Marking 2-Years of New Thinking in Clinical Trials: The Estimand Journey.

The ICH E9(R1) addendum on Estimands and Sensitivity Analyses in Clinical Trials has introduced a new estimand framework for the design, conduct, analysis, and interpretation of clinical trials. We share Pharmaceutical Industry experiences of implementing the estimand framework in the first two years since the final guidance became available with key lessons learned and highlight what else needs to be done to continue the journey in embedding the estimand framework in clinical trials. Emerging best practices and points to consider on strategies for implementing a new estimand thinking process are provided. Whilst much of the focus of implementing ICH E9(R1) to date has been on defining estimands, we highlight some of the important aspects relating to the choice of statistical analysis methods and sensitivity analyses to ensure estimands can be estimated robustly with minimal bias. In particular, we discuss the implications if complete follow-up is not possible when the treatment policy strategy is being used to handle intercurrent events. ICH E9(R1) was introduced just before the start of the COVID-19 pandemic, but a positive outcome from the pandemic has been an acceleration in the adoption of the estimand framework, including differentiating intercurrent events related or not related to the pandemic. In summary, much has been learned on the estimand journey and continued sharing of case studies will help to further advance the understanding and increase awareness across all clinical researchers of the estimand framework.

Phase I trial of pimasertib monotherapy in Japanese patients with solid tumors and those with hepatocellular carcinoma.

PURPOSE: This study aimed to confirm the recommended phase II dose (RP2D) of pimasertib in Japanese patients. METHODS: This two-part, phase I dose-escalation and expansion study was conducted in Japanese patients (≥ 18 years old) with advanced solid tumors (ST) including hepatocellular carcinoma (HCC). In Part 1, patients with ST (Arm A) and HCC (Arm B) received escalating doses (3 + 3 design) of oral pimasertib [starting at 45 mg twice daily (BID)] in 21-day cycles, until disease progression or unacceptable toxicity. Dose levels could be escalated/de-escalated depending on tolerance. The primary outcome was the number of patients who experienced ≥ 1 dose-limiting toxicity (DLT). Safety and efficacy were also studied. Part 2 aimed to confirm observations in Part 1. RESULTS: In total, 26 patients (ST, n = 19; HCC, n = 7) were treated with pimasertib in Part 1: 30 mg (ST, n = 4; HCC, n = 5), 45 mg (ST, n = 9; HCC, n = 2), and 60 mg (ST, n = 6). Four patients reported DLTs [ST: hypokalemia (60 mg), and both stomatitis and muscle weakness (60 mg); HCC: retinal detachment (30 mg) and diarrhea (45 mg)]. All patients had ≥ 1 treatment-related adverse event. Partial response (n = 3) and stable disease (n = 1) were seen in patients with ST (pimasertib 45 mg). CONCLUSION: A maximum tolerated dose of pimasertib 45 mg BID was established in Japanese patients with ST, but not established in patients with HCC. The global RP2D of 60 mg BID was not confirmed in Japanese patients. Pimasertib monotherapy in unselected patients with ST may not warrant further investigation; Part 2 was not conducted.

[Transretinal Biopsy of Intraocular Lymphoma]. / Transretinale Biopsie beim intraokularen Lymphom.

BACKGROUND: Intraocular lymphoma is in most cases a diagnostic challenge. Gold standard is a diagnostic vitrectomy. Vitreous biopsy and transretinal biopsies are therefore employed. METHODS: A retrospective analysis was undertaken of all cases of cytological or histological proven intraocular lymphoma between 2002 and the beginning of 2015 in our clinic. RESULTS: The diagnosis of intraocular lymphoma could be established in 16 cases by cytological or histological analysis. Six patients had previously been treated with steroids in the assumption of uveitis. Five of 16 patients had a systemic or CNS lymphoma in their history. The diagnosis of intraocular lymphoma could be made on the basis of a vitreous biopsy in only in 3 cases. In 7 cases an additional vitrectomy with transretinal biopsy was needed. In 1 case a transretinal biopsy was performed initially and in 1 case a re-transretinal biopsy was needed to establish the diagnosis. Two patients underwent iris biopsy to diagnose a secondary metastatic intraocular lymphoma. One amaurotic eye was diagnosed with intraocular lymphoma after enucleation. DISCUSSION: Due to the high relevance for the diagnosis intraocular lymphoma, when a vitreous biopsy was non-informative, a transretinal biopsy should always be considered in cases of retinal or subretinal involvement.

