Synchronous Primary Malignancies Research Articles

Synchronous primary malignancy of breast and endometrium in premenopausal women - A rare case report

Synchronous primary malignancy of breast and endometrium in premenopausal women - A rare case report

Multi-detector computed tomography evaluation of synchronous hepatocellular carcinoma and other solid malignancies.

To review the findings of multi-detector computed tomography (MDCT) in synchronous hepatocellular carcinoma (HCC) and other solid malignancies. A total of 74 cases were included in this retrospective analysis, all of them confirmed with a diagnosis of synchronous HCC and other solid malignancies. They were 41 women and 33 men (mean age, 63.36 years). The whole body and triphasic abdominal CT scanning utilized 128 MDCT scanners in all 74 patients. The pathological diagnoses of all 148 malignancies were confirmed in all 74 cases. Out of 3480 patients with HCC, 74 patients (2.1%) were diagnosed with another synchronous primary solid malignancy. The pathology of all 148 cancers was verified, and each one was correctly characterized, assessed, and staged. Hepatocellular carcinoma was detected in all 74 patients. The most frequent extra-hepatic primary malignant sites were breast (18/74, 24.3%), followed by kidney (15/74, 20.3%), lymphoma (9/74, 12.2%), uterus (7/74, 9.5%), ovary (5/74, 6.8%), colon (5/74, 6.8%), prostate (5/74, 6.8%), urinary bladder (3/74, 4.1%), thyroid (2/74, 2.7%), gall bladder (1/74, 1.4%), stomach (1/74, 1.4%), pancreas (1/74, 1.4%), esophagus (1/74, 1.4%) and lung (1/74, 1.4%). The possibility of synchronous double malignancies with HCC should always be considered during pretreatment evaluation. Using an MDCT scanner, researchers were able to assess this occurrence accurately. An increased number of such findings may lead to an improved therapeutic method for these patients.

Adenocarcinoma Lung Diagnosed as a ‘Synchronous Primary Double Malignancy’ in Treated Case of Carcinoma of Breast: Case Report

Double primary malignancies are rarely observed in breast malignancy, and frequently documented in hematological and gynecological malignancies due to genetic mutations. In present case report, 48-year female presented with left breast carcinoma undergone surgical treatment and received first chemotherapy cycle. Her general health deteriorated and present in our center due to worsened dyspnea. Her radiological workup shown possible metastatic lung process from on treatment carcinoma left breast

Ipsilateral Renal Cell Carcinoma and Transitional Cell Carcinoma: Synchronous Dual Primary Malignancies of Kidney

Ipsilateral Renal Cell Carcinoma and Transitional Cell Carcinoma: Synchronous Dual Primary Malignancies of Kidney

P8‐176: Synchronous double primary malignancies of the lung and colon presenting with superior vena cava syndrome and colonic obstruction

P8‐176: Synchronous double primary malignancies of the lung and colon presenting with superior vena cava syndrome and colonic obstruction

Hypopharyngeal Carcinoma With Synchronous and Metachronous Multiple Malignancies: Clinical Characteristics and Prognosis Analysis of 673 Real World Cases

