Strategic Partnerships in Pharmacovigilance: Business, Legal, and Regulatory Domains.

Pharmaceutical development is a highly regulated industry through numerous worldwide guidance, laws, and regulations. Issues related to the safety of pharmaceutical products have been the most common cause of withdrawals from the market, as well as restrictions on distribution and limitations on labeling. Collaboration (hereafter referred to as partnership) between pharmaceutical companies in drug development has been recognized as critically significant to maximize the efficiency of drug development. In general, pharmaceutical companies might benefit from partnering in conducting pharmacovigilance (PV) activities, resulting in enhanced safety monitoring, improved clinical outcomes, and support of optimal benefit-risk assessment. However, some challenges exist. Differences between partners in strategy, culture, and processes can impact the harmonization of safety practices and decision-making processes, necessitating open communications and consensus-building to effectively address safety concerns. Both successful and unsuccessful partnership attempts within the pharmaceutical industry provide valuable business cases and lessons for the future. This paper sheds light on some of the critical aspects of PV in partnerships within the pharmaceutical industry. It addresses issues of the benefits and risks of partnerships, regulatory/legal expectations, and best practices for safety teams' integration.

Uterine vascular abnormalities linked to pregnancy complications: color and power Doppler-assisted transvaginal ultrasound evaluation.

Aim: Abnormal uterine vascular pattern can be observed during transvaginal ultrasound examination used for investigating post-abortion bleeding and secondary postpartum hemorrhage. The purpose of this series of cases was to evaluate almost all the rare causes of uterine vascular abnormalities linked to pregnancy complications, and determine how to arrive at the diagnosis to optimize patient management, which is crucial for preventing life-threatening massive vaginal bleeding. Material and methods: Retrospective observational case series study including 20 women with postpartum or post-abortion vaginal bleeding who were found to have an abnormal uterine vascular pattern during a transvaginal color duplex assessment. Results: The study yielded the following findings: 10 cases of enhanced myometrial vascularity, two cases of pseudoaneurysm in the uterine artery, one case of myometrial venous varix, one case of large uterine venous pseudoaneurysm, one case of uterine arteriovenous malformation, one case of retained placental polyp, one case of invasive vesicular mole, and three cases of subinvolution of the placental implantation site. Conclusions: Transvaginal color duplex ultrasound plays a crucial role in detecting uterine vascular abnormalities as a cause of post-abortion or secondary postpartum hemorrhage and can help differentiate the pathologies responsible for the abnormal vascular pattern, which is highly recommended to optimize patient management.

Rare occurrence of ovarian choriocarcinoma: ultrasound evaluation.

Choriocarcinoma of the ovary is a rare, highly malignant tumor showing malignant trophoblastic cells and produces human chorionic gonadotropins. It can be classified as gestational and non-gestational choriocarcinoma. Non-gestational choriocarcinoma is extremely rare. Treatment is Methotrexate-based chemotherapy for the gestational type. This case study is a rare case of ovarian choriocarcinoma managed by surgical resection, followed by methotrexate-based chemotherapy, and aimed to evaluate the ultrasound characteristics of ovarian choriocarcinoma and how to arrive at the diagnosis. In cases with an elevated serum beta-human chorionic gonadotropin (beta hCG), the finding of a highly vascularized adnexal mass on ultrasound evaluation should be underlined as a clue for suspecting choriocarcinoma, particularly if the female was young with no marriage history or history of sexual intercourse and also to be highly considered in married females with history of repeated abortions, molar pregnancy or uterine choriocarcinoma.

A Review of the Cardiovascular Safety of Prucalopride in Patients With Chronic Idiopathic Constipation.

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.

The ultrasound of subcutaneous extrapelvic endometriosis.

