Preliminary Report of the Academic CAR-T (ISIKOK-19) Cell Clinical Trial in Turkey: Characterization of Product and Outcomes of Clinical Application

Objective: Chimeric antigen receptor T (CAR-T) cell therapies have already made an impact on the treatment of B-cell malignancies. Although CAR-T cell therapies are promising, there are concerns about commercial products regarding their affordability and sustainability. In this preliminary study, the results of the first production and clinical data of an academic CAR-T cell (ISIKOK-19) trial in Turkey are presented. Materials and Methods: A pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy for patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. The production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusions are presented in this study. Results: Nine patients were enrolled in the trial [5 with acute lymphoblastic leukemia (ALL) and 4 with non-Hodgkin lymphoma (NHL)], but only 7 patients could receive treatment. Two of the 3 participating ALL patients and 3 of the 4 NHL patients had complete/partial response (overall response rate: 72%). Four patients (57%) had CAR-T-related toxicities (cytokine release syndrome, CAR-T-related encephalopathy syndrome, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up. Conclusion: Production efficacy and fulfillment of the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles were also acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19+ tumors. However, the findings of this study need to be supported by the currently ongoing ISIKOK-19 clinical trial.

Clinical characteristics and therapeutic outcomes of paroxysmal nocturnal hemoglobinuria patients in Turkey: a multicenter experience.

The aim of this study is to collect paroxysmal nocturnal hemoglobinuria (PNH) patient data from hematology centers all over Turkey in order to identify clinical features and management of PNH patients. Patients with PNH were evaluated by a retrospective review of medical records from 19 different institutions around Turkey. Patient demographics, medical history, laboratory findings, and PNH-specific information, including symptoms at the diagnosis, complications, erythrocyte, and granulocyte clone size, treatment, and causes of death were recorded. Sixty patients (28 males, 32 females) were identified. The median age was 33 (range; 17-77) years. Forty-six patients were diagnosed as classic PNH and 14 as secondary PNH. Fatigue and abdominal pain were the most frequent presenting symptoms. After eculizumab became available in Turkey, most of the patients (n = 31/46, 67.4%) were switched to eculizumab. Three patients with classic PNH underwent stem cell transplantation. The median survival time was 42 (range; 7-183 months) months. This study is the first and most comprehensive review of PNH cases in Turkey. It provided us useful information to find out the differences between our patients and literature, which may help us understand the disease.

Successful technique of manual vacuum aspiration for treatment of type 2 cesarean scar pregnancies: evaluation of 40 cases.

OBJECTIVE: To demonstrate the effectiveness and safety of the defined manual vacuum aspiration (MVA) technique for treatment of type 2 cesarean scar pregnancies (CSPs). METHODS: We treated 40 patients with CSP by MVA at the Early Pregnancy Clinic of our hospital between 1 January 2012 and 31 December 2014. The files of patients were reviewed and evaluated retrospectively. Eligibility criteria were hemodynamic stability and at least 2 mm myometrial thickness at the anterior part of the CSP. The key-point of successful MVA procedure is to keep away from entering the cesarean scar cavity directly; instead, CSP is displaced from the implantation site by applying vacuum, only while the cannula is passing near. RESULTS: During the study period, the ratio of CSP to total pregnancies was 1/1000. The ratio of CSP to cesarean delivery (CD) was 1/372. In that time period, CSPs were constituted 4.41% of all ectopic pregnancies. Total of 40 patients were treated with dilatation and MVA. Complications such as excessive hemorrhage, persistence of CSP, and any need of extra intervention were not observed. The beta-hCG values of 21 patients (52.5%) decreased below 10 mIU/mL after the first 15 days, and the rest decreased below 10 mIU/mL after 3 weeks following MVA. CONCLUSIONS: This MVA technique for treatment of CSP is easily applicable and effective method with high success and low complication rates. For appropriately selected patients, we think that this method can be considered as the first- line treatment.

Post-partum tubal ligation at time of cesarean delivery or via laparoscopy as an interval sterilization has similar effects on ovarian reserve

Objective: To observe and compare the effect of postpartum tubal ligation (TL) procedures on ovarian reserve at women desiring TL as a contraceptive method at the end of pregnancy. Material and Methods: Eighty-one women were included in the prospective study. TL was performed at the time of cesarean delivery (CD) (n=49) and as an interval procedure by laparoscopy (LS) in the postpartum period (n=32). Anti-müllerian hormone (AMH) was used to determine ovarian reserve. Blood samples were taken twice from each subject; the first sample was taken before delivery from all subjects and the second sample was taken 4 months after sterilization. AMH level differences were compared in each group and between groups. Results: The preoperative AMH values of CD and LS groups were similar 2.30 (maximum: 5.20, minimum: 0.42) ng/mL and 1.80 (maximum: 3.50, minimum: 0.40) ng/mL, respectively (p=0.262). The postoperative AMH values of the CD and LS groups were 1.30 (maximum: 2.60, minimum: 0.30) ng/mL and 0.90 (maximum: 2.50, minimum: 0.20) ng/mL, respectively (p=0.284). When the preoperative and postoperative values of each group were compared the change was statistically significant for both groups p<0.001. The decrease in mean AMH values in the CD and LS groups were 37.83% and 44.15%, respectively. The percentage changes of AMH values were not statistically significant (p=0.286). Conclusion: TL at the time of CD and interval sterilization with LS have similar effects on ovarian reserve.