Hypopharyngeal carcinoma (HPC) is one of the most devastating malignancies among head and neck cancers. Our aim is to analyze the clinical characteristics and prognosis of synchronous and metachronous second primary malignancies (SPMs) in patients with hypopharyngeal carcinoma.We retrospectively reviewed 673 patients diagnosed in our institution between May 2009 and October 2019. Endoscopic examination was performed in 97.1% (654/673) of patients before treatment. We defined a synchronous SPM as which developed within 6 months of the index HPC diagnosis, while a metachronous SPM as which developed more than 6 months after initial diagnosis of HPC. The Kaplan-Meier method, propensity score-matched (PSM) and Cox model were used to analyze the data.Within the median follow-up of 66.5 months, 71 (10.5%) patients developed gastric/esophageal tumor in situ (Tis) and 143 (21.2%), patients developed SPMs, consisting of 78 with synchronous SPMs and 75 with metachronous SPMs, respectively, with patient overlap. Among the 143 patients, the most common secondary site was esophagus (n = 85), followed by the head and neck squamous cell carcinoma (HNSCC, n = 36), lung (n = 20) and other cancers (n = 19). The 5-year overall survivals (OS) for non-SPMs (n = 459), SPMs (n = 143) and Tis group (n = 71) were 43.8% vs 37.1% vs 42.9%, respectively. Accordingly, the disease-specific survivals (DSS) were 46.3% vs 56.2% vs 47.8%, respectively. We compared synchronous SPMs and no-SPMs groups, the 5-year OS and DSS were 37.1% and 56.2% for synchronous SPMs group (n = 78), compared with 43.8% (P = 0.093) and 46.3% (P = 0.098) for no-SPMs group (n = 459). We use PSM to balance two arms with the ratio of 1:1, resulting in the number of 62 patients in each group. The adjusted 5-year OS and DSS were 23.6% and 32.7% for synchronous SPMs group (n = 62), compared with 49.8% (P < 0.001) and 52.4% (P < 0.001) for no-SPMs group (n = 62). For synchronous and metachronous SPMs, the 5-year OS and DSS were 27.3% and 40.8% for synchronous SPMs group (n = 78) vs 48.8% (P = 0.001) and 70.7% (P = 0.001) for metachronous SPMs group (n = 75). According to the site of the SPMs, the 5-year OS and DSS were 24.5% and 40.4% for esophagus (n = 85), 51.9% and 66.9% for HNSCC (n = 36), 52.0% and 75.1% for lung (n = 20), 60.7% and 83.9% for others (n = 19). The SPMs in esophagus had worse OS than the other three groups (P<0.05). In multivariable analysis, synchronous SPMs, site of the SPMs, alcohol consumption and N stage were independently significant for OS.Approximately 30% of patients with HPC develop multiple malignancies during the course of disease and the most frequently involved site is the upper aero digestive tract. We should be aware of the possible coexistence of SPMs in HPC. Co-existence of gastric/esophageal tumor in situ does not affect outcome. The OS and DSS for synchronous SPMs are significantly worse than that for metachronous SPMs and no-SPMs. The SPMs in esophagus is the most common site and present the worst outcome than others.

Synchronous double primary lymphoma and thyroid cancer: A single-institution retrospective study.

Synchronous double primary malignancies of lymphoma and thyroid cancer are rare. In this retrospective study, we investigated the pathology, clinical characteristics, and treatment outcomes of patients with synchronous lymphoma and thyroid cancer.Of the 1156 newly diagnosed lymphoma patients treated in our hospital between January 1, 2016 and February 1, 2021, 8 cases had lymphoma complicated with thyroid cancer. The clinical data and treatment strategies of 8 cases with synchronous lymphoma and thyroid cancer were retrospectively analyzed.The median age of patients was 56 (25–64) years. All the 8 patients were female and papillary thyroid cancer. Only 1 patient had peripheral T-cell lymphoma, and the other 7 were B-cell lymphoma. Seven of 8 patients had normal free triiodothyronine and free thyroxine at the time of diagnosis. Seven thyroid cancer patients received total thyroidectomy and levothyroxine and the remaining 1 patient has a plan for surgery. At the last follow-up, 7 patients with B-cell lymphoma are alive; the patient with peripheral T-cell lymphoma complicated with thyroid cancer died due to lymphoma progression.Synchronous lymphoma and thyroid cancer are more predominant in women. Histologically, B-cell lymphomas and papillary thyroid cancer subtypes are more common. Attention should be paid to the presence of thyroid nodules in the diagnosis of lymphoma. Biopsy or ultrasound-guided fine needle aspiration of the suspicious thyroid nodule should be performed to exclude thyroid malignancy.

Utility of different positron emission tomography/computed tomography tracers in the evaluation of incidentally detected dual malignancies: An experience from a tertiary care center

ABSTRACTMultiple primary malignancies in a cancer patient are not a rare occurrence. The most common presentation of multiple primary malignancies is dual malignancies. The usefulness of different positron emission tomography (PET)/computed tomography (CT) tracers in the evaluation of dual synchronous primary malignancies is not well documented. Here, we present a case series, where two patients, referred for PET/CT, after being diagnosed with one primary malignancy were found to be having a second primary malignancy, diagnosed incidentally in PET/CT, further validated by PET/CT with another tracer.

MDCT evaluation of synchronous breast carcinoma and other solid malignancies.

