bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of vitamin C supplementation on lipid profile of type 2 diabetic patients: a systematic review and meta-analysis of clinical trials
Authors: Tareke Amare Abera , Hadgu Addis Alem
Published: March 2021

Background and aims

We conducted a systematic review and meta-analysis of clinical trials evaluating the role of vitamin C supplementation on lipid profiles among diabetic patients to summarize the available findings.

Methods

A comprehensive search of PubMed, ScienceDirect, Google Scholar, and Cochrane Library databases was performed. Clinical trials conducted on adult type 2 diabetic patients evaluating the effect of vitamin C supplementation and reported lipid profiles (cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL)) were included. Weighted mean difference (WMD) was calculated.

Results

Vitamin C supplementation had no significant effect on TC (WMD = − 4.36 mg/dl (95% CI − 10.24, 1.52) p-value = 0.146), LDL level (WMD = 2.73 mg/dl (95% CI − 1.72, 7.17) p-value = 0.229), and HDL level (WMD = 0.91 mg/dl (CI − 0.45, 2.27) p-value = 0.191). However, it reduced TG and secondary outcomes (FBS and HgA1C): TG (WMD = − 11.15 mg/dl (95% CI − 21.58, − 0.71) p-value = 0.036), FBS (WMD = − 16.94 mg/dl CI − 21.84, − 12.04, p-value = 0.000), and HgA1C (WMD = − 1.01% CI − 1.18, − 0.83, p-value = 0.001. Subgroup analysis also depicted younger patients, longer duration of treatment and higher dose were important factors. In addition, meta-regression analysis indicated the significant role of patient age, duration of treatment, supplementation dose, BMI and other baseline variables.

Conclusion

There is no adequate evidence to support vitamin C supplementation for dyslipidemias in diabetic patients. Specific group of patients might have benefited including younger diabetic patients. Future researches should give emphasis on the duration of treatment, the dose of vitamin C and baseline values.
Basilar artery occlusion presenting as sudden bilateral deafness: a case report
Authors: Kinouchi Tomoya , Ishitani Keisuke , Uyama Shinichi , Miyamoto Tadashi , Fujimoto Naomi , Ueta Hiromi
Published: March 2021

Background

Most sudden-onset hearing loss is due to otolaryngologic- and very rarely to cerebrovascular disease. We report a woman with sudden bilateral sensorineural hearing loss. This case suggests that even in the absence of brainstem or cerebellar signs, magnetic resonance imaging (MRI) and MR angiography (MRA) should be performed since such studies may reveal signs of life-threatening vertebrobasilar artery occlusion.

Case presentation

A 73-year-old Japanese woman with a history of hypertension, hyperlipidemia, and atrial fibrillation who suffered bilateral deafness with vertigo and vomiting was transferred from a local hospital to our department. On admission her consciousness was clear and vertigo was absent. Neurological examination revealed only bilateral sensorineural hearing loss. Head computed tomography (CT) returned no significant findings. The next morning she gradually developed severe drowsiness. Diffusion-weighted MRI demonstrated acute cerebral infarction in the brainstem and bilateral cerebellum; MRA showed basilar artery occlusion due to a cardioembolic thrombus. Revascularization was obtained by endovascular treatment. However, her condition worsened progressively during the following hours. CT revealed new brainstem lesions, massive cerebellar swelling, and obstructive hydrocephalus. She died on the second day after her admission.

Conclusions

When hearing loss is due to vertebrobasilar occlusive disease, the prognosis is very poor. We suggest that vertebrobasilar stroke be suspected in patients with bilateral sensorineural hearing loss who present with risk factors for stroke such as atrial fibrillation and other neurologic signs.
Pneumatosis intestinalis in a radioactive iodine-refractory metastasic thyroid papillary carcinoma with BRAFV600E mutation treated with dabrafenib–trametinib: a case report
Authors: Martín-Soberón M. C. , Ruiz S. , De Velasco G. , Yarza R. , Carretero A. , Castellano D. , Sepúlveda-Sánchez J. M.
Published: March 2021

Background

Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors.

Case presentation

A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography–computed tomography (PET–CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib–trametinib withdrawal, the patient developed tumor progression with significant clinical worsening.