[Intraocular medulloepithelioma - series of 10 cases and review of the literature]. / Intraokulare Medulloepitheliome - klinische Serie mit 10 Fällen.

Intraocular medulloepithelioma is an extremely rare unilateral intraocular tumor arising from the nonpigmented ciliary epithelium. Medulloepitheliomas may be classified as benign and malignant and as teratoid and nonteratoid tumors. As a rule a long latency period occurs after first symptoms until the final diagnosis of a medulloepithelioma is made. Differential diagnosis includes in particular unilateral retinoblastoma. Intraocular medulloepithelioma may occur as masquerade-syndrome simulating uveitis. We present 10 patients with intraocular medulloepithelioma. In 7 of these patients the eye had to be enucleated. Metastasis did not occur, but epiretinal tumor seeding did occur in one patient. In one of the 3 not enucleated eyes, ruthenium-106 brachytherapy could salvage the tumor containing eye.

Driver reaction time before and after treatment for lumbar radiculopathy.

STUDY DESIGN: Prospective observational pilot study. OBJECTIVE.: To investigate the effect of right and left radiculopathy on driver reaction time (DRT), and the effect of selective nerve root block (SNRB) on DRT. SUMMARY OF BACKGROUND DATA: The effect of many orthopedic procedures on DRT has already been assessed. To date the effect of radiculopathy and SNRB on DRT has not been studied. METHODS: DRTs of 20 radiculopathic patients (10 right, 10 left) were measured using a custom-built car simulator. Each patient was tested pre-SNRB, immediately post-SNRB, and 2 and 6 weeks post-SNRB. As controls 20 age- and sex-matched normal subjects were tested once. Full departmental, institutional, and ethical committee approval were obtained. RESULTS: Mean DRT of the control group was 452 milliseconds. Mean DRT of patients with right or left radiculopathy pre-SNRB was 521 milliseconds (P < 0.045) and 535 milliseconds (P < 0.018), respectively. In the right radiculopathic group, the measurements immediately post-SNRB, 2 weeks, and 6 weeks were 656 milliseconds (P < 0.005), 589 milliseconds (P < 0.019), and 564 milliseconds (P < 0.10), respectively. The delay immediately and at 2 weeks post-SNRB translates into an increase in stopping distance of 3.8 and 1.9 m, respectively at the speed of 100 km/h. In the left radiculopathic group, the measurements immediately post-SNRB, 2 weeks, and 6 weeks were 585 milliseconds (P < 0.037), 534 milliseconds, and 530 milliseconds, respectively. The delay immediately post-SNRB translates into an increase in stopping distance of 1.4 m at the speed of 100 km/h. CONCLUSION: The study identified significant DRTs' changes both in radiculopathy and after SNRB. Right and left radiculopathic patients should be advised about the possible changes in their DRTs post-SNRB. Future research with regard to the suitability for radiculopathic patients to drive and the best time to resume driving post-SNRB is needed.

Ruthenium-106 plaque brachytherapy for symptomatic vasoproliferative tumours of the retina.

AIM: To investigate the safety and efficacy of beta ray brachytherapy in treatment of vasoproliferative tumours of the retina (VTR). METHODS: 35 consecutive patients with symptomatic VTR were treated with a ruthenium-106 ((106)Ru) plaque. Three tumours had been treated previously (two with cryotherapy; one with transpupillary thermotherapy). 32 VTR (91.4%) were located in the lower half of the retina and all of them were found between the mid-periphery and the ora serrata. The mean tumour thickness was 2.8 mm. An exudative retinal detachment was present in 25 eyes (71.4%) and in 15 cases (42.9%) hard exudates were found in the macula. The major symptom was loss of vision (77.1%). RESULTS: Brachytherapy was well tolerated by every patient. The mean applied dose was 416 Gy at the sclera and 108 Gy at the tumour apex. In all but four eyes (88.6%), it was possible to control the VTR activity. The median follow up time was 24 months. Three of the above mentioned four eyes with treatment failure had had secondary glaucoma before therapy. There was no case of radiation induced neuropathy or retinopathy. Cataract surgery was necessary for five patients. The development of epiretinal gliosis was the most common event during follow up (n = 10, 28.6%). The mean visual acuity decreased slightly (0.33 before and 0.29 after brachytherapy). Multivariate analysis showed that the presence of macular pathology before treatment was associated with a 6.1-fold risk of vision of 0.25 or better (p = 0.03). CONCLUSIONS: beta ray brachytherapy with (1106)Ru plaques was able to control the activity of VTR and retain vision. Cases with secondary glaucoma before treatment had a very poor prognosis.