Multiple primary malignancies are two or more malignancies in an individual without any relationship between the tumors. The development of improved diagnostic techniques, increased survival of cancer patients and the growing life expectancy have all contributed to the increased frequency of this phenomenon. The aim of this study is to review the multidetector computed tomography (MDCT) findings of synchronous breast carcinoma and other solid malignancies. This retrospective study included 65 patients confirmed with diagnosis of synchronous breast carcinoma and other solid malignancies. CT scanning was performed using 128 MDCT in all patients. All one hundred-thirty malignancies underwent pathological evaluation. Out of 4120 patients with breast carcinoma; 65 patients were diagnosed with other synchronous primary solid malignancy. All one hundred-thirty malignancies were confirmed pathologically. Breast carcinoma detected in all 65 patients; of them metastatic breast carcinoma detected in 8 patients. Hepatocellular carcinoma was detected in 18 patients, Non-Hodgkin lymphoma (NHL) in 12 patients, endometrial carcinoma in 8 patients, uterine sarcoma in 3 patients, malignant mixed Müllerian tumor in one patient, ovarian carcinoma in 5 patients, renal cell carcinoma in 4 patients, thyroid carcinoma in 4 patients, gastric carcinoma in 2 patients, colonic carcinoma in 2 patients, ano-rectal carcinoma in one patient, hilar cholangiocarcinoma in 2 patients, malignant melanoma in 2 patients and bronchogenic carcinoma in one patient. Patients with breast carcinoma have a risk of other synchronous primary malignancy. So, careful preoperative examination is recommended to improve the patients' prognosis. MDCT scanning is accurately imaging modality for evaluation of synchronous breast carcinoma and other solid malignancies. The aim of treatment in cancer patients should always be curative even in the presence of multiple malignancies.

P-122 Combined, single-session robotic surgery for synchronous primary malignancies of oropharynx and thorax

P-122 Combined, single-session robotic surgery for synchronous primary malignancies of oropharynx and thorax

High-Tech radiotherapy for primary prostate cancers and synchronous other tumor in elderly

Aims: To report feasibility and efficacy of high-tech Radiotherapy (RT) for the treatment of synchronous Multiple Primary Malignancies (sMPM) for elderly patients with primary Prostate Cancer (PC). Methods: Two elderly patients with PC and synchronous Anal Cancer (AC) and sacrum chordoma, respectively, were described. The first one was treated with radical radio-chemotherapy. A total dose of 70 Gy / 65.5 Gy (28 fractions) was prescribed to prostate/ seminal vesicles, and concomitantly, 56 Gy / 50.4 Gy / 45 Gy were prescribed to tumor, anal canal/mesorectum/pelvic nodes, and inguinal nodes, respectively. For the second case, after resection of chordoma, adjuvant and prostate radical RT (65.5 Gy / 70 Gy) in 28 fractions were used. In both cases, Volumetric-Arc RT was performed. Results: Patients completed the planned treatment without severe toxicities. After a median follow-up of 12 months, no sign of PC and a controlled/reduction of chordoma/AC were observed. Conclusion: High-tech RT is safe and effective for sMPM elderly patients. Keywords: Synchronous cancers; Elderly; Treatment; Radiotherapy; Multidisciplinary evaluation.

Multiple myeloma and frequency of synchronous and second primary malignancies

Malignancies accompanying multiple myeloma (MM) can be observed at diagnosis or during the course of the disease. Several trials have investigated the type, frequency, and effects of these malignancies on the overall survival of MM patients. Here, we aimed to investigate the frequency and types of previous/synchronous and second primary malignancies, median duration to develop a second primary malignancy during the course, and the effect of these malignancies on overall survival in our MM patients. Three hundred ten symptomatic MM patients were included and analyzed retrospectively. Malignancies detected before or after MM diagnosis were recorded. The SPSS 26.0 (NY, USA) software program was used for the statistical analysis, and a p-value below 0.05 was considered significant. Eight (2.5%) and 5 patients (1.6%) had previously/synchronous and second primary malignancies, respectively. Chronic lymphocytic leukemia, prostate cancer, primary breast cancer, metastatic breast cancer, and endometrial cancer were the most common previous or synchronized malignancies (0.3%, 1%, 0.6%, 0.3%, and 0.3%, respectively). During the follow-up, stomach, larynx, lung, and colon cancers were reported at rates of 0.6%, 0.3%, 0.3%, and 0.3%, respectively. The median time to develop a second malignancy was 17.2 months. Patients with a second malignancy had shorter overall survival than patients without malignancy (29 ± 3.9 versus 67 ± 4.9 months, p: 0.038). Although existing studies conflict with each other in some points due to their design, our study detected a 2.5% of secondary malignancy occurrence rate with a significantly decreased survival.

Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report

Abstract Multiple primary malignancies in a single patient are relatively rare; however, the frequency of this has increased significantly in recent decades. Here, we retrospectively reported an unusual case of a 70-year-old man who was admitted to the hospital with mantle cell lymphoma (MCL) and colon cancer and aimed to explore measures to reduce missed diagnosis. Based on the data, the investigation of the related literatures, colonoscopy examination, and abdominal computed tomography (CT) scan were conducted for the detection of colon cancer. Following this, a precise diagnosis of MCL was confirmed by immunohistochemistry and bone marrow biopsy, which were performed to analyze the clinical characteristics and essentials for the diagnosis and differential of the disease. The results of colonoscopy showed that the patient had colon cancer, while the abdominal CT scan demonstrated colon cancer accompanied by multiple lymphadenopathy throughout the entire body. Besides, the results of immunohistochemistry confirmed that the patient suffered from MCL. The bone marrow biopsy revealed the active hematopoietic tissue hyperplasia but no tumor issue involvement in the bone marrow. In conclusion, our study combined the analysis and summary of the diagnosis and treatment of the colon cancer with MCL to provide clinical guidance for the rare multiple primary malignancy.

Distinct patterns of occurrence, common associations, and survival of patients with second primary maligancies: A 5-year single institute experience with review of literature.

Multiple primary malignancy (MPM) is defined as occurrence of two or more synchronous or metachronous primary malignancies. With the rise in cancer burden and meticulous screening of index primary malignancy (IPM) during treatment, increased incidence of second primary malignancy (SPM) is expected. This study was undertaken with an attempt to analyze the incidence, commonest associations, management strategies, and clinical outcomes of MPM. This is an observational retrospective study carried out in a single institute with patients registered between 1st January 2015 and 31st August 2019. The International Association of Cancer Registries and International Agency for Research on Cancer (IACR/IARC) definition was used for identification of IPM and SPM. Synchronous SPM was defined as malignancy occurring within 6 months from the diagnosis of IPM. Out of 16,461 registered patients during the study interval, 44 (0.26%) cases were found to have MPM. A total of 31 (70.5%) cases were women and 13 (29.5%) cases were men. Median age at presentation of IPM was 48 years and of SPM was 56 years, with median duration between two primaries being 38 months. Seven patients (15.9%) had synchronous malignancies. Gynecological tumors were the most common site of IPM presentation (n = 14, 31.8%) followed by breast (n = 09, 20.5%) and head and neck tumors (n = 07, 15.9%), respectively. The most common SPM was gynecological tumors (n = 12, 27.3%) followed by gastrointestinal malignancies (n = 10, 23.3%). Curative treatment was offered to 88% of patients with IPM and 70% patients with SPM. At a median follow-up of 365 days, 21 (47.72%) patients were disease free, six (13.6%) died of disease and nine (20.5%) were lost to follow-up. The study emphasizes the importance of detecting SPM as a result of improved diagnostic and screening procedures. Clinicians should be aware of it and offer multidisciplinary management.

A Rare Presentation of Carcinoma Post Cricoid with Unusual Synchronous Primary Malignancy in the Sigmoid Colon

A Rare Presentation of Carcinoma Post Cricoid with Unusual Synchronous Primary Malignancy in the Sigmoid Colon

Lobular to Lobule: Metastatic Breast Carcinoma to Olfactory Neuroblastoma.