Background: The presence of ectopic functional endometrial glands and struma anywhere except in the lining of the uterine cavity is considered as endometriosis. Extrapelvic endometriosis involving the abdominal wall cesarean section scar is uncommonly seen, and it rarely involves the perineum, umbilicus, pleura, kidneys, lungs and liver. Objectives: The purpose of the present study is to highlight rare ectopic sites, explain the pathogenesis of extrapelvic endometriosis, and evaluate the diagnostic significance of clinical findings, serum CA 125 level, and ultrasonography. Materials and methods: 24 female patients with extrapelvic endometriomas in whom the final diagnosis was based on the surgical results and histopathological reports of the excised specimens. The patients underwent a clinical examination, an ultrasound scan, and evaluation of the serum CA 125 level. They were also examined by transvaginal ultrasound to rule out ovarian endometriosis or uterine adenomyosis. They were further subjected to abdominal wall ultrasound in cases of cesarean section scar or umbilical region swellings, and transperineal ultrasound for perianal lesions. Transvaginal ultrasound was performed in patients with perineal endometrioma to assess the relation between the lesion and the external anal sphincter. Results: In 19 patients, abdominal wall cesarean section scar endometrioma was detected. Three patients had perianal endometriomas, and two patients - umbilical endometriomas. Conclusion: Ultrasound scanning was a useful diagnostic tool to evaluate extrapelvic endometriosis and its extension, especially in cases without typical clinical features that can be suggestive of endometrioma, low diagnostic sensitivity of serum CA 125, and low incidence of concomitant intrapelvic disease.

Dosimetric Limitations in Treating Breast Cancer with Accelerated Partial Breast Irradiation Using Strut Adjusted Volume Implant (SAVI).

We present one case of accelerated partial breast irradiation (APBI) using strut adjusted volume implant (SAVI) where there were limitations in delivering the dose as per the standard guidelines. The device was placed close to both the chest wall and the skin with little tissue surrounding the tip. Two plans were made in an attempt to achieve the standard therapeutic doses without over-treating the chest wall or the skin. Similar cases reported in the literature were reviewed. The dosimetry of the two plans was compared to the cases discussed in the literature.

Phase I study of imalumab (BAX69), a fully human recombinant antioxidized macrophage migration inhibitory factor antibody in advanced solid tumours.

AIM: Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation. METHODS: In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent. RESULTS: Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). CONCLUSIONS: Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.

To Evaluate and Explain the Occurrence of Recurrent Ectopic Pregnancy after Ipsilateral Salpingectomy, Using the Ultrasound.

The current case report evaluated a female patient with a history of right salpingectomy subsequent to right tubal ectopic pregnancy that was presented with amenorrhea followed by vaginal bleeding and lower abdominal severe pain. The transvaginal ultrasound examination revealed the presence of ipsilateral right interstitial ectopic pregnancy. The patient was subjected to cornual wedge resection and uterine repair. The pathology report of the excised specimen revealed decidua, chorionic villi, and blood. Recurrent interstitial ectopic pregnancy after previous ipsilateral tubal ectopic pregnancy managed with salpingectomy is very rare, with only a few cases described in the literature. The current study was to evaluate and explain the occurrence of recurrent ectopic pregnancy after ipsilateral salpingectomy using the ultrasound.

Intrauterine arterial pseudoaneurysm, a rare cause of per vaginal bleeding.

The current study evaluated two cases of pervaginal bleeding subsequent of intrauterine arterial pseudoaneurysm. Each case was complaining of intermittent attacks of heavy vaginal bleeding: one case with history of cesarean section and the other case after uterine curettage. Intrauterine arterial pseudoaneurysm can be caused by a traumatic injury to the vessel wall with subsequent formation of periarterial hematoma that liquefies forming periarterial bloody cyst, which communicates through the narrow neck with the arterial lumen. Transvaginal ultrasound aided with color duplex capability is an accurate tool for assessment.

Uncommon obstetric and gynecologic emergencies associated with pregnancy: ultrasound diagnosis.

INTRODUCTION: Many uncommon obstetric and gynecologic problems associated with pregnancy and the early postpartum period can lead to severe abdominal pain and be life-threatening. The patient will be in urgent need of a quick and accurate decision. The means of management will depend on the ability to differentiate between these problems to achieve an optimal diagnosis. MATERIALS AND METHODS: 30 pregnant females attended a private obstetric ultrasound clinic with clinical picture of acute abdomen with pregnancy. All were subjected to an ultrasound exam, the results were recorded, and the final diagnosis was reached based on the postoperative results. RESULTS: Patients were classified according to their duration of pregnancy into cases with acute abdomen that occurred during the first trimester, during the second trimester, during the third trimester, and in the early postpartum period. CONCLUSION: Ultrasonography is a valuable tool for detecting the etiology and guiding the management in cases of emergency situations faced by the obstetrician and gynecologist during pregnancy and the early postpartum period.

Hypofractionation Radiotherapy vs. Conventional Fractionation for Breast Cancer: A Comparative Review of Toxicity.