The Effect of Preoperative Neutrophil-To-Lymphocyte Ratio and Platelet-To-Lymphocyte Ratio on Predicting Rupture Risk in Tubal Ectopic Pregnancies.

BACKGROUND: Consecutive measurements of ß-hCG levels and sonographic evaluation of adnexae are critical for choosing the optimal management in ampullar tubal ectopic pregnancies (EP). To select suitable patients for conservative approach, there is a need for an affordable and reliable marker for determining rupture risk. Evaluation of systemic inflammatory markers in combination with serum ß-hCG levels and ultrasound might help to decide the appropriate treatment option. OBJECTIVE: The purpose of the present study was to evaluate the diagnostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in determining the rupture risk in ampullar tubal EPs and to compare with intraoperative findings. METHODS: A total of 142 patients who underwent surgery for tubal EP were included. Seventy-two patients were in the intraoperatively diagnosed tubal rupture group and 70 patients without rupture findings were included in the control group. Both groups were compared for inflammation markers, ß-hCG levels, and sonographic findings. RESULTS: Both NLR and PLR levels were found to be significantly higher in the tubal rupture group (4.62 ± 3.13 vs. 2.67 ± 1.43, 162.94 ± 63.61 vs. 115.84 ± 41.15, p < 0.01, respectively). According to the receiver operating characteristic analysis performed for the diagnostic performance of tubal diameter measurement, ß-hCG, NLR, and PLR levels were significantly associated with histopathologically confirmed tubal rupture (p < 0.01). CONCLUSION: Systemic inflammatory markers are feasible and affordable tools for predicting tubal rupture risk in ampullar EPs and might be useful for determining surgery decision especially in low resource settings.

Double balloon catheters: A promising tool for induction of labor in multiparous women with unfavorable cervices

Objective: To compare the effectiveness and safety of oxytocin and a cervical ripening balloon in women with unfavorable cervices for inducing labor. Material and Methods: A total of eighty pregnant women between 37-41 gestational weeks having singleton pregnancies and intact membranes with unfavorable cervices were randomized into two groups, cervical ripening balloon (n=40) and oxytocin infusion (n=40). The primary outcomes were the labor time and the route of delivery. Secondary outcomes were the effect of parity on time of labor, and obstetric and perinatal outcomes. Results: The median time to delivery was 9.45 hours in cervical ripening balloon group and 13.2 hours in the oxytocin group in multiparous women. The differences were statistically significant (p<0.001). The median time until delivery was 11.48 hours in cervical ripening balloon group and 13.46 hours in the oxytocin group; the differences were statistically significant (p<0.001). Cesarean delivery ratios were similar in both groups (p=0.431). Conclusion: The results of the present study are promising for balloon use, especially in multiparous women. It is beneficial to support these data with wide ranging population-based studies.

New Entity of Skull Lesions due to Birth Trauma: Kanat (Wing) Fractures.

AIM: To discuss a special type of skull lesion detected after delivery. We reviewed our experience on scalp swelling in term neonates to further investigate the relationship between cranial injuries and labor process. MATERIAL AND METHODS: A total of 55 newborns with scalp swellings were assessed with medical records retrospectively between January 2007-July 2017. A radiologist and a pediatric neurosurgeon re-analyzed all skull X-ray images via picture archiving and communication system of the hospital. RESULTS: A special type of skull fracture, called Kanat (wing) fracture, was detected. The fractures appeared unique, were located in the midline parietal bone, and were difficult to detect by X-ray. Kanat fractures accounted for 12.7% of the 55 cases (n=7). Patients without (group-1) and patients with (group-2) Kanat fractures were compared based on the head circumference of the newborns (p=0.881), fetal birth weight (p=0.20), maternal age (p=0.04), duration of second stage of labor (p=0.217), maternal body mass index (p=0.278), total labor time (p=0.922) and parity (p=0.375). No statistically significant difference between the two groups was determined for the compared parameters. CONCLUSION: The present study is the first research describing and discussing the possible effects of maternal, fetal and delivery characteristics on Kanat fractures. Designing clinical and experimental researches to enhance awareness and acknowledgement of skull injuries and labor process could improve the clinical outcome of the newborns.

Triple Synchronous Malignancies in Genital Tract; Primary Endometrial, Ovarian and Fallopian Tube Carcinoma: A Case Report.