Conclusions

This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib–trametinib. Conservative treatment is feasible if there are no abdominal symptoms.
A dermoid cyst misdiagnosed as a lipoma due to atypical magnetic resonance images: a case report
Authors: Mikami Taro , Maeda Chie , Aoki Fumihiko , Iwai Toshinori , Yabuki Yuichiro , Okabe Tetsuhiko , Ohashi Kenichi , Maegawa Jiro
Published: March 2021

Background

Dermoid cysts are well-known lesions that manifest as subcutaneous tumors around the lateral sides of the eyebrows in young patients. Computed tomography or magnetic resonance imaging (MRI) is often performed to confirm the diagnosis. On the other hand, a lipoma is usually a circular lesion, which is sometimes observed in the upper part of the face. The signals of both T1-weighted and T2-weighted images of MRI of a lipoma are, in general, relatively highly homogenous, and the signals decrease in fat-suppressed images. Therefore, differential diagnosis between a dermoid cyst and a lipoma is usually made with MRI, especially based on fat-suppressed images. Here, we present a case of misdiagnosis of a dermoid cyst as a lipoma because of atypical magnetic resonance images.

Case presentation

We report a case of a 24-year-old Japanese woman with a dermoid cyst around the lateral edge of the eyebrow. The cyst had been gradually increasing in size for the past 2 years. On MRI, it showed high internal signals on T1- and T2-weighted images. However, the signal intensity decreased homogeneously in the fat-suppressed T2-weighted images. The observed tumor had a yellowish appearance under the endoscope. On the basis of these findings, the lesion was considered a lipoma until it ruptured intraoperatively. The pathological diagnosis confirmed it to be a dermoid cyst.

Conclusion

Some dermoid cysts contain lipid-rich liquid, and these may be misdiagnosed as lipomas by MRI. When a tumor is located at a common site for a dermoid cyst, the MRI images should be validated carefully if it appears like a lipoma, and the differential diagnosis should be considered carefully.
Severe acute respiratory syndrome coronavirus 2-induced acute aortic occlusion: a case report
Authors: Minalyan Artem , Thelmo Franklin L. , Chan Vincent , Tzarnas Stephanie , Ahmed Faizan
Published: March 2021

Background

Severe acute respiratory syndrome coronavirus 2 infection can lead to a constellation of viral and immune symptoms called coronavirus disease 2019. Emerging literature increasingly supports the premise that severe acute respiratory syndrome coronavirus 2 promotes a prothrombotic milieu. However, to date there have been no reports of acute aortic occlusion, itself a rare phenomenon. We report a case of fatal acute aortic occlusion in a patient with coronavirus disease 2019.

Case report

A 59-year-old Caucasian male with past medical history of peripheral vascular disease presented to the emergency department for evaluation of shortness of breath, fevers, and dry cough. His symptoms started 5–7 days prior to the emergency department visit, and he received antibiotics in the outpatient setting without any effect. He was found to be febrile, tachypneic, and hypoxemic. He was placed on supplemental oxygen via a non-rebreather mask. Chest X-ray showed multifocal opacifications. Intravenous antibiotics for possible pneumonia were initiated. Hydroxychloroquine was initiated to cover possible coronavirus disease 2019 pneumonia. During the hospitalization, the patient became progressively hypoxemic, for which he was placed on bilevel positive airway pressure. D-dimer, ferritin, lactate dehydrogenase, and C-reactive protein were all elevated. Severe acute respiratory syndrome coronavirus 2 reverse transcription polymerase chain reaction was positive. On day 3, the patient was upgraded to the intensive care unit. Soon after he was intubated, he developed a mottled appearance of skin, which extended from his bilateral feet up to the level of the subumbilical plane. Bedside ultrasound revealed an absence of flow from the mid-aorta to both common iliac arteries. The patient was evaluated emergently by vascular surgery. After a discussion with the family, it was decided to proceed with comfort-directed care, and the patient died later that day.

