete), so three subjects (8, 10, 11) had repeat surgery, not two. The sentence does not say "only", and the next sentence ("Both of these subjects had incomplete resections in their initial surgery") fits subjects 8 and 11 but not subject 10, so the text may deliberately cover only the Figure 4 subjects. That makes it an incomplete or ambiguous statement rather than a wrong number. The spelling "metastectomy" is used consistently in the table and is a cosmetic (S4) point folded into this cluster.
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Typo Author contributions give "F.D., K.S., K.K., B.V. and L.A.D., Jr. developed" although the byline lists "Kenneth W Kinzler" and other authors' middle initials are kept (M.A.C., S.A.S., L.A.D.).
- p. 1 Author contributions
F.D., K.S., K.K., B.V. and L.A.D., Jr. developed
Judge's note: Checked the page 1 crop and the byline. "K.K." is printed; no other author has those initials, so identity is unambiguous. This is a consistency slip only.
Second check: none (judge only)
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Typo Stray article in "In a marked contrast, no recurrence occurred"; the idiom is "In marked contrast".
- p. 3 Results, ctDNA dynamics
In a marked contrast, no recurrence
Judge's note: Seen on the page 3 image. Cosmetic; the meaning is unchanged.
Second check: none (judge only)
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Typo Methods name "The Johns Hopkins Medical Institutes using routine procedures", whereas the affiliations, the IRB statement and the CEA methods all use "Johns Hopkins Medical Institutions".
- p. 5 Methods, Subjects and study design
The Johns Hopkins Medical Institutes
- p. 5 Methods, Subjects and study design
The Johns Hopkins Medical Institutes using routine procedures
Judge's note: Seen on the page 5 crop. "Institutions" appears in the page 1 affiliations, in the first sentence of the same Methods section, and in the page 6 CEA methods (crop viewed). This is an internal inconsistency in the institution's name.
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Typo Figure 2 legend, panel (d): "the fraction mutant DNA fragments increased further to 0.66%" is missing "of"; panels a–c read "the fraction of mutant DNA fragments".
- p. 9 Figure 2 legend, panel (d)
the fraction mutant DNA fragments increased further to 0.66%
Judge's note: Seen on the page 9 crop. Panels a, b and c use "fraction of mutant DNA fragments"; panel d drops the word.
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Typo Table 1 footnote: "PIK3CA; phosphoinositide-3-kinase, catalytic, αpolypeptide" uses a semicolon after the gene symbol where the other definitions use a comma, and lacks a space in "αpolypeptide".
- p. 14 Table 1 footnote
PIK3CA; phosphoinositide-3-kinase, catalytic, αpolypeptide
Judge's note: Viewed the page 14 upright image. The footnote prints "APC, adenomatous polyposis coli; KRAS, Kirsten rat sarcoma viral oncogene homolog; PIK3CA; phosphoinositide-3-kinase, catalytic, αpolypeptide; TP53, tumor protein p53". The semicolon after PIK3CA and the run-together "αpolypeptide" are both visible on the image, so this is not an extraction artefact. Cosmetic only.
Second check: none (judge only)