Tumor-to-tumor metastasis (TTM) is a rare, but well-described phenomenon occurring in patients with multiple synchronous or metachronous primary malignancies. Olfactory neuroblastoma (ONB) is a rare malignant, neuroectodermal sinonasal tract tumor that occurs within the ethmoid sinus involving the cribriform plate. Very few cases of ONB have been documented to metastasize to other primary malignancies, but the reverse scenario is exceptional. During an evaluation for anosmia, a right nasal polyp was identified on imaging and endoscopy in a 66-year-old woman, with a polypectomy performed. Histologic examination showed classical features of a low-grade olfactory neuroblastoma, but within the tumor wereisolated epithelioid cells which were strongly pancytokeratin immunoreactive. Review of the clinical history revealed lobular breast carcinoma treated 10years earlier. Further evaluation with immunohistochemistry showed strong and diffuse nuclear estrogen and progesterone receptor reactivity, along with GATA3. These results confirmed TTM of an invasive lobular breast carcinoma to ONB. By employing a limited immunohistochemistry panel for all small round blue cell tumors that includes pancytokeratin, p40, S100 protein, SOX10, synaptophysin, desmin, CD99, and CD45, one is able to more accurately diagnose the classical tumor types, while also showing potentially unusual tumor features or exceptionally rare events like metastatic lobular breast carcinoma to ONB.

Whole-exome sequencing in a patient with synchronous triple primary malignancies involving lung cancer: a case report.

The incidence of multiple primary malignancies (MPMs) has been increasing rapidly in recent years, however, the genetic pathogenesis is largely unknown on account of rare cases, especially for those patients who are diagnosed with three or more tumors. Under these circumstances, whole-exome sequencing (WES) may help to provide more comprehensive genomic information and guidance to proper therapeutic strategies. Here, we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies: esophageal squamous cell carcinoma (ESCC), lung adenocarcinoma (LA), and hepatocellular carcinoma (HCC). Tumors were surgically removed within 3 months. WES was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were predicted. Each tumor displayed a distinct somatic mutation profile, providing direct evidence of independent origins. No shared driver gene mutation or neoantigen was detected among the three tumors. Two germline alterations of cancer susceptibility genes—SPINK1 c.194 + 2T>C and JAK3 c.425G>A were identified. This case is the first report of synchronous primary triple cancers covering the esophagus, lung, and liver. Our findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds, the occurrence of MPMs can be a random event and driven by distinct somatic gene mutations. Synchronous multiple primary cancers that originated from different organs may not have common therapeutic gene targets, and it can be difficult to find a treatment to cover all the tumors.

Genetic polymorphisms of the X‐linked transcription factor forkhead box P3 predispose to synchronous secondary primary malignancy (SPM) of esophagus in head and neck squamous cell carcinoma patients

AbstractPatients with head and neck squamous cell carcinoma (HNSCC) are prone to develop second primary malignancy (SPM) at the esophagus synchronously, especially those with increased forkhead box P3 (FOXP3) positive regulatory T (Treg) cell infiltration in tumor tissue. We tested whether FOXP3 genetic polymorphisms can be associated with Treg cell infiltration and synchronous SPM in HNSCC patients. HNSCC patients received screening esophagogastroduodenoscopy during 2008 to 2016 were enrolled consecutively. After excluding and matching cigarette smoking and alcohol drinking status, the final cohort went on investigation. Three tag single nucleotide polymorphisms (tag SNPs) of the FOXP3 gene (rs2232365, rs3761548, and rs3761549) were selected from the HapMap database and genotyped by RT‐PCR. FOXP3 immunohistochemistry was done to evaluate Treg cell amount in tumor tissues. A total of 270 male HNSCC patients were included, including 135 in the synchronous SPM (SynSPM group) and 135 in the HNSCC alone group. Compared with HNSCC alone group, synchronous SPM group had a HNSCC that was more commonly located at oro/hypopharynx (55.0% vs 39.6%, P = .012) and at earlier TNM stage with borderline significance (38.8% vs 29.0%, P = .124). In addition, carriage of G allele in rs3761549 of the FOXP3 gene significantly increased synchronous SPM risk (crude OR = 2.21, P = .009). After adjustment of HNSCC location and staging, rs3761549 G allele remained significantly associated with synchronous SPM risk (adjusted OR = 2.10, P = .024). Patients with G allele in rs3761549 also had higher FOXP3+ Treg cell infiltration in the tumor tissue than those with A allele (mean FOXP3+ cell number/mm2: 55.93 vs 36.39, P = .008). Male HNSCC patients with G allele in rs3761549 of the FOXP3 gene has a higher risk of synchronous SPM development and merit earlier screening endoscopy.

