Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. The authors state that PubMed and Google Scholar were searched, but they do not provide the search date, search period, or complete search strings.
2. The authors used only “malakoplakia”; however, this disease is also commonly referred to as “malacoplakia” in the literature. Failure to include this spelling variant may have resulted in missed cases. In addition, the search terms were mainly focused on the colon, kidney, liver transplantation, kidney transplantation, AML, and hematologic malignancy. This may introduce selection bias, because the study aims to summarize the overall clinical spectrum of malakoplakia in immunocompromised patients, whereas the search strategy itself is not comprehensive.
3. The authors state that case reports, case series, and observational studies with histologically confirmed malakoplakia were included. However, they do not clarify whether the presence of Michaelis–Gutmann bodies was required, whether cases diagnosed only by imaging or clinical findings were included, whether pediatric cases were excluded, whether non-immunocompromised patients were excluded, or how duplicate cases were specifically identified and removed.
4. The authors state that malakoplakia resolved or improved in 24 patients, accounting for 46% of the total cohort. However, they also state that clinical outcomes were not reported in the remaining cases. If outcome data were unavailable for many cases, the total cohort of 52 patients should not be used as the denominator to calculate the response rate.
5. Did the patient die from progressive AML, or was the death directly related to malakoplakia?
6. The authors list multiple antibiotics but do not explain why these agents were selected. This is particularly important because treatment of malakoplakia usually emphasizes antibiotics with good intracellular penetration, such as fluoroquinolones and trimethoprim-sulfamethoxazole.
7. There are several English and formatting issues.The heading format is inconsistent. For example, “2.2. Results:” should not include a colon and should be written as “2.2. Results”. There is also a punctuation error in the search terms: “‘Acute Myeloid Leukemia” contains an unnecessary single quotation mark, and the capitalization is inconsistent. In the antibiotic list, there is an extra comma in “doxycycline, , and levofloxacin”. In addition, the phrase “isolated immunosuppressive drug therapy” is unclear and may be confusing to readers.

Author Response

1. The authors state that PubMed and Google Scholar were searched, but they do not provide the search date, search period, or complete search strings.

(Thank you for this valuable suggestion. We agree that additional methodological details improve the transparency and reproducibility of the literature review. Accordingly, we have revised the Materials and Methods section to specify the date on which the literature search was conducted, the period covered by the search, and the complete search strategy, including the databases searched and search terms used, 

The search included studies published from database inception to [insert search date] using combinations of the following search terms: ('malakoplakia' OR 'malacoplakia') AND ('immunocompromised' OR 'transplant' OR 'hematologic malignancy' OR 'acute myeloid leukemia' OR 'inflammatory bowel disease' OR 'ulcerative colitis').

 

2. The authors used only “malakoplakia”; however, this disease is also commonly referred to as “malacoplakia” in the literature. Failure to include this spelling variant may have resulted in missed cases. In addition, the search terms were mainly focused on the colon, kidney, liver transplantation, kidney transplantation, AML, and hematologic malignancy. This may introduce selection bias, because the study aims to summarize the overall clinical spectrum of malakoplakia in immunocompromised patients, whereas the search strategy itself is not comprehensive.

(Thank you for this important observation. We agree that inclusion of the alternative spelling "malacoplakia" improves the comprehensiveness of the search strategy. Accordingly, we have revised the search methodology to include both spellings and broadened the search terms to capture additional immunocompromised conditions and organ systems. This modification reduces the risk of missing eligible reports and minimizes potential selection bias. we revise the search terms to include: ("malakoplakia" OR "malacoplakia") rather than only "malakoplakia")

3. inclusion and exclusion criteria are insufficiently described.