Whole-body fluorine-18 fluordeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in staging of advanced uveal melanoma.

Fluorine-18 fluordeoxyglucose positron emission tomography (FDG-PET) is an useful tool in diagnosing and monitoring of malignant cutaneous melanoma. However, the feasibility and usefulness of FDG-PET in uveal melanoma is not yet established. We present a patient with suspected advanced uveal melanoma who underwent combined FDG-PET/computed tomography (CT) for staging. FDG-PET/CT images demonstrated vital intraocular tumor. Anatomical assignment of the malignancy to the choroid was possible by means of the coregistered computed tomography. Furthermore, PET revealed an unknown otherwise undetected vital liver metastasis. We conclude that combined FDG-PET/CT has potential to further improve staging and therapy planning in patients with advanced uveal melanoma.

High resolution magnetic resonance imaging of retinoblastoma.

BACKGROUND/AIMS: Diagnosis of retinoblastoma is mainly based on indirect ophthalmoscopy, but additional imaging techniques are indispensable for the staging of the disease. A new high resolution magnetic resonance imaging (MRI) technique for the examination of the eye was evaluated. A new surface coil with a diameter of 5 cm allows a field of view of 60 mm with an in-plane resolution of 0.8 mm. We compared preoperative MRI scans with the histology after enucleation in 21 cases of retinoblastoma. Parameters studied were appearance of retinoblastoma, choroidal and scleral infiltration, extraocular extension, optic nerve infiltration, and vitreous seeding. RESULTS: All retinoblastomas could be visualised as hypointense to vitreous on T2 weighted images and slightly hyperintense to vitreous on plain T1 weighted images with a moderate enhancement after contrast application. Histology revealed seven cases with infiltration of the optic disc or optic nerve. Preoperative MRI scans depict juxtapapillary tumour masses, but it was impossible to differentiate between a juxtapapillary retinoblastoma, a prelaminar infiltration of the optic disc, or a just postlaminar optic nerve infiltration. In five of 14 cases with a proved tumour infiltration of the choroid, MRI scans showed an inhomogeneous contrast enhancement of the choroid in enhanced T1 weighted sequences beneath the retinoblastoma. Whether this sign is specific for a choroidal infiltration or is just an artefact remains unclear. High resolution MRI scans did not allow the exclusion of this form of intraocular tumour extension. All nine cases with proved vitreous seeding were not detected by MRI scans. None of these cases showed scleral infiltration or orbital tumour extension. Therefore, it is not possible to judge the rank of this technique in detecting orbital tumour growth. CONCLUSION: The new MRI technique is of limited value in visualisation of prelaminar or postlaminar infiltration of the optic nerve. Advanced choroidal infiltration might be visualised by contrast enhanced T1 weighted MRI scans, but the available spatial resolution did not allow the exclusion this critical form of tumour growth by MRI scans. Nevertheless, high resolution MRI with the new surface coil has superior contrast and spatial resolution compared to computed tomograph (CT) or other available imaging techniques. MRI cannot replace CT in detecting tumour calcification but with increasing experience with this new technique it should be possible to renounce CT scans in the majority of cases of retinoblastoma.

Thermochemotherapy in hereditary retinoblastoma.