Discussion

Viral infections have been identified as a source of prothrombotic states due to direct injury of vascular tissue and inflammatory cascades. Severe acute respiratory syndrome coronavirus 2 appears to follow a similar pattern, with numerous institutions identifying elevated levels of thrombotic complications. We believe that healthcare providers should be aware of both venous and arterial thrombotic complications associated with coronavirus disease 2019, including possible fatal outcome.
Architectural ruins: geoculture of the anatomy of buildings as illustrated by Casa Ippolito, Malta
Authors: Bianco Lino
Published: March 2021

Ruins are a statement on the building materials used and the construction method employed. Casa Ippolito, now in ruins, is typical of 17th-century Maltese aristocratic country residences. It represents an illustration of secondary or anthropogenic geodiversity. This paper scrutinises these ruins as a primary source in reconstructing the building’s architecture. The methodology involved on-site geographical surveying, including visual inspection and non-invasive tests, a geological survey of the local lithostratigraphy, and examination of notarial deeds and secondary sources to support findings about the building’s history as read from its ruins. An unmanned aerial vehicle was used to digitally record the parlous state of the architectural structure and karsten tubes were used to quantify the surface porosity of the limestone. The results are expressed from four perspectives. The anatomy of Casa Ippolito, as revealed in its ruins, provides a cross-section of its building history and shows two distinct phases in its construction. The tissue of Casa Ippolito—the building elements and materials—speaks of the knowledge of raw materials and their properties among the builders who worked on both phases. The architectural history of Casa Ippolito reveals how it supported its inhabitants’ wellbeing in terms of shelter, water and food. Finally, the ruins in their present state bring to the fore the site’s potential for cultural tourism. This case study aims to show that such ruins are not just geocultural remains of historical built fabric. They are open wounds in the built structure; they underpin the anatomy of the building and support insights into its former dynamics. Ruins offer an essay in material culture and building physics. Architectural ruins of masonry structures are anthropogenic discourse rendered in stone which facilitate not only the reconstruction of spaces but also places for human users; they are a statement on the wellbeing of humanity throughout history.
Magnetic resonance diffusion tensor imaging of acute spinal cord injury in spinal trauma
Authors: Alkadeem Radwa Mohamed Diaa Eldeen Abd Alsam , El-Shafey Mohammad Hassan Rashad , Eldein Ali Ebrahim Mohammad Seif , Nagy Hanan Ahmad
Published: March 2021

Background

It was important to develop a non-invasive imaging technique for early evaluation of spinal cord integrity after injury; MRI was the method of choice for evaluation of any cord abnormalities. However, some patients have symptoms with no detectable abnormalities by MRI. The purpose of our study was to assess the role of diffusion tensor MRI in evaluating the integrity of spinal cord fibers in case of spinal trauma.

Results

Out of the studied 30 patients, conventional MRI revealed abnormalities in the spinal cord in 23 patients (76.67%), diffusion tensor tractography revealed abnormalities in the spinal cord in 27 patients (90%), the mean FA value at the level of injury (0.326±0.135) was less than the mean FA value (0.532 ± 0.074) in control group (p value < 0.001), and the mean ADC value at the level of injury (1.319 ± 0.378) was less than the mean ADC value (1.734 ± 0.768) in the control group. FA was sensitive than ADC in the detection of the spinal cord abnormalities with a sensitivity of 93.33% versus 67.66% respectively.

Conclusion

DTI can be used to detect structural changes of spinal cord white matter fibers in acute spinal cord injury. A significant decrease of fractional anisotropy and apparent diffusion coefficient has been found at the site of spinal cord injury.
CheckMate 9KD Arm B final analysis: Efficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer.
Authors: Fizazi Karim , González Mella Pablo , Castellano Daniel , Minatta Jose Nicolas , Rezazadeh Arash , Shaffer David R. , Vazquez Limon Juan Carlos , Sánchez López Héctor Manuel , Armstrong Andrew J. , Horvath Lisa , Dzik Carlos , Amin Neha P. , Li Jia , Unsal-Kacmaz Keziban , Retz Margitta , Saad Fred , Petrylak Daniel Peter , Pachynski Russell Kent
Published: March 2021

