Comment on: Viral infections in pediatric brain tumor patients treated with targeted therapiesAimen Waqar KhanDepartment of Medicine, Jinnah Sindh Medical University, Karachi, PakistanDear Dr. Newburger,We have read with great enthusiasm the article titled Viral infections in pediatric brain tumor patients treated with targeted therapies by Lisa Mayr et al [1]. We commend the authors’ efforts in collating epidemiologic data and investigating infectious outcomes between pediatric patients being treated with targeted therapy versus conventional therapies. It was a pleasure to read such a well-written paper. We concur with the conclusion that patients receiving targeted therapies are made more susceptible to developing viral infections than those receiving conventional treatment. However, we would like to draw attention to some key points regarding the study following a thorough appraisal.To begin with, the retrospective nature of the study adds several unavoidable biases such as recollection bias and incorrect data retrieval, which may have been mitigated had the investigators included current cases at the time. The study is also limited in its single-centered scope making it difficult to generalize the findings to this particular pediatric demographic. Moreover, the comparison between the two subsets of brain tumor patients is also subject to several partialities. For instance, it is noted that those receiving targeted therapies were managed in an outpatient setting and by extension, exposed to greater environmental stressors than those being managed on conventional chemotherapy. As a result, a greater proportion of virological infections were reported in children receiving targeted therapy than those being managed conventionally. Further, due to the lack of available data correlating disease severity with treatment option, the possibility that patients receiving conventional chemotherapy simply had a lower disease grade than those on targeted therapies and vice versa exists. Knowing this is pertinent as the body’s ability to fight off infections is greatly influenced by the grade of cancer and hence degree of inflammation [2]. Next, it remains to be seen what the baseline nutritional status of the participants was as nutrition and metabolism are known to have a bearing on immune status and hence infectious susceptibility [3]. Finally, the deduction that patients treated with bevacizumab or mTOR (mechanistic target of rapamycin) inhibitors suffered more infections than those treated with other targeted therapeutic drugs cannot be made with certainty as not enough patients were treated with drugs other than bevacizumab or mTOR inhibitors for a fair and accurate comparison.In conclusion, multi-centered prospective studies are required to better lay claims regarding infectious outcomes and attention to potential influencers of immunity must be given to minimize bias in future studies.

Evaluating Serum HE4: Some Serious ConsiderationsAimen Waqar Khana, Hussain Haider Shahba: Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan.b: Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan.Dear Dr Papageorghiou,We have perused with great interest the scholarly article ”Serum HE4 predicts progestin treatment response in endometrial cancer and atypical hyperplasia: A prognostic study” by Chloe Barr et al. [1]. We applaud the authors’ diligent efforts in investigating a biomarker that could independently predict the response to conservative therapy. However, we wish to draw attention to certain noteworthy aspects upon a comprehensive evaluation.Firstly, it is noteworthy that all the women who participated in the study underwent a preliminary endometrial biopsy before the initiation of progestin. However, there is no mention of whether women with relative contraindications such as cervical stenosis, coagulopathy or obstructive cervical lesions were sampled if they were included in the study. It is essential to consider these factors as they can significantly affect the accuracy and reliability of the biopsy results. Furthermore, it is necessary to note that insufficient tissue sampling is a common complication of endometrial biopsy, with an average of 31% of tissues obtained requiring improvement [2]. Considering that this is typically more prevalent in postmenopausal women, and 61% of the participants were 50 years or older, it is crucial to standardize the volume of tissue obtained to ensure fair and precise results. As outlined in the study, the primary form of progestin therapy was levonorgestrel-releasing intrauterine system (LNG-IUS). Still, for women whose devices had been misplaced more than once, an alternative treatment of oral medroxyprogesterone acetate 500mg was administered twice daily. This raises a concern regarding whether these women were closely monitored for compliance with the prescribed treatment regimen. This is particularly important as non-compliance, particularly with extended oral therapies, is a common issue that, if present, could skew the study’s findings. The prognostic potential of pretreatment serum HE4 in predicting therapeutic response has been extensively researched; however, studies have also reported elevated serum HE4 levels in various other cancers, including ovarian, pancreatic, breast, lung, and stomach [3]. Therefore, it is crucial to exclude such patients thoroughly, as their inclusion could lead to inaccurate results by falsely accounting for the non-responder count.Moreover, serum HE4 levels are also known to be influenced by renal function and status, necessitating adjustment [4]. It is, therefore, essential to consider and standardize these factors when analyzing the serum HE4 levels to obtain reliable and valid results. Lastly, it should be noted that a CLEIA technique was employed for analysis, which has been reported to significantly overestimate serum HE4 as compared to EIA [5]. This may raise concerns regarding the validity of the reported findings, and hence, caution must be exercised when interpreting the results.The study focused on endometrial biopsy in women receiving progestin therapy, but potential complications such as insufficient tissue sampling and the inclusion of women with contraindications were not addressed. The study primarily used LNG-IUS but also administered oral medroxyprogesterone acetate, and compliance monitoring was not discussed. Serum HE4 levels were examined, but patients with other cancers or renal issues were not excluded, and the CLEIA technique used for analysis may have overestimated results. Therefore, caution is necessary when interpreting the findings of this study.