Tehran University Medical Journal

A journey in anthracycline-induced cardiotoxicity with emphasizing on doxorubicin: a review article

Yaser Azizi

Cancer is the second leading cause of death in the United States and has become a health problem worldwide. The reported incidence of new cancer cases is estimated at 19.3 million, with a mortality rate of 10 million in the world in 2020. There are several therapeutic approaches for cancer, including chemotherapy. Chemotherapy is consuming anti-neoplastic drugs, alone or in combination. However, it causes damages to the normal cells and has many side effects. Cardiac complications are common side effects of some chemotherapy agents. Cardiac myocytes are potentially more susceptible to the long-term adverse effects of chemotherapy agents due to the less regeneration ability in cardiac cells. Moreover, heart muscle dysfunction (cardiomyopathy) and cardiovascular complications may occur in cancer survivors even a year after chemotherapy or radiation therapy and influence their quality of life. Anthracyclines are commonly used in chemotherapy; especially doxorubicin is the most widely used drug of this family. Doxorubicin is an effective anti-malignant agent prescribed for the treatment of some solid tumors (e.g. ovary, breast, and gastrointestinal cancers). Doxorubicin can cause several side effects, ranging from cancer treatment’s common side effects such as fever, nausea, and vomiting to lethal cardiac side effects. Assumed that doxorubicin has many therapeutic and cytotoxic mechanisms, cardiotoxicity induced by doxorubicin is very common and there is no reliable treatment for this problem. The cardiac side effects of doxorubicin during a chemotherapy regimen can be acute, chronic, or even gradually progressive and persistent after the termination of doxorubicin therapy. In patients undergoing doxorubicin therapy, reported symptoms are cardiac rhythm and blood pressure changes, pericarditis, myocarditis, cardiomyopathy, and congestive heart failure. The pathophysiology of doxorubicin-induced cardiotoxicity is very wide. Disruption of normal mitochondrial function, decreased amount of antioxidant factors, production of reactive oxygen species (ROS), an imbalance in calcium hemostasis, activation of inflammatory cytokines, targeting topoisomerase-IIβ (Top2b), and induced DNA damage are associated with doxorubicin-induced cardiotoxicity. Increased doxorubicin in mitochondria activates the redox cycle that ultimately leads to the production of reactive oxygen species in both normal and tumor cells. The present review aims to investigate the cardiotoxic mechanisms of doxorubicin and explain different types of doxorubicin-induced cardiotoxicity.

Evaluation of the brain tissue oxidative stress status during sepsis after mesenchymal stem cell's conditioned medium administration in male rats

Mina Ranjbaran

Background: In the present study, we hypothesized that conditioned medium (CM) derived from mesenchymal stem cells attenuates the brain oxidative stress in sepsis induced by the cecal ligation and puncture (CLP) model.
Methods: This study was performed in the Department of Physiology at Tehran University of Medical Sciences from August 2018 to April 2019. Conditioned medium was collected from mesenchymal stem cells isolated from rat's adipose tissues at the second culture passage. Male Wistar rats weighting (220-250 g) were randomly divided into three experimental groups (n=8 each): Sham, Sepsis and CM. Sepsis was induced by cecal ligation and puncture model in the Sepsis and CM groups. Animals in the CM group received the conditioned medium from 5×10⁵ mesenchymal stem cells (2 h after sepsis induction, i. p., 3-5 mL). The systolic blood pressure and O2 saturation were measured 24 h after the treatment. The plasma and brain tissue samples were taken for inflammatory and oxidative stress assessment, respectively.

Results: Septic rats showed a significantly lower systolic blood pressure and O2 saturation level. They also had a significant increase in the plasma inflammatory indices (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6]) and brain malondialdehyde (MDA) content as well as a significant reduction in the brain superoxide dismutase (SOD) activity compared to the Sham group. The CM group had significantly higher systolic blood pressure and O2 saturation level compared to the septic rats. The animals in the CM group showed a significant attenuation in the plasma inflammatory indices (TNF-α and IL-6) and brain MDA content while having a significantly higher brain SOD activity compared to the Sepsis group.
Conclusion: Our findings showed that conditioned medium derived from mesenchymal stem cells has protective effects in preventing the inflammatory and oxidative stress status and may be suggested as a promising treatment in patients suffering from sepsis and septic shock.