A Retrospective Study of Risk Factors for Symptomatic Anastomotic Leakage after Laparoscopic Anterior Resection of the Rectal Cancer without a Diverting Stoma.

Background Anastomotic leakage (AL) is a common and devastating postoperative issue for patients who have undergone anterior resection of rectal carcinoma and can lead to increased short-term morbidity and mortality. Moreover, it might be associated with a worse oncological prognosis of tumors. This study is aimed at exploring the risk factors for symptomatic AL after laparoscopic anterior resection (LAR) for rectal tumors without a preventive diverting stoma. Materials and Methods This case control study retrospectively reviewed the data of 496 consecutive patients who underwent LAR of the rectum without a preventive diverting stoma at the Cancer Hospital, Chinese Academy of Medical Sciences between September 2016 and September 2017. All patients were divided into an AL group and a control group based on the occurrence of postoperative symptomatic AL. Factors regarding patient-related variables, operation-related variables, and tumor-related variables were collected and assessed between the two groups through univariate and multivariate logistic regression analyses to identify independent risk factors for AL. Results In total, 18 (3.6%) patients developed postoperative symptomatic AL. Univariate analysis showed that a synchronous primary malignancy of the left hemicolon (P = 0.047), intraoperative chemotherapy (P = 0.003), and level of anastomosis (P = 0.033) were significantly related with AL. Multivariate analysis was subsequently performed to adjust for confounding biases and confirmed that a synchronous primary malignancy of the left hemicolon (odds ratio (OR), 12.225; 95% confidence interval (CI), 1.764-84.702; P = 0.011), intraoperative chemotherapy (OR, 3.931; 95% CI, 1.334-11.583; P = 0.013), and level of anastomosis (OR, 3.224; 95% CI, 1.124-9.249; P = 0.030) were independent risk factors for symptomatic AL for patients who received LAR for rectal neoplasms without a preventive diverting stoma. Conclusions Synchronous primary malignancy of the left hemicolon, intraoperative chemotherapy, and a low anastomotic level can increase the risks of postoperative symptomatic AL after LAR of the rectum without a protective diverting stoma.

Synchronous Breast Carcinoma and Other Solid Malignancies: MDCT Evaluation

Background and Objectives: The incidence of synchronous primary malignant tumors is increasing due to the ageing of the population and advances in medical technology. In this retrospective study; we review the multidetector computed tomography (MDCT) findings of synchronous breast carcinoma and other solid malignancies. Methods and Materials: This retrospective study included 65 patients confirmed with diagnosis of synchronous breast carcinoma and other solid malignancies. The patients aged ranged from 35 – 78 years. CT scanning was performed using 128 MDCT in all patients. All one hundred-thirty malignancies were underwent pathological evaluation. Results: Out of 4120 patients with breast carcinoma; 65 patients were diagnosed with other synchronous primary solid malignancy. All one hundred-thirty malignancies were confirmed pathologically. Breast carcinoma detected in all 65 patients; of them metastatic breast carcinoma detected in 8 patients. Hepatocellular carcinoma detected in 18 patients. Non-Hodgkin lymphoma (NHL) detected in 12 patients. Endometrial carcinoma detected in 8 patients. Uterine sarcoma detected in 3 patients. Malignant mixed Mullerian tumor detected in one patient. Ovarian carcinoma detected in 5 patients. Renal cell carcinoma detected in 4 patients. Thyroid carcinoma detected in 4 patients. Gastric carcinoma detected in 2 patients. Colonic carcinoma detected in 2 patients. Ano-rectal carcinoma detected in one patient. Hilar cholangiocarcinoma detected in 2 patients. Malignant melanoma detected in 2 patients. Bronchogenic carcinoma detected in one patient. Conclusions: Patients with breast carcinoma have a risk of other synchronous primary malignancy. So, careful preoperative examination is recommended to improve the patients’ prognosis. MDCT scanning is accurately imaging modality for evaluation of synchronous breast carcinoma and other solid malignancies. The aim of treatment in cancer patients should always be curative even in the presence of multiple malignancies. Funding Statement: There was no financial support for this research and publication. Declaration of Interests: The author declares that there is no conflict of interest. Ethics Approval Statement: The study was approved by the institutional research ethics review committee (Mansoura University/Faculty of Medicine/ Egypt). IRB reference number is “R.20.02.753