Synchronous malignancies, including three or more tumours, are extremely rare. Herein, we present a case of a woman with a concurrent simultaneous endometrial, ovarian and fallopian tubal carcinoma with different histopathological characteristics. A 55-year-old postmenopausal woman with a diagnosis of endometrial adenocarcinoma by pipelle biopsy, underwent surgical staging. Final pathology result was reported as synchronous stage IA grade 2 endometrioid adenocarcinoma of the uterus, stage IA grade 2 mucinous adenocarcinoma of the right ovary and in situ serous cystadenocarcinoma of the right fallopian tube. In the postoperative period, patient followed without adjuvant therapy. To our knowledge, this a very rare case report in the literature of sychronous triple gynaecologic cancers including fallopian tube cancer and with the longest disease free survival time with over 39 months due to better prognosis than metastatic or advanced primitive diseases.

Vitamin B12 levels in familial Mediterranean fever patients treated with colchicine.

OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterised by paroxysmal attacks of serosal inflammation. Colchicine is highly effective in preventing these attacks but it may also disrupt the intestinal absorption of vitamin B12. We hypothesised that patients treated with colchicine for a prolonged period could develop deficiency of the vitamin. METHODS: Ninety-five adult FMF patients on regular colchicine treatment for at least 2 years and age and sex-matched 90 healthy controls were enrolled and complete blood count with platelets, vitamin B12 and folic acid were measured in each person. We also investigated 15 adult FMF patients who were not yet on colchicine. RESULTS: The mean vitamin B12 values were not significantly different between the groups (352.12 (SD=171.62) pg/mL vs. 360.96 (SD=146.53) pg/mL, p=0.71), but there were significantly more vitamin B12 deficient cases among FMF patients (12 vs. 3; p=0.021) and 3 out of these 12 had megaloblastic anaemia. None of the vitamin B12 deficient controls had anaemia. We could not identify any disorder which might have causative effect for the deficiency among this subgroup. The mean vitamin B12 value of 15 colchicine-naïve cases was not significantly different from patients on colchicine (p=0.356). CONCLUSIONS: We did not observe significant vitamin B12 deficiency among colchicine-treated FMF patients but some cases may be more prone to developing this potentially serious disorder.

Can ovarian damage be reduced using hemostatic matrix during laparoscopic endometrioma surgery? A prospective, randomized study.

PURPOSE: To compare the effect of hemostatic matrix (HM) and electrosurgical bipolar coagulation (EBC) on ovarian reserve in patients undergoing endometrioma surgery. METHODS: Thirty patients with single ovarian endometrioma ≥4 cm were randomized to two groups. Ovarian reserve after laparoscopic excision of endometrioma was assessed by serum anti-Müllerian hormone (AMH); preoperatively and in postoperative months 1 and 3. RESULTS: The preoperative AMH levels were similar between the groups. Intra-group comparisons: the AMH levels were significantly lower in the first and third postoperative months as compared to basal levels in both groups. In each group, AMH levels were significantly higher in the third postoperative month as compared to first postoperative month. Inter-group comparisons: AMH levels were significantly lower in the EBC as compared to the HM at 1st postoperative month (1.64 ± 0.93 vs. 2.72 ± 1.49 ng/mL). However, the AMH levels were increased and became similar at 3rd postoperative month. CONCLUSIONS: Although acute ovarian damage was more in EBC group, ovarian reserve was compensated at 3rd month. Further studies with long-term follow-up will clarify the importance of these findings.

Colitis-induced oxidative damage of the colon and skeletal muscle is ameliorated by regular exercise in rats: the anxiolytic role of exercise.

Epidemiological studies have shown that exercise protects the gastrointestinal tract, reducing the risk of diverticulosis, gastrointestinal haemorrhage and inflammatory bowel disease, while many digestive complaints occurring during exercise are attributed to the adverse effects of exercise on the colon. In order to assess the effects of regular exercise on the pathogenesis of colitis, Sprague-Dawley rats of both sexes were either kept sedentary or given exercise on a running wheel (0.4 km h(-1), 30 min for 3 days week(-1)). At the end of 6 weeks, under anaesthesia, either saline or acetic acid (4%, 1 ml) was given intracolonically. Holeboard tests were performed for the evaluation of anxiety at 24 h before and 48 h after induction of colitis. Increased 'freezing time' in the colitis-induced sedentary group, representing increased anxiety, was reduced in the exercised colitis group (P < 0.05). On the third day following the colonic instillation, the rats were decapitated under brief ether anesthesia and the distal 8 cm of the colons were removed. In the sedentary colitis group, macroscopic and microscopic damage scores, malondialdehyde level and myeloperoxidase activity were increased when compared to the control group (P < 0.01-0.001), while exercise prior to colitis reduced all the measurements with respect to sedentary colitis group (P < 0.05-0.001). The results demonstrate that low-intensity, repetitive exercise protects against oxidative colonic injury, and that this appears to involve the anxiolytic effect of exercise, suggesting that exercise may have a therapeutic value in reducing stress-related exacerbation of colitis.