The effect of bone marrow-derived mesenchymal stem cells to induce PD-L1 molecule on splenic lymphocytes

Saeid Abediankenari

Background: Mesenchymal stem cells are non-hematopoietic stromal cells that are used in the treatment of many chronic and autoimmune diseases by modulating the immune system. Due to the limitations of using autologous mesenchymal stem cells, the use of allogeneic stem cells is a promising therapeutic approach in the treatment of immunological disorders. This study aimed to investigate the ability of allogeneic mesenchymal stem cells to induce Programmed death-ligand 1(PD-L1) expression on the surface of splenic lymphocytes and the role of this molecule in the mesenchymal stem cell-treated cells tolerogenicity.
Methods: This study was conducted from February 2019 to December 2020 in the department of Immunology of Mazandaran University of medical sciences. Mesenchymal stromal cells were isolated from the femur and tibia of C57 mice. C57 bone marrow-derived mesenchymal stem cells were co-cultured with allogeneic BALB/c splenic cells. After 72 hours, the expression of PD-L1 on the surface of splenic lymphocytes was evaluated by flow cytometry. Interferon-gamma (IFN-γ) and Interleukin-10 (IL-10) cytokine assay were done in the cell culture supernatant. Mesenchymal stem cell-treated BALB/c lymphocytes were then exposed to allogeneic C57 splenocyte as stimuli in the mixed lymphocyte reaction (MLR) and the rate of proliferation was assessed by CFSE.

Results: The amount of PD-L1 positive BALB/c splenic lymphocytes were significantly increased after allogeneic C57 mesenchymal stem cells exposure (P=0.001). The levels of IFN-γ and IL-10 cytokines in the supernatant of cell culture also increased significantly (respectively, P=0.0009, P=0.01). C57 splenocytes proliferation notably decreased after mesenchymal stem cell-treated BALB/c lymphocytes exposure compared to the group were cultured with naïve BALB/c lymphocytes (P=0.002).
Conclusion: Allogeneic mesenchymal stem cells are capable to induce of PD-L1 on the surface of lymphocytes. PD-L1 expression on mesenchymal stem cell-treated cells makes them less immunogenic than naïve cells. These tolerogenic cells can reduce allogeneic responses. It seems that PD-L1 plays an important role in mesenchymal stem cell immunomodulation

Translation of guidelines for perioperative care in gynecologic/oncology: enhanced recovery after surgery (ERAS) society recommendations-2019 update

Fariba Behnamfar

Background: Enhanced recovery after surgery (ERAS) is now firmly established as a global surgical quality improvement initiative that results in both clinical improvements and cost benefits to the healthcare system. ERAS guidelines are based on the highest quality evidence available and as such require updating on a regular basis. The ERAS Gynecologic/Oncology guidelines were first published in February 2016. This is the first updated Enhanced Recovery After Surgery (ERAS) Society guideline presenting a consensus for optimal perioperative care in gynecologic/oncology surgery.^1,2
Methods: Starting from the original ERAS Gynecologic/Oncology guidelines, the first author and senior authors identified topics for inclusion. International authors known for their expertise in gynecologic/oncology perioperative care were invited to participate in the guideline update. A database search of publications using Embase and PubMed was performed. Studies on each item within the ERAS gynecologic/oncology protocol were selected with an emphasis on meta-analyses, randomized controlled trials, and large prospective cohort studies. These studies were then reviewed and graded according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system,³ whereby recommendations are given as follows: Strong recommendations: The panel is confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects, weak recommendations: The desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but the panel is less confident.