BACKGROUND/AIM: The combination of chemotherapy and transpupillary thermotherapy, thermochemotherapy (TCT) has become an established part of the treatment plan in advanced retinoblastoma. The aim of this study was to identify safe indications, the complications as well as the limitations of this new treatment for retinoblastoma. METHODS: Tumour response and side effects of TCT with an indirect laser ophthalmoscope (spot size about 400 micro m) in 55 tumours of 26 children with bilateral retinoblastoma were analysed. Using the Reese-Ellsworth classification system, nine of 35 eyes were classified as type I, 13 eyes as type II, 10 eyes as type III, and three eyes as type V. The mean age of the children was 0.74 (SD 0.61) years. The mean tumour height was 3.5 (2.3) mm with a mean diameter of 6.1 (4.1) mm. Treatment parameters were 4.3 (1.6) (median 5) thermochemotherapy sessions with a mean energy of 539 (211) mW and a mean duration of 13.5 (5.6) minutes. Chemotherapy courses (vincristine, etoposide, and carboplatin) were repeated every 3 weeks. The mean follow up period was 1.25 (0.6) years. RESULTS: Local recurrence occurred in 21 tumours (38%), with a mean onset of 3.2 (2.9) months after TCT. The risk of tumour recurrence was correlated with tumour height. The recurrence rate was 17% for tumours with a height less than 2 mm, 37% for tumours with a height between 2 and 4 mm, and 63% for larger retinoblastomas. Multivariate analysis identified fish flesh regression after TCT (p = 0.0007) as the most important risk factor for tumour recurrence besides tumour height (p = 0.001) and the necessity of increased laser power during TCT sessions (p = 0.018). Complications during therapy included transient corneal opacification in two eyes (6%), focal iris atrophy (three eyes, 8.5%), peripheral lens opacity (two eyes, 6%), circumscribed transient retinal detachment (one eye, 3%) and diffuse choroidal atrophy (one eye, 3%). CONCLUSION: TCT using an indirect laser ophthalmoscope with a spot size of about 400 micro m was efficient for retinoblastoma with a tumour height less than 4 mm. In larger tumours, the recurrence rate was unacceptably high. Fish flesh regression after TCT correlates with a higher rate of local tumour recurrence. Treatment related complications occurred in less than 9% of the treated eyes.

Pharmacodynamic effects and plasma pharmacokinetics of single doses of cetrorelix acetate in healthy premenopausal women.

OBJECTIVE: To investigate the pharmacodynamic effects and plasma pharmacokinetics of single subcutaneous doses of cetrorelix acetate in healthy premenopausal women. SETTING: Phase I clinical research unit. PATIENT(S): Healthy, premenopausal women aged 19 to 35 years. INTERVENTION(S): Single subcutaneous morning doses of cetrorelix acetate (1, 3, or 5 mg peptide base) were investigated in a randomized, single-blind, placebo-controlled, parallel-group design. After a control cycle, 36 women received cetrorelix acetate (12 per dose) and 12 received placebo on the eighth individual cycle day. Transvaginal ultrasound was performed, and blood samples for LH, FSH, E2 were collected during both cycles and for pharmacokinetics up to 168 hours after dosing. The serum hormone levels were determined by electrochemicoluminescence immunoassay and plasma cetrorelix concentrations by radioimmuno assay. RESULTS: Cetrorelix acetate administration led to a rapid, marked, and reversible suppression of serum LH, E2, and to a lesser extent FSH concentrations. The median intra-individual shifts between treatment and control cycle were -1.0, 4.0, 8.0, and 9.5 days for serum LH maximum and -1.0, 4.5, 7.0, and 10.0 days for ovulation following placebo or 1, 3, and 5 mg cetrorelix acetate, peptide base, respectively. The area under the concentration-time curve (AUC) and peak cetrorelix concentrations in plasma (Cmax) increased proportionally with dose. CONCLUSIONS: Cetrorelix acetate showed pronounced and reversible LH and E2 suppression and a dose-dependent postponement of LH surge and ovulation after single subcutaneous administrations to healthy premenopausal women. Dose proportionality over the range of 1 mg to 5 mg cetrorelix acetate, peptide base was demonstrated.

Differences between men and women in anxiety early after acute myocardial infarction.

