Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach.

Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.

Medical students' perception and academic performance after team-based and seminar-based learning in human anatomy.

Objectives: Student-centered educational strategies like problem-based learning (PBL), case-based learning (CBL), team-based learning (TBL), and seminars enhance group and self-learning. This study was carried out to evaluate students' achievements in anatomy topics delivered through TBL sessions and seminars and to survey student preferences regarding these two modalities in anatomy learning. Methods: TBL was conducted through individual readiness assurance tests (IRATs), group readiness assurance tests (GRATs), mini-lectures, and application exercises. Seminars included pretests, peer lecturing, and posttests. The performance of 117 students in three TBL sessions and three seminars was compared after standardizing the questions. The students were second-year (42), third-year (40), and fourth-year (35) students at the College of Medicine, University of Bisha, KSA, during the 2019/2020 academic year. Results: A gradual increase in the means of TBL grades was noticed among second-, third-, and four-year students (means ± SD: 68.6 ± 9.56, 82.8 ± 12.25, and 92.7 ± 4.70, respectively), but their seminar grades were nearly stationary (means ± SD: 80.0 ± 9.66, 85.11 ± 10.16, and 85.9 ± 8.80, respectively). Cohen's d-test to check the strength of the relationship between the two activities showed 1.03, 0.16, and 0.74 in the same order. We statistically analyzed perception and preference questionnaire results received from 39, 35, and 28 second-, third-, and four-year students, respectively. The majority of the students selected TBL as their preferred learning modality. However, their acceptance of the seminars was very poor. Conclusions: It can be concluded that TBL is more beneficial to the students, even in practical sciences like anatomy, most likely because group peer teaching enhances the sense of collegial competition, as opposed to the self-learning nature of seminars, which might suppress the sense of competition.

Charcoal Localization for Surgical Resection of Non-Palpable Suspicious Breast Lesions.

Background: Breast cancer is more frequently detected as radiographic non-palpable lesions with the increased utilization of national screening programs. Moreover, the sizes of tumors detected have decreased in recent years, increasing the need for accurate image-directed localization for surgical excision in a significant portion of cases. Although Wire guided localization has been the most commonly used method for many years, inherent problems remain and limit its practice. Radio-guided occult lesion localization (ROLL) is currently the standard method of localization, however, it is unavailable in most low resource communities. This encourages us to use charcoal localization which is a simple and cheap method of surgical localization of non-palpable suspicious breast lesions. Methods: This prospective study included 34 patients who presented with non-palpable suspicious breast lesions (BIRADS 4 or 5). All patients were injected 1-3 ml of sterilized 3% aqueous suspension of charcoal granules under the guidance of ultrasound at the superficial border of the suspicious lesion and the track between the lesion and the needle entry point in the skin which will occur at the future incision. This method was carried out in most patients one day before the operation, however, two patients underwent surgical excision after 6 days of localization without any interruption. Results: Thirty-four patients had 36 Lesions. The median age was 43 years. The mean diameter of lesions was 10.9 mm. Of 36 lesions; the BIRADS as follow10 (4a), 12 (4b), 8 (4c), and 6 (5). Postoperative investigations revealed 16 malignant lesions and 20 benign lesions. All 20 benign lesions were managed by wide local excision; All 14 BIRADS 4a lesions were proved to be benign. Sixteen malignant lesions were managed as the following; nine patients had breast-conserving surgery, five patients had modified radical mastectomy (three patients had past history of modified radical mastectomy, one patient had Multicentric IDC and one patient had infiltrated safety margins on conservation), and one patient had Nipple Sparing Mastectomy with immediate breast reconstruction by Latissimus Dorsi Flap. There was no reaction or infection reported in our study. Conclusion: Charcoal localization has many advantages and helps surgical localization.

Safety and Efficacy of Using Staplers and Vessel Sealing Devices for Laparoscopic Splenectomy: A Randomized Controlled Trial.

Background. Laparoscopic splenectomy (LS) is considered the operation of choice on elective basis for managing patients with certain hematological disorders. Hemostatic control of the splenic pedicle is one of the crucial steps in LS. This study compares the safety and efficacy of using endoscopic staplers and vessel sealing devices to control the splenic pedicle in patients with nonsevere splenomegaly. Methods. Fifty-one consecutive patients with different blood disorders including idiopathic thrombocytopenic purpura (ITP), hypersplenism, and lymphoma were randomized for elective LS. Traditional steps of LS, via lateral approach, were followed, and pedicle control was done with either endovascular gastrointestinal anastomosis stapler (n = 26) or vessel sealing device (Ligasure) (n = 25). Results. No difference was noted with different splenic spans when using either methods of pedicle control (P = .145). The volume of blood loss was higher in the Ligasure group compared to the staplers group (182 mL vs 131 mL, respectively), but was not statistically significant (P = .249). Conversion to open was notably higher in the Ligasure group (P = .034), but the intraoperative complications were comparable in both groups (P = .357). Conclusion. The use of vessel sealing devices for splenic pedicle control has comparable surgical outcomes compared with the use of endoscopic staplers for LS, but with higher rate of conversion to open surgery.