(Thank you for this helpful suggestion. We agree that the eligibility criteria required further clarification. We have expanded the Methods section to specify that only histopathologically confirmed cases were included, with confirmation based on characteristic pathological findings including Michaelis–Gutmann bodies where reported. Cases diagnosed solely on clinical or radiological findings were excluded. Duplicate reports were identified through comparison of patient demographics, institution, publication details, and clinical characteristics. Because our review focused on immunocompromised hosts, cases without documented immunocompromising conditions were excluded. Only histopathologically confirmed cases of malakoplakia were included. Cases diagnosed solely on clinical or radiological findings without pathological confirmation were excluded. When reported, the presence of Michaelis–Gutmann bodies was considered confirmatory. Duplicate publications describing the same patient were identified by comparing demographic and clinical characteristics and were excluded added in methods section)

4. English and formatting issues.

(Thank you for these careful observations. We have thoroughly revised the manuscript to improve English language, formatting, grammar, and consistency. Specifically, we corrected heading formatting, punctuation, capitalization, typographical errors, and unclear terminology throughout the manuscript. changes include as seen in the word file.

5. Did the patient die from AML or malakoplakia?

(Thank you for this observation. We agree that the original wording could be misinterpreted. We have revised the manuscript to clarify that the patient died from progressive relapsed acute myeloid leukemia and its associated complications rather than from malakoplakia)

 

6. The rationale for antibiotic selection should be explained.

(Thank you for this valuable suggestion. We agree that additional discussion regarding antimicrobial selection would improve the manuscript. Accordingly, we have expanded the Discussion to explain that antibiotics with good intracellular penetration, particularly fluoroquinolones and trimethoprim-sulfamethoxazole, are generally preferred because they achieve high intracellular concentrations within macrophages, where the causative organisms persist. We also clarify that antimicrobial selection in our cases was individualized according to microbiological findings, patient comorbidities, potential adverse effects, and drug interactions.  Because the pathogenesis of malakoplakia involves defective intracellular bacterial killing by macrophages, antimicrobial agents with good intracellular penetration, particularly fluoroquinolones and trimethoprim-sulfamethoxazole, are generally preferred. Selection of therapy should also consider microbiological culture results, antimicrobial susceptibility, patient comorbidities, drug interactions, and tolerance. In our series, treatment decisions were individualized according to these clinical factors. Added in discussion section)

 

7. Outcome percentages should not use the total cohort if outcome data were unavailable.

(Thank you for this important comment. We agree that using the total cohort as the denominator may underestimate the proportion of patients with favorable outcomes because outcome data were unavailable for many published cases. Accordingly, we have revised the Results section to clearly distinguish between the number of patients with reported outcomes and those without available follow-up data, avoiding interpretation of the reported proportion as an overall response rate. Instead of "24 patients (46.2%)" we changed it to "Clinical outcomes were reported for 25 of the 52 patients. Among those with available follow-up data, malakoplakia resolved or improved in 24 patients, whereas one patient died due to progressive acute myeloid leukemia unrelated to malakoplakia." 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors described four cases of malakoplakia occurring in various organs in immunocompromised patients. They also reviewed the literature and identified 48 cases in the literature and summarized its clinical spectrum, management, and outcomes. Malakoplakia is rare and overall the manuscript is well written. I have one question:

Line 109-110: The authors mentioned "one patient in our case series died, corresponding to an overall mortality rate of 1.9%." As the authors mentioned, malakoplakia is benign and the manuscript mentioned that this patient died from relapsed AML and its complications. Stating an overall mortality rate for malakoplakia appears not accurate.

Author Response

Line 109–110: The authors mentioned "one patient in our case series died, corresponding to an overall mortality rate of 1.9%." As the authors mentioned, malakoplakia is benign and the manuscript mentioned that this patient died from relapsed AML and its complications. Stating an overall mortality rate for malakoplakia appears not accurate.

(Thank you for this important observation. We agree that the original wording could be misinterpreted as implying mortality attributable to malakoplakia. The patient in our case series died from progressive relapsed acute myeloid leukemia and its associated complications rather than from malakoplakia itself. Accordingly, we have revised the text to clarify that one patient died due to the underlying hematologic malignancy, and we have removed the statement referring to an overall mortality rate. This revision improves the accuracy of the interpretation and avoids attributing mortality to malakoplakia. 