12

Background: CheckMate 9KD (NCT03338790) is a phase 2 trial of nivolumab (NIVO; anti-PD-1) in combination with rucaparib, docetaxel (DOCE), or enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). DOCE is a standard-of-care chemotherapy for mCRPC that may potentiate antitumor immune responses, thus supporting its use in combination with NIVO, which has shown limited antitumor activity in mCRPC as monotherapy. We report final analysis results for Arm B (NIVO + DOCE) of CheckMate 9KD. Methods: Arm B enrolled patients with chemotherapy-naive mCRPC with ongoing androgen deprivation therapy and ≤ 2 prior novel antiandrogen therapies (NATs; i.e., abiraterone, enzalutamide, etc.). Patients received NIVO 360 mg + DOCE 75 mg/m2 Q3W + prednisone 5 mg BID for ≤ 10 cycles, followed by NIVO 480 mg Q4W until disease progression/unacceptable toxicity (up to 2 years). Coprimary endpoints were objective response rate (ORR) and prostate-specific antigen response rate (PSA-RR; defined as a ≥ 50% PSA reduction). Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 84 treated patients with a median age of 71 years (range: 53-88), 27% had visceral disease and 54% had measurable disease. The median number of docetaxel cycles was 8; the median number of nivolumab doses was 11. Median follow up was 15.2 months. The table displays the efficacy outcomes, which appear to show comparable ORR in patients receiving versus not receiving prior NAT. There was 1 (2.2%) complete objective response and 17 (37.8%) partial responses in 45 patients with measurable disease. Any-grade treatment-related AEs (TRAEs) occurred in 95.2% of patients, most commonly fatigue (39.3%), diarrhea (35.7%), and alopecia (34.5%). Grade 3-4 TRAEs occurred in 47.6% of patients, most commonly neutropenia (16.7%). TRAEs led to discontinuation in 29.8% of patients. The most common immune-related AEs were GI (35.7%) or skin-related (26.2%). There were 3 treatment-related deaths (1 pneumonitis related to NIVO; 2 pneumonias related to DOCE). Conclusions: NIVO + DOCE has encouraging clinical activity in patients with chemotherapy-naïve mCRPC, regardless of prior NAT, with a safety profile consistent with those of the individual agents. These outcomes support the ongoing phase 3 CheckMate 7DX trial of NIVO + DOCE vs placebo + DOCE for mCRPC (NCT04100018). Clinical trial information: NCT03338790. [Table: see text]
Considerations for active surveillance in select Gleason grade group 2 patients: A preliminary study.
Authors: Egan Jillian , Williams Cheyenne , Khondakar Nabila , O'Connor Luke P. , Daneshvar Michael , Yerram Nitin , Merino Maria , Choyke Peter L. , Wood Bradford , Turkbey Baris , Pinto Peter A.
Published: March 2021

206

Background: While active surveillance (AS) has become the preferred management strategy for patients with NCCN very-low and low risk prostate cancer, its use in the setting of intermediate risk disease continues to be controversial. Current guidelines state that AS can be considered in favorable intermediate risk disease, but data on outcomes in this cohort of patients is lacking. We aim to report on our experience with AS of Gleason grade group (GG) 2 at the National Cancer Institute (NCI)/National Institutes of Health (NIH). Methods: Our IRB-approved, institutional database was reviewed for men who enrolled on our AS protocol at NIH with GG2 disease from 2007-2020. All patients received MRI-targeted and systematic biopsy at the time of enrollment, diagnosing or confirming GG2 disease. MRI and PSA were performed annually, and majority of patients underwent annual combined MRI targeted and systematic prostate biopsy. If PSA and MRI were stable, annual biopsy was postponed in several patients based on their preference. Differences in PSA and PSAD at enrollment on AS and at progression were compared using Wilcoxon signed rank test. P value < 0.05 was considered significant. Results: 98 patients with GG2 disease enrolled in AS at NIH. Average age at enrollment was 64 years old and the majority of patients were Caucasian. 36/98(37%) of these patients progressed to GG3 or higher while on AS. Median PSA at time of progression was significantly higher than at the time of enrollment on AS (5.2 [IQR 4.0-8.9] vs 8.5 [IQR 5.8-10.9], z = -3.12, p < 0.01). PSAD was also significantly higher at time of progression (0.12[IQR 0.1-0.16] vs 0.13[IQR 0.10-0.22], z = -2.65, p < 0.01). Highest PIRADS score on MRI was largely unchanged. Median time to progression was 71 months. The majority of patients progressed to GG3, and progression was the trigger for definitive treatment. All patients were alive at the end of the follow up period. Conclusions: AS is a reasonable option for compliant patients diagnosed with GG2 prostate cancer. While a significant percentage of these men will progress on AS, they do so at a median of 71 months, avoiding treatment-related harms of definitive therapy for over 5 years. Further research with larger sample sizes are needed to better evaluate the oncologic outcomes of AS for GG2 disease, as well as predictors of more aggressive disease that may be better served with upfront definitive treatment. [Table: see text]
Evaluating the correlation between early and late quality-of-life declines using the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) after definitive stereotactic body radiotherapy, intensity-modulated radiotherapy, or brachytherapy for prostate cancer.
Authors: Parzen Jacob Samuel , Quinn Thomas J , Thompson Andrew B , Chang Peter , Collins Sean P. , Suy Simeng , Michalski Jeff M. , Mantz Constantine Anastasios , Seymour Zachary , Hamstra Daniel A.
Published: March 2021