Early and Late Functional Outcomes of Anal Sphincter-Sparing Procedures With Total Mesorectal Excision for Anorectal Adenocarcinoma

BACKGROUND: The study aims to assess the functional outcome of anal sphincter sparing procedures (SSP) with TME for anorectal adenocarcinoma. METHODS: In a multicentric, prospective, single-group study in the period between December 2012 and November 2017, 93 patients presented with anorectal adenocarcinoma were included in the study. Sixty-nine patients underwent SSP with TME. SSP included the combined approach of transabdominal TME with intersphincteric resection (ISR) or transanal transabdominal TME (TATA). Using the Per Anal Examination Scoring System (PASS), postoperative anal function was assessed after one year. RESULTS: Bowel motility time was 50 (±19) hours. The time needed for narcotic analgesia was 54 (±18.8) hours. Mean hospital stay was 15.4 (±10.25) days. Incidence of evident fecal incontinence after ISR is 10.6% (7/67 cases). The Per Anal Examination Scoring System (PASS) findings of 69 cases are as follows: extremely hypotonic 8.6% (6 cases), slightly hypotonic 26.1% (18 cases), normal tone 58% (40 cases), slightly stenotic 3 cases (4.3%), or occluded 2.9% (2 cases). Urinary dysfunction occurred in one case (1.4%). Temporary diversion was performed in 61 patients (87.1%). CONCLUSION: Sphincter preservation with TME for anorectal adenocarcinoma helps avoid permanent stoma and provides a reasonable functional outcome. PASS is a new application for postoperative assessment of anal function.

A New Concept of Interval TRAM for Immediate Breast Reconstruction in Obese Women.

Performing pedicled TRAM in obese women carries risk of flap loss or native breast envelop necrosis. Our technique depends on performing total flap delay at the same setting with mastectomy with flap suture in situ to be followed 1 week later by flap transfer. This study included 24 operable women who were candidates for skin sparing or modified radical mastectomy. In one case, delay was only done and followed by mastectomy and flap transfer. In later experience, delay plus mastectomy was done first and followed later by flap transfer. Operative data and postoperative complications were recorded. The mean BMI was 37 ± 2.75. The mean total operative time was 200 ± 20.37. The mean total hospital stay was 9.1 ± 3.35 days. The mean total volume of blood loss was 380 ± 82.33 ml. Breast envelop necrosis was encountered in four cases; three of them were replaced by the TRAM skin. There was no total flap loss while partial loss was recorded in five cases. Fat necrosis occurred in eight cases. Most of mastectomy bed and abdominal complications were in average. Most of cases showed satisfactory esthetic outcome. Our new concept of "Interval TRAM" enables safe immediate breast reconstruction with pedicled TRAM in obese women and ensures presence of a skin pack up for the native breast envelop skin. We recommend this technique in every obese female who undergoes skin sparing mastectomy with immediate pedicled TRAM flap reconstruction.

Rifampicin for Idiopathic Granulomatous Lobular Mastitis: A Promising Alternative for Treatment.

BACKGROUND: Idiopathic granulomatous lobular mastitis (IGLM) is a chronic, non-caseating, inflammatory breast disease of obscure aetiology characterized by multiple masses, abscesses and sinus formation. There is no standard treatment to date, but surgical procedures and systemic corticosteroids are effective in its treatment despite high recurrence rates. PATIENTS AND METHODS: This prospective study including 30 patients with IGLM between November 2012 and May 2016 aimed to investigate the possibility of administration of Rifampicin (300 mg twice daily for a period of 6-9 months) as an alternative therapy for both surgery and corticosteroids in patients with IGLM. All patients were diagnosed by core needle biopsy. RESULTS: All patients were of reproductive age and had a history of breast feeding, which is the most important predisposing factor for IGLM. The mean age was 31.6 ± 5.8 years (range 23-42 years). Eighteen patients (60%) were treated by Rifampicin for 6 months, whereas 12 patients (40%) were treated for 9 months. Twelve months after the beginning of therapy, all patients showed complete clinical and ultrasonographic responses. No serious side effects were reported to stop the treatment course. The median follow-up after finishing the course of treatment was 15.5 months (average 3-35 months) with no episodes of disease relapse. CONCLUSION: Rifampicin is effective in the treatment of patients with IGLM with complete clinical and ultrasonographic response after 6-9 months and could be used as a solo medical therapy alternative to both surgery and corticosteroids.

Lateral Versus Anterior Approach Laparoscopic Splenectomy: A Randomized-controlled Study.