We have replaced it with "As far as clinical outcomes are concerned, malakoplakia resolved or improved in 24 patients (46.2%). One patient in our case series died due to progressive relapsed acute myeloid leukemia and its associated complications rather than malakoplakia. Clinical outcomes and responses to treatment were not reported for the remaining cases.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript presents a well-documented case series of four patients with malakoplakia occurring in distinct immunocompromised states, supplemented by a literature review of 48 additional cases. The clinical descriptions are detailed and the histopathological documentation is robust. However, several methodological and presentation issues need attention before the paper can be considered for publication.

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I appreciate that the authors tried to review the literature, but I'm struggling to understand exactly what they did. They mention searching PubMed and Google Scholar with certain keywords, but there's no information about:

• When the search was performed

• How many papers they initially found versus how many they ended up including

• Why some papers were excluded

• Whether they assessed the quality of the papers they included

This matters because the 48 cases they found in the literature form a big part of their analysis. Without knowing how they selected these cases, it's hard to know if their findings are reliable. I'd suggest they add a PRISMA flow diagram or at least a more detailed description of their search strategy.

I had to read Table 1 several times to understand it. Some of the categories don't seem to align properly, and the percentages don't add up correctly. For example, the underlying conditions sum to more than 100%, which suggests some patients had multiple conditions, but this isn't explained anywhere.

Also, the row for "Immunosuppression status" is missing its label, and the "Culture-positive cases" row seems misplaced. The organisms section is just a jumbled list - it would be helpful to know which organisms were found in which types of patients.

The last reference I can see is number 25, but the discussion mentions more citations than that. I'm not sure if the reference list was cut off during submission or if there's some other issue, but the authors need to provide the complete reference list.

In Case 1, the patient initially wasn't treated but then later got TMP-SMX. What prompted the change in approach? Was there clinical deterioration? In Case 4, the patient got rifaximin while others got different antibiotics. I'd like to understand the thinking behind these choices. Since there aren't clear treatment guidelines for malakoplakia, the authors' clinical reasoning would be valuable for readers.

Case 3: This patient had recurrent E. coli bacteremia, but the tissue cultures from the kidney were negative. So how do we know E. coli was the culprit? Was it just assumed based on the blood cultures, or was there other evidence? I think this needs to be explained.

Case 2: The patient was described as having "asymptomatic GI presentation" but had relapsed AML. How do we know the malakoplakia was truly asymptomatic versus symptoms being attributed to something else? In these complex patients, it's often hard to know what's causing what.

Case 4: The patient had negative cultures but was still treated with rifaximin. I'm curious about this decision - why choose this particular antibiotic for a patient without a documented organism?

In Table 2, the "Outcome" column for Case 3 says "Clinical recovery; irreversible graft loss" which is a bit ambiguous. Did the patient recover from the infection but lose the kidney? That's what I assume, but it could be stated more clearly.

To strengthen the related work/literature review, discuss the following: Localization and classification of gastrointestinal tract disorders using explainable AI from endoscopic images

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

comments:

A very well described case series of a rare chronic entity: Malakoplekia

Did the pathology report confirm the presence of Michael is gutmann bodies by performing von Kossa stain in the 4 cases?

Author Response

1. 1. Did the pathology report confirm the presence of Michael is gutmann bodies by performing von Kossa stain in the 4 cases?

   ( Thank you for this important question. Michaelis–Gutmann bodies were identified histologically in all four cases, confirming the diagnosis of malakoplakia. Von Kossa staining was performed in Cases 1 and 2, where it highlighted the calcified Michaelis–Gutmann bodies. In Case  4, the diagnosis was established based on the characteristic histomorphologic features seen on routine H&E sections, and additional Von Kossa staining was not performed because it was not considered necessary by the reporting pathologist. Von Kossa staining is a supportive ancillary stain rather than a mandatory requirement for the diagnosis of malakoplakia when the characteristic Michaelis–Gutmann bodies are readily identifiable on routine histopathology)

    

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

No further comments