214

Background: Multiple authorities including an NCI Taskforce have recommended routine evaluation of patient reported outcomes (PRO) in cancer care. The Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) is a single-page quality-of-life (QOL) tool which is easily integrated into routine clinical practice. The EPIC-CP has 5 domains (each scored 0-12). The present study evaluated whether early clinically significant changes in EPIC-CP were correlated with later changes in patients undergoing definitive radiotherapy (RT) for prostate cancer. Methods: A cohort of 979 patients including the PROSTQA study and 3 other institutions with prospective QOL data pooled for analysis were evaluated for patient-reported outcomes. Patients were treated with definitive low-dose rate brachytherapy (n=284), intensity-modulated RT (n=251), or stereotactic body RT (n=444). EPIC-CP scores were derived based upon responses to the EPIC-26. Data were evaluated using minimal clinically important difference (MCID) thresholds to compare QOL at 1-2 months and 24 months from baseline. Univariate analysis was used to assess the correlation between early and late MCID changes. Results: On univariate analysis, early ≥1 MCID change from baseline was strongly associated with a late ≥1 MCID across all 5 domains (urinary incontinence, urinary irritation/obstruction, bowel, sexual, and vitality/hormonal) within EPIC-CP and for the overall EPIC-CP score (Table). When MCID was instead defined as 1 or 3, early toxicity remained predictive of late toxicity for all domains and the overall EPIC-CP score. Conclusions: The EPIC-CP is an easy-to-use QOL assessment with clinically relevant outcomes. Early QOL decline was strongly associated with late QOL decline in patients undergoing definitive RT for prostate cancer across all EPIC-CP domains. Patients with early QOL decline may be candidates for early QOL-based interventions to alleviate their late toxicity burden from treatment. [Table: see text]
Ipilimumab and nivolumab (I+N) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world review in North West of England, United Kingdom.
Authors: Allison Jennifer , Griffiths Richard , Waddell Tom , Pillai Manon Rhys
Published: March 2021

295

Background: Ipilimumab and Nivolumab (I+N) is now an established first line option for patients with advanced RCC of intermediate (I) or poor (P) IMDC risk score. In this retrospective review, we review our experience of this combination in two cancer centres in North West England with a focus on immune related adverse events (irAEs) and their impact on the patient pathway. Methods: Treatment naïve mRCC patients starting I+N between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), the management of irAEs and early survival observations. Results: A total of 69 patients were identified. Median age was 60yr (19-82yr), 77% had clear cell histology. The IMDC risk was 72% I and 28% P. Median follow-up was 11.0 mo (1-22mo). ORR was 45% (CR 9%, PR 36%, SD 28%, PD 23%, NE 4%) Median time to first response was 2.9mo. (1.8- 15.5mo). 10% of patients experienced pseudoprogression. Median PFS and OS are not yet reached with 86% of patients still alive at the time of data cut-off. The majority (75%) of patients completed all 4 doses of I+N. Of the 10% receiving less than 4 doses due to toxicity, 14% continued on single agent N. Overall, 15% discontinued therapy due to toxicity and 28% experienced at least one treatment delay. Any grade irAEs were seen in 74% of patients (G3 35%) with no treatment related deaths. The commonest irAEs were: rash/pruritis 39%; endocrinopathies 30%(G3 7%); diarrhoea 29% (G3 14%); hepatitis 22% (G3 6%); and nephritis 3% (G3 3%). Of the patients developing irAEs, 71% received steroids with 16% requiring additional immunosuppression including infliximab (6%) and mycophenolate mofetil (8%). A third of all patients required admission for irAE management with a total of 37 inpatient episodes across the cohort with a median length of 7 days (1-24). 7% of patients proceeded to surgery for either primary or metastatic disease, which contributed to ongoing disease response in these patients. At the time of data cut-off, 45% of patients were no longer on treatment due to PD (29%), toxicity (15%) or unrelated death (1%). Of those who stopped due to toxicity, 50% subsequently progressed with a median time to progression of 4mo (3-6 mo) and 50% remain on active surveillance with a median follow-up of 7.5mo (1-10). 62% of patients with PD received second line treatment; most frequently, cabozantinib (83%). Conclusions: Our experience of I+N shows comparable efficacy and toxicity profiles to available reports. irAEs requiring intervention are frequent and may be associated with prolonged hospital admission, and patients should be counselled appropriately. Data within mirrors published reports of ongoing responses in a subset of patients who stop treatment due to toxicity and also suggests a possible role for resection of residual or metastatic disease in disease control. Updated survival data will be presented.
Salvage nivolumab plus ipilimumab after prior PD-1/PD-L1 inhibitor treatment in metastatic renal cell carcinoma: A meta-analysis.
Authors: Yin Ming , Mori-Vogt Sherry , Hinkley Megan , Parikh Anish B , Yang Yuanquan , Collier Katharine , Miah Abdul , Li Mingjia
Published: March 2021