Results: The evidence base, recommendations, evidence level, and recommendation grade are provided for each individual ERAS item below. The table 1 shows all the ERAS items with emphasis on changes for the 2019 guideline update. The (Table 2) shows items: (pre-operative optimization, pre-anesthetic medication, nausea and vomiting prophylaxis, urinary drainage, and early mobilization). These items not updated in 2019 guideline (no change in recommendation/evidence. All recommendations on ERAS protocol items are based on the best available evidence. The level of evidence for each item is presented accordingly.
Conclusion: The updated evidence base and recommendation for items within the ERAS gynecologic/oncology perioperative care pathway are presented by the ERAS® Society in this consensus review.

The diagnostic value of ultrasound for ovarian mature cystic teratoma and accordance of it with postoperative histopathologic findings

Shahla Yazdani

Background: Mature cystic teratoma of the ovary is one of the most common benign ovarian tumors, which may be confused with other adnexal lesions due to its extensive manifestations on ultrasound. Therefore, in this study, we tried to reduce the need for pathology frozen sections by examining more accurate preoperative ultrasound results and classifying ovarian lesions based on them.
Methods: In this study, 200 female patients with a definitive diagnosis of mature cystic teratoma of the ovary who have undergone surgery at Ayatollah Rouhani Hospital, February 2009 March 2019 were evaluated. After reviewing the files, demographic information, Ultrasound, intraoperative findings and final pathology were extracted and finally, the data were analyzed using statistical tests.

Results: The age range of patients who were diagnosed with mature cystic teratoma of the ovary in the final pathology was 14-71 years. Most cysts were 5-10 cm in size. 86% of patients had unilateral right-sided ovarian involvement. The most common components of this cyst in the macroscopic report were hair (81%) and fat (80%). The diagnostic value of ultrasound for the diagnosis of mature teratoma of the ovary was 74.5%. The frozen section was used to diagnose and rule out the malignancy in 32.5% of patients.

Conclusion: The results of this study show that the prevalence of these tumors is higher in the reproductive age range. According to this study, these tumors have been seen in single people and pregnant women, Due to youth and fertility in the future, a good decision must be made about the surgical method. These tumors have a wide range of sizes. In addition, their most common complaint is abdominal pain, but it has been reported extensively in periodic ultrasounds for infertility. The diagnostic value of ultrasound for mature ovarian teratoma was high due to the presence of fat and hair in them. Therefore, the use of the frozen section (intraoperative pathology) can be reduced in more often unnecessary in cases.

Evaluation of the difference in surgical margin values in excisional skin lesions during surgery and after formalin fixation

Kamrooz Pouryousef

Background: Surgical margin determination in malignant lesions is essential and has a direct impact on the choice of postoperative treatments and patient follow-up. Therefore, the processes affecting this variable are worth exploring. This study aimed to evaluate the difference in surgical margin values in excisional skin samples during surgery and after formalin fixation.
Methods: A cross-sectional study was performed on forty randomly selected patients with benign and malignant skin lesions who were referred to the plastic surgery ward of Ghaem Hospital in Mashhad from November 2018 to January 2019. Malignant and benign skin lesions were excised with a healthy margin, then the specimens were sent to the pathologist in a formalin-containing container. The amount of tissue shrinkage and the factors affecting them were compared.

Results: Among all 40 participants about 57.5% of the them were male and 42.5% were female. The mean age of the patients was 66.55±14.53 years. Surgical margin was evaluated in three patterns: before surgical incision and after surgical incision (P<0.001), before surgical incision and after formalin fixation (P<0.001), after surgical incision and after formalin fixation (P=0.02). In this study, the relationship between the age and initial length of the skin lesion with sample shrinkage was not statistically significant.
Conclusion: The results of this study showed that tissue shrinkage occurs both after incision and after formalin fixation. The highest rate of shrinkage was seen after surgical excision, which was due to the elasticity of the tissue itself. Increasing age and initial length of skin lesion did not affect this shrinkage. Also tumoral tissue contracted less than healthy tissue due to flexibility of fatty tissue and water and lipid content.