The use of postoperative radiation therapy after breast-conserving surgery was longstanding standard practice. The treatment protocol used a standard fractionation of 50 Gy in 25 fractions plus a boost. Recently, the hypofractionation approach has gained support based on Canadian and English studies that claimed equal tumor control and similar toxicity to the standard protocol. We conducted a review of the literature of hypofractionation studies and compared the reported toxicity with the general literature. We placed special emphasis on breast fibrosis after hypofractionation versus standard fractionation. We found a striking difference in the breast toxicity reported by the hypofractionation literature regarding breast fibrosis as compared to standard fractionation. Breast fibrosis should be explored further via additional studies and discussed with potential breast-conserving surgery patients.

Use of Ultrasonography in Clarifying the Etiology of Anal Pain.

INTRODUCTION: Anal pain is defined as pain originating from the anal canal or the perianal area that can be attributed to a variety of medical problems. The current study's aim was to evaluate the role of combined endoanal, transperineal, and in married women, transvaginal ultrasound in clarifying the etiology of anal pain among our patient study group. METHODOLOGY: A total of 180 patients presented to our radiology department complaining of anal pain and were examined using transperineal, endoanal, and in women, transvaginal ultrasound aided with three-dimensional capability. The final diagnosis was reached, according to the surgical results and the histopathology reports in cases diagnosed with anorectal neoplasms and perianal masses. RESULTS: A total of 100 patients were diagnosed with perianal fistulas. Twenty-five cases presented with anal abscesses. In four cases, pilonidal sinus extended to the perianal spaces. Three cases had hiradenitis suppurativa, 13 cases showed occult anal sphincter defects, two cases had anorectal neoplasms, and one case was diagnosed with soft tissue ependymoma overlying the coccyx. Three cases were diagnosed with perianal soft tissue masses. One case was detected with recto vaginal fistulas, 10 cases showed thick internal anal sphincter, two cases had perianal cysts, and one case had perianal hematoma. Two cases showed hemorrhage in Douglas' pouch, and one case had pelvic collection sequelae of perforated pelvic appendicitis. Three cases had pelvic endometriosis; one case was detected with missed contraceptive device in the rectum. Three cases were diagnosed with prostatitis and two cases with prostatic abscesses. Two cases had prostatic carcinoma and one case had prostatic sarcoma. CONCLUSION: The combined approaches of endoanal, transperineal, and in women, transvaginal ultrasound aided with three-dimensional capability proved highly valuable in clarifying the etiology of anal pain in our study group.

Endosonography of benign myometrium cysts and cyst-like lesions.

INTRODUCTION: Many pathological causes are responsible for the sonographic presentation of myometrium cysts and cyst-like lesions, where the distinction between these etiologies is required. THE AIM OF THE WORK: The current work is aimed at discerning between different etiologies of myometrium cysts and cyst-like lesions for an optimum management. METHODOLOGY: In the course of daily practice of gynecological transvaginal ultrasound, 66 cases of myometrium cysts and cyst-like lesions have been discerned, where all were examined with endovaginal ultrasound using a multifrequency endocavitary probe having color Doppler capability. RESULTS: Adenomyosis uteri detected in 15 cases, invasive mole in 4 cases, congested arcuate veins in 20 cases, incidental cysts in 4 cases, cystic degeneration of myoma in 3 cases, C-section scar cysts and cyst-like lesions in 13 cases, interstitial ectopic pregnancy in 2 cases, incomplete abortion with congested myometrium vessels in 4 cases, and arteriovenous malformation in 1 case. The number of cases with cervical nabothian cysts was not considered since they were too frequent. CONCLUSION: Endosonography is an important tool in differentiating between the various diseases that are responsible for benign myometrium cysts and cyst-like lesions, which are all important since some of them are visualized as serious clinical situations and others turn out to be of little clinical significance.

The value of superficial parts and endoanal ultrasonography in evaluating pilonidal disease and exclusion of perianal sepsis.

INTRODUCTION: Pilonidal disease is a benign anorectal inflammatory disease that involves the subcutaneous adipose tissue overlying the sacrococcygeal region. THE AIM OF THE WORK: The current study aimed to assess the value of preoperative evaluation of pilonidal disease and the exclusion of perianal sepsis using superficial parts ultrasonography and endoanal ultrasound. METHODOLOGY: Referred 30 patients were clinically diagnosed as pilonidal disease, all were examined with superficial parts ultrasonography and if the disease was extending to the perianal region further endoanal US was performed to exclude perianal sepsis. RESULTS: 7 patients showed subcutaneous abscesses and 23 patients showed pilonidal sinus tracts. Among patients with pilonidal sinus tracts, six tracts (26 %) seen as superficially situated, short narrow tracts with straight course, no side branches and with a blind end situated away from the anal canal wall. 2 (9 %) tracts showed vertical orientation and three tracts (13 %) were wide and deeply situated reaching the presacral fascia. 7 cases (30 %) showed branching pilonidal sinus tracts, two cases of them showed more than one external opening. 5 patients (22 %) showed abnormally long tracts seen reaching the perianal region. CONCLUSION: Ultrasonography is an available, inexpensive, safe imaging modality that yields a high degree of accuracy in evaluating pilonidal disease and in exclusion of perianal sepsis.