PURPOSE OF THE STUDY: The study compares prospectively the hospital stay and postoperative complications of anterior (ALS) versus lateral (LLS) approach for laparoscopic splenectomy. MATERIALS AND METHODS: Between September 2011 and April 2015, 94 patients with splenomegaly were referred to the surgical unit in the Oncology Center of Mansoura University, Egypt. Only 80 patients with splenomegaly <30 cm underwent an open-label randomized allocation into 2 equal parallel groups. Indications were hematological in 52 patients (65%) and malignant splenic conditions in 28 patients (35%). Two patients younger than 18 years, 4 patients with splenomegaly >30 cm, and 8 patients with associated surgical comorbidities were excluded. Three days' hospital stay reduction with LLS was suggested with a power of 80% and P-value of 0.05. RESULTS: The mean hospital stay was significantly shorter (P=0.001) after LLS. Laparoscopic splenectomy was completed in 68 patients (85%). Twelve patients (15%) required open splenectomy with no difference between groups. The operation time was significantly shorter in LLS (P=0.013). Blood loss (P=0.057) and blood transfusion (P=0.376) showed no difference between the two groups. The times until resumption of oral intake (P=0.019) and drain removal (P=0.011) were statistically shorter in LLS. CONCLUSIONS: LLS is more safe and feasible with shorter hospital stay compared with ALS.

Genital Sparing Cystectomy for Female Bladder Cancer and its Functional Outcome; a Seven Years' Experience with 24 Cases.

The surgical treatment of bladder cancer is the curative treatment especially in early cases. In this study, our aim was to assess the outcome of preservation of internal genital organs in selected females both oncologically and functionally, and to assess the feasibility of technique and its complication. 24 females with clinically and radiologically diagnosed T2 bladder cancer underwent gynecologic-tract sparing cystectomy (GTSC). Age ranged from 45 to 60 years. Patients with diffuse carcinoma-in-situ, those with tumors involving the bladder neck, those with poor general condition and those with preoperative incontinence were excluded. 1 patient, who developed local recurrence after 6 months. One patient lost follow up after 15 months. No recurrence developed in the retained genital organs. The remaining 20 patients remained free of disease. Among women who were eligible for functional evaluation, Daytime and nighttime continence were satisfactory in 21/22 (95.4 %) and in 20/22 (90.9 %) respectively. Chronic urinary retention, pouch-vaginal fistula was not noted. Most of patients showed superior Sexual Function index. Cystectomy with preservation of the internal genital organs is feasible in female with early, solitary or T2 bladder cancer with satisfactory functional and oncologic outcomes with proper case selection.

Evaluation of the Quilting Technique for Reduction of Postmastectomy Seroma: A Randomized Controlled Study.

Background. Postmastectomy seroma causes patients' discomfort, delays starting the adjuvant therapy, and may increase the possibility of surgical site infection. Objective. To evaluate quilting of the mastectomy flaps with obliteration of the axillary space in reducing postmastectomy seroma. Methods. A randomized controlled study was carried out among 120 females who were candidates for mastectomy and axillary clearance. The intervention group (N = 60) with quilting and the control group without quilting. All patients were followed up routinely for immediate and late complications. Results. There were no significant differences between the two groups as regards the demographic characteristics, postoperative pathological finding, and the immediate postoperative complications. The incidence of seroma was significantly lower in the intervention group compared with the control group (20% versus 78.3%, P < 0.001). Additionally, the intervention group had a shorter duration till seroma resolution (9 days versus 11 days, P < 0.001) and a smaller volume of drainage (710 mL versus 1160 mL, P < 0.001) compared with the control group. Conclusion. The use of mastectomy with quilting of flaps and obliteration of the axillary space is an efficient method to significantly reduce the postoperative seroma in addition to significantly reducing the duration and volume of wound drainage. Therefore we recommend quilting of flaps as a routine step at the end of any mastectomy.

Surgical management of adenocarcinoma of the pancreatic uncinate process in a cancer hospital in egypt.

INTRODUCTION: Pancreatic carcinoma affecting the uncinate process is a challenging surgical condition. Several considerations affect the management plan, including the need for vascular resection and the ability to achieve a clear margin. METHODS: The data of 19 patients who had curative resection for pancreatic adenocarcinoma of the uncinate process were reviewed. Operative mortality and morbidity, and disease-free survival (DFS) were calculated. RESULTS: The study population included 13 male and 6 female patients with a mean age of 55 years. Nine patients (47.4%) had stage I disease, seven patients (36.8%) had stage II disease, and three patients (15.8%) had stage III disease. A total of 12 patients had Whipple procedure and 7 patients had total pancreatectomy. In total, there were 9 R0 and 10 R1 resections. Operative mortality rate was 10.5% (2/19), postoperative leakage rate was 21.1% (4/19), and wound sepsis rate was 21.1%. Median DFS was 19.2 months. Survival was superior in the Whipple procedure group than in the total pancreatectomy group (median survival 19 months vs 4 months, respectively). Vascular resection and retroperitoneal safety margin status did not affect disease relapse. CONCLUSION: Non-metastatic pancreatic adenocarcinoma of the uncinate process should be offered R0 or R1 resection whenever technically feasible.