Relationship between some indices of cardiovascular functions and pulse pressure as a predictor index for heart diseases: a case-control study

Khairollah Asadollahi

Background: Pulse pressure has recently been considered as a predictor of coronary heart disease. The difference between systolic and diastolic blood pressure is called pulse pressure. Various factors including increased age, vascular stiffness, stenosis, and hypertension are associated with pulse pressure. The present study, therefore, aimed to investigate the relationship between some cardiovascular function indicators such as vascular stenosis, blood pressure and cardiac output with pulse pressure as a predictor of cardiovascular diseases.
Methods: This case-control study was performed on 544 patients who were referred to Imam Ali Hospital in Kermanshah, Iran, from March 2015 to February 2016. In this study, according to the angiographic findings, individuals with artery stenosis were considered as the case group (n=272) and those without artery stenosis were considered as the control group (n=272). Statistical analysis was performed using descriptive statistics, Chi-square and odds ratio estimation by SPSS22 software.

Results: According to the findings of this study, ages over 50 (OR: 3.3, 95% CI: 2.1-5.2), high systolic blood pressure (OR: 8, 95% CI: 4.3-15.2), high diastolic blood pressure (OR: 4.9, 95% CI: 2.0-11.7), cardiac output less than 50% (OR: 1.8%, 95% CI: 1.3-2.7) and vascular stenosis (OR: 3.5, 95% CI: 2.4-5.1) were associated with high pulse pressure. The male gender had a preventive role in increasing of pulse pressure (OR: 0.7, 95% CI: 0.5-0.9). A significant relationship was demonstrated between systolic blood pressure and pulse pressure (P<0.0001).
Conclusion: Based on the findings of the present study, the chances of having high pulse pressure are high among individuals over 50 years of age, female gender, those with elevated systolic and diastolic blood pressure, and individuals with high coronary artery stenosis. This chance is associated with decreased cardiac output and coronary stenosis. Increased pulse pressure is a predictive indicator of cardiovascular disease and it is recommended that pulse pressure measurements of all referrals, especially those who are being referred to cardiology clinics, are taken into account by medical professionals to prevent adverse clinical outcomes.

Evaluation of common risk factors for cholangiocarcinoma in patients referred to Firoozgar Hospital, Tehran, Iran: a cross-sectional study

Masoume Pouladi

Background: Cholangiocarcinoma is a cancer of the bile duct epithelium that originates from the bile ducts inside or outside the liver. Although this tumor is not common, its mortality rate is high. This tumor accounts for about 3% of all gastrointestinal malignancies. Many patients are being detected when the disease has spread. Evaluating risk factors affecting the incidence of cholangiocarcinoma is very important to avoid exposure to them. Therefore, this study was performed to evaluate the risk factors for cholangiocarcinoma in a population in Iran.
Methods: This was a descriptive cross-sectional study. It was performed on 276 patients with cholangiocarcinoma who had been referred to Firoozgar Hospital affiliated with the Iran University of Medical Sciences in Tehran from March 2020 to February 2021. Demographic information, family and personal history, social history (tobacco or drug use) and blood group of patients were extracted from their files. SPSS version 16 was used for data analysis. A P-value below 0.05 was considered statistically significant.

Results: The mean±SD age of patients was 65.97±13.07 years, of whom 65.6% were male and 34.4% were females. The most common site of cholangiocarcinoma was the distal part of the bile ducts and the most common blood group was O+. The main manifestations were jaundice and pruritus. Among the risk factors, the most common ones were smoking, high blood pressure, history of gallstones, opium use, history of cancer of other systems in the family, history of cholecystectomy and diabetes mellitus. While, the lowest prevalence of risk factors was related to heroin use, IBD, Gallbladder polyps, pancreatitis and alcohol consumption. None of the patients in our study had a history of viral hepatitis or PSC.
Conclusion: This was a cross-sectional study and only in the group of cholangiocarcinoma patients, therefore, larger prospective studies are recommended to examine underlying mechanisms of malignant transformation in the biliary tree.