Stereotactic body radiotherapy as an alternative to brachytherapy in gynecologic cancer.

INTRODUCTION: Brachytherapy plays a key role in the treatment of many gynecologic cancers. However, some patients are unable to tolerate brachytherapy for medical or other reasons. For these patients, stereotactic body radiotherapy (SBRT) offers an alternative form of treatment. METHODS: Retrospective review of patients prospectively collected on SBRT database is conducted. A total of 11 gynecologic patients who could not have brachytherapy received SBRT for treatment of their malignancies. Five patients have been candidates for interstitial brachytherapy, and six have required tandem and ovoid brachytherapy. Median SBRT dose was 25 Gy in five fractions. RESULTS: At last followup, eight patients were alive, and three patients had died of progressive disease. One patient had a local recurrence. Median followup for surviving patients was 420 days (median followup for all patients was 120 days). Two patients had acute toxicity (G2 dysuria and G2 GI), and one patient had late toxicity (G3 GI, rectal bleeding requiring cauterization). CONCLUSIONS: Our data show acceptable toxicity and outcome for gynecologic patients treated with SBRT who were unable to receive a brachytherapy boost. This treatment modality should be further evaluated in a phase II study.

Orthopaedic surgeons frequently underestimate the cost of orthopaedic implants.

BACKGROUND: A poor understanding of cost among healthcare providers may contribute to high healthcare expenditures. Currently, it is unclear whether and how much surgeons know about the costs of implantable medical devices (IMDs). QUESTIONS/PURPOSES: We (1) determined the level of comfort with orthopaedic IMD costs among orthopaedic residents and attending surgeons, (2) quantified how accurately surgeons understand the costs of orthopaedic IMDs, and (3) identified which constructs yield the most accurate cost estimations among residents and attending surgeons. METHODS: A questionnaire was presented to 60 residents and 37 attending orthopaedic surgeons from two large academic medical centers. Respondents estimated the cost of 13 commonly used orthopaedic devices. Fifty-one surgeons participated (36 residents, 15 attending surgeons), for an overall response rate of 53%. Cost estimates were compared against the actual material costs, and we recorded the percentage error for each estimate. RESULTS: More than ½ of the respondents rated their knowledge of IMD cost as poor. The mean percentage error in estimation for all respondents was 69% (range, 29%-289%). Overall, 67% of responses were underestimations and 33% were overestimations. Residents demonstrated a mean percentage error of 73% (range, 29%-289%) while attending surgeons had a mean percentage error of 59% (range, 49%-79%). Residents and attending surgeons demonstrated differences in accuracy within groups and between groups based on the IMD being estimated. CONCLUSIONS: We found the knowledge of orthopaedic IMD costs among the orthopaedic residents and attending surgeons surveyed was poor. Further investigation of how physicians conceptualize material costs will be important to healthcare cost control.

The anterolateral approach for the transcranial resection of pituitary adenomas: technical note.

We sought to quantify the mean surface area of the exposed diaphragma sellae and the mean sellar volume in the subfrontal and anterolateral approaches to pituitary adenomas and to detail our expansion of the superficial and deep window in the anterolateral approach. We performed a retrospective data analysis and cadaveric study in a clinical and skull base laboratory. We studied eight patients who had anterolateral approach for transcranial resection of pituitary macroadenoma and seven cadaveric specimens. Main outcome measures were degree of tumor resection, cerebrospinal fluid (CSF) leak, cranial nerve outcome, and quantification of the exposed sella via the anterior (subfrontal) and anterolateral approach. We observed complete resection in one; visual outcome: stable in three, improved in four, worsened in one; CSF leakage in two; transient CN III palsy in three; mean surface area (mm(2)) of exposed diaphragma sellae,115.3 (subfrontal approach) versus 94.7 (anterolateral approach; p = 0.1); mean sellar volume (mm(3)) exposed, 224.8 (subfrontal approach) versus 569.3 (anterolateral approach; p < 0.0001). Our technical note supports the increased exposure of sellar volume via the anterolateral approach. Despite the relatively high complication rate, complex cranial surgeons should maintain the skills and knowledge of transcranial approaches. Indeed, the rapid expansion of transsphenoidal techniques will continue to decrease the number of cases but will also continue to increase the complexity of those adenomas that are referred for transcranial resection.