305

Background: Although not officially approved, salvage nivolumab plus ipilimumab (nivo/ipi) treatment after prior PD-1/PD-L1 immune checkpoint inhibition is frequently used in metastatic renal cell carcinoma (mRCC). However, very limited data are available to guide such therapy. Methods: A search in Medline database and conference abstracts published in English before September 1, 2020 yielded 4 studies reporting salvage nivo/ipi outcomes of mRCC patients. We added additional information from 27 mRCC patients who received salvage nivo/ipi at The Ohio State University after prior PD-1 pathway inhibition. Hence, we performed a meta-analysis of five studies to further characterize the safety and efficacy of salvage nivo/ipi treatment. Results: Among 155 patients with measurable treatment response, we found that salvage nivo/ipi had an objective response rate of 19% (95% CI, 0.13-0.25), which was significantly lower than response to prior PD-1/PD-L1 inhibition (odds ratio, 0.35, 95% CI, 0.18-0.67; p < 0.01). Response to prior PD-1/PD-L1 inhibition did not correlate with salvage nivo/ipi response (odds ratio, 1.41, 95% CI, 0.51-3.87; p = 0.51). Additionally, salvage nivo/ipi was associated with 26% (95% CI, 0.19-0.33) grade ≥ 3 adverse events, which was lower than the toxicity in the upfront setting reported in Checkmate-214 trial. Conclusions: It is feasible to have salvage nivo/ipi treatment in mRCC. Salvage nivo/ipi treatment has a lower efficacy and lower toxicity compared with its use in the first-line setting.
SEMS trial: Result of a prospective, multi-institutional phase II clinical trial of surgery in early metastatic seminoma.
Authors: Daneshmand Siamak , Cary Clint , Masterson Timothy A. , Einhorn Lawrence , Boorjian Stephen A. , Kollmannsberger Christian K. , Schuckman Anne K. , So Alan , Black Peter C. , Bagrodia Aditya , Skinner Eila C. , Alemozaffar Mehrdad , Brand Timothy C. , Eggener Scott E. , Pierorazio Phillip M. , Stratton Kelly Lynn , Nappi Lucia , Nichols Craig R. , Hu Brian
Published: March 2021