BACKGROUND: Anxiety after acute myocardial infarction influences both short- and long-term recovery. Therefore, determining specific subgroups of patients who have relatively higher anxiety levels is important. Published findings about gender differences in anxiety after acute myocardial infarction are conflicting. OBJECTIVES: To determine whether gender differences in anxiety after acute myocardial infarction exist and whether any of the sociodemographic and clinical variables that often differ between men and women with acute myocardial infarction interact with gender to influence anxiety. METHODS: A total of 424 patients with confirmed acute myocardial infarction were enrolled in this multicenter prospective study. Patients' anxiety level was measured within 72 hours of their arrival at the hospital by using the State Anxiety Inventory and the Brief Symptom Inventory. RESULTS: Women had significantly higher anxiety than did men according to both the State Anxiety Inventory (42 +/- 12.9 vs 37.7 +/- 12.5; P = .001) and the Brief Symptom Inventory (0.83 +/- 0.97 vs 0.63 +/- 0.71; P = .02). Of the sociodemographic and clinical variables examined, only marital status and income significantly interacted with gender to influence anxiety. Married women had higher anxiety than did single and widowed women, and married men had lower anxiety than did single men. Women with lower income had higher anxiety than did women with higher income; income was not related to anxiety in men. CONCLUSION: Women report significantly greater anxiety early after acute myocardial infarction than men do. Women's greater anxiety may be partially explained by marital status and lower income at the time of the infarction.

Pituitary and gonadal endocrine effects and pharmacokinetics of the novel luteinizing hormone-releasing hormone antagonist teverelix in healthy men--a first-dose-in-humans study.

UNLABELLED: BACKGROUND. Teverelix is a novel synthetic peptidic luteinizing hormone-releasing hormone (LHRH) antagonist. METHODS: Single subcutaneous morning doses of teverelix acetate (either 0.5, 1, 2, 3, or 5 mg base) were investigated in a randomized, single-blind, placebo-controlled, dose-escalating parallel-group design in healthy men. Six subjects received teverelix, and two subjects received placebo per dose level. Blood samples for lutropin, luteinizing hormone (LH), and follitropin, follicle-stimulating hormone (FSH), and testosterone, as well as for pharmacokinetics, were withdrawn up to 120 hours after dosing. Serum hormone levels were determined by electrochemicoluminescence immunoassays, and plasma teverelix concentrations were determined by radioimmunoassay. RESULTS: Teverelix led to a rapid, marked suppression of LH, testosterone and, to a lesser extent, FSH. Median maximum suppressions compared with predose levels were -93% for LH and -54% for FSH after teverelix 5 mg, and -93% for testosterone after teverelix 3 mg, respectively. After 5 mg teverelix, testosterone suppression <1 ng/mL started a median of 12 hours after dosing and lasted for a median of 33 hours. The duration of testosterone suppression increased with dose. Geometric means of peak teverilix plasma concentrations were 4.5 ng/mL (0.5 mg teverelix) to 49.0 ng/mL (5 mg teverelix) and tmax occurred between 1 and 4 hours after dosing. Geometric means of the area under the teverelix plasma concentration-time course from zero to time of the last quantifiable plasma concentration [AUC(O-tlast)] were 54.9 ng x h/mL (0.5 mg teverelix) to 881.8 ng x h/mL (5 mg teverelix). Median values for apparent terminal half-lives ranged from 24 to 75 hours. The most frequently reported adverse events were short-lasting mild injection-site reactions. CONCLUSIONS: Teverelix showed pronounced LH and testosterone suppressive effects after single subcutaneous doses in healthy men. Duration of hormone suppression increased with dose. Teverelix was well tolerated. This profile indicates potential for further clinical use.

Phacoemulsification following treatment of choroidal melanoma.