Ecological studies on Al-Khadoud Spring, Al-Hassa, Saudi Arabia.

Al-Khadoud spring is one of the most important water resources in Al-Hassa Governorate, Saudi Arabia. However, much of its biotic information is still unknown. This study presented preliminary ecological information of this aquatic body. Regarding to macrophytes, a total of eight species were observed along the study sites. These species include two submerged aquatic plants (Potamogeton pectinatus L. and Ceratophyllum demersum L.). The common distributed species are Phragmites australis (Cav.) Trimex Steud and Cyperus rotundus (L.). On the other hand, a total of 20 algal genera were recorded with 7 genera of Chlorophyceae, 8 of Bacillariophyceae, 4 of Cyanophyceae and one of Euglenophyceae. The common phytoplankton occurred in all three investigated sites were Chlorella vulgaris, Mougeotia sp., Oscillatoria sp. and Actinastrum sp. Regarding to the biotic fauna, different forms of unicellular zooplankton such as Paramecium and Amoeba were recorded. Invertebrates such as freshwater insects and some freshwater snails were documented in the study sites including Melanodies tuberculata, Melanopsis praemorsa and Lymnaea auricularia. As regard to vertebrates, one species of fish, Aphanius dispar, dominate the spring basin and its extended channels.

The carotid-oculomotor window in exposure of upper basilar artery aneurysms: a cadaveric morphometric study.

OBJECTIVE: The carotid-oculomotor window remains the traditional deep window in the exposure of aneurysms of the upper basilar artery. Although several techniques have been described to expand this window, few morphometric studies document either the degree of its expansion or its contribution to the exposure of the basilar artery. We review the microsurgical anatomy of the carotid-oculomotor window, describe expansion techniques, and analyze morphometrically the contribution of each step (i.e., extradural anterior clinoidectomy, mobilization of the internal carotid artery [ICA], and posterior clinoidectomy) to the expansion of the window and/or exposure of the artery. METHODS: Ten formalin-fixed, alcohol-preserved, cadaver heads injected with pigmented silicone were prepared for bilateral dissection. The vertebrobasilar system was injected with pigmented silicone mixed with barium (1:1), rendering it radiopaque. After completing a frontotemporal-orbitozygomatic craniotomy, we performed dissection in two stages: Stage I consisted of a conventional transsylvian exposure of the upper basilar artery through the carotid-oculomotor window; and Stage II added anterior clinoidectomy, ICA mobilization, and posterior clinoidectomy. A clip was applied to the lowest accessible point of the basilar trunk at each stage. Measurements obtained during each stage included: 1). the transverse carotid-oculomotor distance, that is, anteriorly between the oculomotor foramen and ICA, and posteriorly between the oculomotor nerve and ICA; and 2). the exposed length of the basilar artery, as seen under the microscope and on angiograms. RESULTS: Measurements were obtained before and after the addition of anterior clinoidectomy, mobilization of the ICA, and posterior clinoidectomy. Increases in expansion of the window and exposure of the upper basilar artery were documented as percentages of the control values. The anterior carotid-oculomotor distance averaged 7.1 mm (range, 5-10 mm) and 10.1 mm (range, 7-15 mm) before and after the additional surgical steps to expand the window, respectively. The posterior carotid-oculomotor distance averaged 12.7 mm (range, 9-18 mm) and 16.1 mm (range, 11-22 mm) before and after the additional surgical steps to expand the window, respectively. The exposed length of the basilar artery from the bifurcation to the clip was 4.2 mm (range, 1-13 mm) before expansion and 7 mm (range, 3-15 mm) after expansion. CONCLUSION: Anterior clinoidectomy and ICA mobilization increased the carotid-oculomotor space 44% anteriorly and 28% posteriorly. Posterior clinoidectomy increased the exposed length of the basilar artery by 69%. Superficial wide field exposure, expansion of the carotid-oculomotor window, and increased exposure of the upper basilar artery facilitate both visualization of the aneurysm for clip application and the use of proximal vascular control as an adjunct to basilar aneurysm surgery.