Review Reports - Significance of Pelvic Fluid Observed during Ovarian Cancer Screening with Transvaginal Sonogram

Round 1

Reviewer 1 Report

In this article, the authors examine the frequency and duration of free fluid during TVS exams in a large screening population and correlate the findings with the patient diagnosis. The primary objective was to determine if free fluid provides additional information in predicting ovarian malignancy compared to ultrasound alone. The manuscript is straightforward, well written, and concise and has clear results within the scope of a prospective analysis. Definitely deserves to be published and is a valuable contribution to the “diagnostics” journal. Some minor flaws need to be addressed before publication.

Minor points:

[1] “1. Introduction”, Lines 34-51:

The introduction section should include some epidemiological data of ovarian cancer (mortality, morbidity), the pathogenesis, a statement about the lack of screening methods, the genetic background (BRCA genes, homologous recombination), the therapeutic strategies, etc.

[2] General comment:

I would recommend the authors to incorporate an additional table, summarizing the 4 reported in the manuscript ovarian cancer screening trials utilizing transvaginal sonography (references 4-7). The variables that could be included are

Study design
Screening tests
Number screened/detected patients
Number of invasive cancers
Stage of the disease (I, II, III and IV)
Survival benefit (Yes vs No)

Author Response

Comments and Suggestions for Authors

Reviewer 1

Minor points:

[1] “1. Introduction”, Lines 34-51:

“The introduction section should include some epidemiological data of ovarian cancer (mortality, morbidity), the pathogenesis, a statement about the lack of screening methods, the genetic background (BRCA genes, homologous recombination), the therapeutic strategies, etc.”

In accordance with Reviewer #1, the manuscript has been revised to present epidemiological data of ovarian cancer (mortality, morbidity), the pathogenesis, a statement about screening methods, the genetic background (BRCA genes, homologous recombination), and therapeutic strategies. This modification ends at line 52 and is included below. A summary of screening effectiveness is added in Table 1.

Ovarian cancer continues to be the most lethal gynecological cancer with most patients facing a diagnosis of late stage metastatic disease that is associated with a 5-year survivals of only 30%. While the lifetime risk of ovarian cancer is less than breast cancer, it has a death-to-incidence ratio that is 3-4 times more than breast cancer [[1],[2],[3]]. Ovarian cancers can arise from the ovary as well as the fallopian tube [[4],[5],[6],[7],[8],[9],[10],[11]] and occur as five major histological subtypes (high grade serous, low-grade serous, endometrioid, clear cell and mucinous) that have been explored by immunochemical, genetic and homologous recombination approaches [[12]]. Deleterious mutations in DNA repair genes can drive defective homologous recombination and are emerging biomarkers of sensitivity/insensitivity to PARP inhibitors which interfere with the ability of poly-ADP ribose polymerase (PARP) to repair treatment-mediated DNA damage in cancer cells [[13]]. Despite technically advanced treatment strategies in precision medicine and immunotherapy, long term durable treatment responses have not yet been achievable [[14],[15]]. However, long-term survival rates that are greater than 90% in women with stage I ovarian cancer have focused an advocacy for screening efforts to detect early stage disease [[16]].

[2] General comment:

Study design
Screening tests
Number screened/detected patients
Number of invasive cancers
Stage of the disease (I, II, III and IV)

Survival benefit (Yes vs No)

In accordance with Reviewer #1 this summary has been added as Table 1, as shown below and occurring at line 154 with text edits lines 56-60.

Table 1. Summary of Ovarian Screening Trials

Study		KYOVS		PLCO		SCSOCS	UKCTOCS
Study Design	Prospective Cohort (Ongoing)		Intent to Treat RCT (Closed)		Intent to Treat RCT (Closed)			Intent to Treat RCT (Closed)
Number Screened	48,925^a		34,253^b 34,304*		41,688^b 40,799*			50,625^c 50,623^a 101,314*
Total Screens	326,998		150,598		156,747			345,570^c 327,775^a
Invasive Ovarian Cancers Detected	78		212^b		27			522c 517a 1016*
Shift to Early Stage Disease^d	Yes (63%)		No		Yes (67%)			Yes (39.2%)
Survival Benefit	Yes		No		No			Yes

^aUSS alone, ^bUSS alone followed by Ca125, ^cCa125 followed by USS, *control, ^dStage I & II

Reviewer 2 Report

In the present manuscript, “Significance of Pelvic Fluid Observed During Ovarian Cancer Screening with Transvaginal Sonogram,” the authors investigated the significance of pelvic fluid in ovarian cancer screening using a large-scale dataset. The purpose of the study is clinically interesting, and this study potentially has a significant value. However, the result of the investigation feels strange and difficult to understand despite the simple concept. One of the reasons is that the study design is inappropriate to investigate the purpose of the study. In the introduction section, the authors mentioned that the purpose of the study is to determine if free fluid provides additional information in predicting ovarian malignancy compared to ultrasound alone. However, the authors classified the patients based on the final diagnosis. I think that the patients should be stratified with ultrasound findings; for example, those with ovarian tumor with fluid, those with ovarian tumor without fluid, those with no ovarian mass but fluid, and those without any finding. Therefore, I think the authors should re-analyze the dataset, which will improve the impact of the study.

Author Response

In the present manuscript, “Significance of Pelvic Fluid Observed During Ovarian Cancer Screening with Transvaginal Sonogram,” the authors investigated the significance of pelvic fluid in ovarian cancer screening using a large-scale dataset. The purpose of the study is clinically interesting, and this study potentially has a significant value. However, the result of the investigation feels strange and difficult to understand despite the simple concept. One of the reasons is that the study design is inappropriate to investigate the purpose of the study. In the introduction section, the authors mentioned that the purpose of the study is to determine if free fluid provides additional information in predicting ovarian malignancy compared to ultrasound alone. However, the authors classified the patients based on the final diagnosis I think that the patients should be stratified with ultrasound findings; for example, those with ovarian tumor with fluid, those with ovarian tumor without fluid, those with no ovarian mass but fluid, and those without any finding. Therefore, I think the authors should re-analyze the dataset, which will improve the impact of the study.

In accordance with reviewer #2, we re-analyzed the data with added information on sonographic findings in lines 133-145. In particular, information has been added on fluid in TVS exams prior to the final diagnosis.

Since 1987, the University of Kentucky Ovarian Screening Program has performed 326,998 TVS screens on 48,925 women. We observed free fluid in 2,001 (4.1%) of those encounters. True positive screens included 78 ovarian malignancies (13 fluid-positive, 16.7%), 20 tumors of low malignant potential (two fluid-positive, 10%), and 23 malignancies of non-ovarian origin (three fluid-positive, 13%). Only one of the true positive cases was observed to have fluid present in a prior normal TVS exam. There were 614 FP screens classified as high risk for ovarian cancer but found to have benign pathology (31 fluid-positive, 5%). Nine of these cases occurred on a prior normal TVS exam. The TN screens included 41,996 cases that screened negative for malignancy and did not develop ovarian carcinoma (1,948 fluid-positive, 4.6%: 1,071 fluid positive cases were associated with a normal TVS exam while 877 were associated with an abnormal TVS exam). There were 21 cases of ovarian cancer diagnosed within 12 months of a FN TVS scan (4 fluid-positive, 19%). All of these cases occurred in the absence of an abnormal TVS exam.

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