BACKGROUND: Little is known about the risks, effects and results of phacoemulsification following treatment with different modalities of choroidal melanoma. METHODS: In a retrospective study, records were evaluated of 72 patients who underwent cataract surgery after treatment of choroidal melanoma (35 were treated with iodine-125 plaques, 27 with ruthenium-106 plaques, eight by tumor excision, and two with proton beam irradiation). The data were analyzed with respect to complications, effects on postoperative tumor care and visual outcome. RESULTS: Phacoemulsification was performed at a mean interval of 21.5 months after primary tumor therapy. An intraocular lens (IOL) was implanted in 93% of the cases. The mean postoperative follow-up time was 16.2 months. Preoperative problems were rubeosis iridis (30.5%), secondary glaucoma (34.7%) and posterior synechiae (41.6%). Intraoperatively, defects of the posterior capsule occurred in 12.5%. Visual acuity equal to or better than preoperative vision was found in 95.8% of the patients as the best postoperative measurement and in 72.2% at the last follow-up measurement. A deterioration of more than two lines in visual acuity was observed in 4.2% as the best postoperative vision and in 27.8% at the last documented examination. Phacoemulsification was not the cause of deterioration in any of the cases. After cataract surgery, tumor retreatment was necessary in 19.4%. Treatment of radiation retinopathy was performed for the first time in 13.8%. Metastases developed in six patients (8.3%). CONCLUSION: Phacoemulsification following treatment for choroidal melanoma is both possible and advisable. The majority of patients have enhanced visual acuity. No decrease of vision occurred as a result of cataract extraction. The postoperative care of intraocular tumors and the treatment of radiation retinopathy is improved by timely cataract surgery.

Choroidal hemangioma: MR findings and differentiation from uveal melanoma.

BACKGROUND AND PURPOSE: The aim of this study was to establish the MR imaging characteristics of choroidal hemangioma and to compare them with those of uveal melanoma. METHODS: Among 41 patients examined at 1.5 T (4-cm surface coil, T1-weighted and fast spin-echo T2-weighted sequences), 25 had uveal melanoma and 16 had circumscribed choroidal hemangioma. After i.v. bolus injection of gadopentetate dimeglumine, dynamic and T1-weighted sequences were acquired. RESULTS: In patients with choroidal hemangioma, uniform signal characteristics were detected on fast T2-weighted images. In 15 of 16 patients with choroidal hemangioma, lesions were isointense with vitreous on fast spin-echo T2-weighted images, whereas lesions in 24 of 25 patients with uveal melanoma were hypointense. Signal characteristics of uveal melanoma and hemangioma did not differ significantly on plain T1-weighted images. Enhancement was earlier and much stronger for circumscribed choroidal hemangioma than for uveal melanoma. After i.v. bolus application of gadopentetate dimeglumine, the increase of signal intensity was higher for circumscribed choroidal hemangioma (signal intensity ratio, 5.8) than for uveal melanoma (signal intensity ratio, 2.2). CONCLUSION: Circumscribed choroidal hemangioma may be difficult to differentiate from melanoma by ophthalmologic examination. Differentiation may not be possible if direct viewing of uveal space-occupying lesions is hampered by opaque vitreous media. The characteristic findings on fast spin-echo T2-weighted MR images and early enhanced images aid in differentiating choroidal hemangioma from uveal melanoma.

Clinicopathologic features of retinoblastoma after primary chemoreduction.

BACKGROUND: Primary chemotherapy is a new treatment approach in retinoblastoma, aiming to avoid radiogenic adverse effects, such as second tumor-associated mortality, as observed following external beam irradiation. OBJECTIVE: To describe the clinical and histopathologic regression pattern after primary chemotherapy in retinoblastoma. METHODS: Five patients with sporadic bilateral retinoblastoma underwent planned enucleation of their functionally blind eye after 2, 3 (in 2 patients), 4, and 6 courses of primary chemotherapy with carboplatin, etoposide, cyclophosphamide, and vincristine. The eyes were examined histopathologically, using light microscopy and immunohistochemical analysis with proliferation markers. RESULTS: One patient had a type 1 (cottage cheese) regression and 4 patients had either a type 2 (fish flesh) or a type 3 (combined) regression pattern. Histopathologic examination revealed a complete tumor necrosis in 1 patient with type 1 regression after 3 courses of chemotherapy and in 1 patient with type 3 regression after 4 courses of chemotherapy. The remaining 3 patients with type 2 or type 3 regression had histologically still active proliferative tumor cells after 2, 3, and 6 courses of chemotherapy. CONCLUSION: This article correlates histopathologically the clinically described efficacy of primary chemotherapy in the treatment of retinoblastoma, underlining, however, the necessity of careful observation and the use of ancillary treatment whenever there is no complete tumor regression.