The percentage of otitis types in patients being reffered to ENT clinic: a brief report

Maryam Amizadeh

Background: Otitis is the most common infectious disease of the ear with internal and external cranial complications. If the infection is in the middle ear, it causes otitis media. If the infection is in the external ear, it’s along with otitis externa (OE). Different types of otitis media include acute otitis media (AOM), chronic otitis media (COM) and Otitis media with effusion (OME). This study aimed to investigate the different types of otitis and its symptoms.
Methods: This cross-sectional study was conducted from March 2019 to February 2020 for 200 patients who have been referred to the ENT center of Shafa hospital, Kerman, Iran. Sampling was conducted with ease and no need for specified sampling distribution. The type of otitis was written in a questionnaire by the physician after the examination. The present research investigated types of otitis along with its symptoms. Also, their demographic information was determined.

Results: This study was done among 200 patients. 106(53%) participants were diagnosed with external otitis and the most common symptoms include discharge from the ear, inflammation and pain of the ear. 53 patients (26.5%) had acute otitis media with the most common symptoms of tympanic membrane color change and otalgia. 22 patients (11%) were diagnosed with chronic otitis media. So, perforation of the tympanic membrane and otorrhea were considered as the most common symptoms for these patients. 9(9.5%) of participants had otitis media with effusion that aural fullness and reduction of hearing were the most common signs. In this research, most of the patients were between the age of 11 to 30.57% of patients in this study were men and 43% were women. Most of the patients were between the age of 30-40 and the least number of patients were over the age of 70. Among the 200 patients, most of them lived in cities and provinces rather than villages. 67.5% of patients didn’t have an academic certificate.
Conclusion: Considering the high prevalence of otitis among patients with ENT disorder, it was recommended that otitis should be recognized and cured.

Primary intraosseous squamous cell carcinoma of mandible: a case report

Elahe Vazavandi

Background: Primary intraosseous squamous cell carcinoma (PIOC) of the mouth is a very rare but well-known carcinoma. It is locally invasive and its prognosis is quite poor. It may originate from the walls of an odontogenic cyst or de novo from the remnant epithelium at this region. Because the early symptoms of such malignancies are sometimes similar to those of inflammatory or periodontal diseases, early diagnosis is the most important step toward appropriate treatment.
Case Presentation: The case was a 46-year-old female with a sudden luxation of two posterior mandibular molars referred to a general dentist in May 2019. With diagnosis of periodontitis, the teeth were extracted without finding the cause of the tooth luxation. After four months, because of pain, swelling and non-healing socket of extracted teeth she referred to the department of Oral medicine in Mashhad Faculty of Dentistry. The patient was healthy with no systemic disease, drug history or familial history of cancer and no history of trauma, habits, tobacco, alcohol, and smoking. ln clinical examination, a nodular swelling with extensive ulcer and rolled borders along with hyperkeratosis and erythema on the posterior part of the right mandibular ridge was observed. The Extraoral examination revealed a tender mobile lymph node in the right submandibular region. After radiographic evaluation, with an initial diagnosis of SCC originated from the socket of extracted mandibular molars, incisional biopsy was performed, and histopathological analysis of the specimen revealed a primary intraosseous squamous cell carcinoma (grade II) and then necessary treatments (surgery, radiotherapy, chemotherapy) were performed.

Conclusion: Dentists should know that any sudden changes in the mouth or teeth such as tooth luxation should be considered as a possible sign of malignancy. With proper diagnosis and early initiation of treatment, the prognosis of the disease can be improved and the patient can be treated with minimal complications of necessary treatments of surgery, radiotherapy, or chemotherapy.

The direct and indirect costs of the Covid-19 pandemic on households and the health care system: a letter to the editor

Abedin Saghafipour