375

Background: Chemotherapy or radiotherapy are standard treatments for stage II seminoma, though they are associated with significant long-term treatment-related toxicities. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors but little data exists on its efficacy as a front-line treatment in early metastatic (stage II) seminoma. This is a single-arm, multi-institutional (NCT02537548), phase II study of retroperitoneal lymph node dissection (RLND) as first-line treatment for testicular seminoma with isolated retroperitoneal disease. Methods: Twelve sites in the United States and Canada prospectively enrolled patients (16 years of age) with testicular seminoma and isolated retroperitoneal lymphadenopathy between 1-3 cm in size. Patients were excluded if they received prior therapy (except orchiectomy) for testicular cancer. Open, modified-template RPLND was performed by qualified surgeons with a primary endpoint of 2-year recurrence-free survival. Data on complication rates (short and long-term), pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. Results: A total of 55 patients were enrolled and underwent RPLND. Fourteen patients had initial stage I disease who developed isolated retroperitoneal relapse while 41 patients had clinical stage IIA-B at presentation. With a median follow-up of 24 months (8-52 months), there were a total of 10 recurrences. The overall recurrence rate was 18% with a median time to recurrence of 8 months. Of the recurrences, 8 underwent chemotherapy (6 BEP X 3, 1 EP X 4, 1 carbo/etoposide) and 2 underwent additional surgery. The two-year recurrence free survival was 87% and the overall survival was 100%. There were 7 (13%) patients who experienced short-term complications within 1 year of RPLND. Of these, 5 (9%) were classified as Clavien Dindo I-II and 2 (3.6%) were classified as Clavien Dindo III. No patients have reported long-term complications. Conclusions: This trial establishes RPLND as a therapeutic option as a first-line treatment in early metastatic seminoma. The surgery offers cancer control rates similar to those seen in non-seminomatous germ cell tumors. Clinical trial information: NCT02537548.
Safety and efficacy of perioperative cisplatin/gemcitabine (cis/gem) and durvalumab (durva) for operable muscle-invasive urothelial carcinoma (MIUC): SAKK 06/17.
Authors: Cathomas Richard , Rothschild Sacha , Hayoz Stefanie , Spahn Martin , Schardt Julian , Seiler Roland , Erdmann Andreas , Aeppli Stefanie , Mach Nicolas , Strebel Raeto , Hadaschik Boris A. , Berthold Dominik R. , Pless Miklos , Zihler Deborah , Schmid Mathias , Schneider Martina , Maniecka Zuzanna , Petrausch Ulf
Published: March 2021

430

Background: The combination of cisplatin-based chemotherapy with immune checkpoint inhibitors is extensively investigated in urothelial carcinoma. Using this combination in the neoadjuvant setting for patients (pts) with MIUC might improve pathological response rate (PaR: <ypT2N0) but carries the risk of increased perioperative morbidity. Methods: SAKK 06/17 is an open-label single arm phase II trial for pts with operable MIUC cT2-T4a cN0-1. Treatment consists of 4 cycles of neoadjuvant cis/gem q3w in combination with 4 cycles durva 1500mg q3w followed by resection. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival (EFS) at 2 years. 58 pts are needed based on type I error of 10% and a power of 80% for H1 EFS at 2 years ≥ 65% compared to H0 EFS at 2 years ≤ 50%. We report the secondary endoints PaR, pathological complete remission (pCR: ypT0 N0), and safety on the full analysis set (FAS, received at least one dose of durva). Results: 61 pts were included between 7/18 and 9/19 at 12 sites. The FAS consists of 58 pts (79% male, median age 67.5 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage were present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. 95% of pts received all 4 doses of neoadjuvant durva, 81% all 4 cycles of cis/gem and 17% switched to carboplatin. In total grade 3 and 4 adverse events (AE) during neoadjuvant treatment occurred in 48% and 27%, respectively. AEs related to durva were G3 in 7 pts (12%) and G4 in one patient (2%). Resection was performed in 53 pts (91%; 51 radical cystectomy, 2 nephroureterectomy), 4 pts refused surgery and one patient was irresectable due to a frozen pelvis. R0 resection was achieved in 52 pts (98%), one had R1. Postoperative complications included Clavien-Dindo III in 13 pts (24%) and IV in 5 pts (9%). PaR was found in 60% (95% CI 46.0%-73.5%) with 18 pts achieving pCR (34%; 95% CI 21.5%-48.3%) and 14 patients (26%) ypT1/ypTis. Conclusions: The first FAS results for neoadjuvant durvalumab in combination with cis/gem for operable MIUC confirm elevated pathological response rates and demonstrate acceptable safety. Postoperative morbidity is relevant but not exceeding the expected frequency or severity. Clinical trial information: NCT03406650.
Atezolizumab (atezo) monotherapy versus chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma (mUC): Clinical outcomes by PD-L1 status in cisplatin (cis)-ineligible pts from the phase III IMvigor130 study.
Authors: Galsky Matt D. , Bamias Aristotelis , Arranz Arija Jose Angel , Davis Ian D. , De Santis Maria , Kikuchi Eiji , Garcia del Muro Xavier , Park Se Hoon , De Giorgi Ugo , Alekseev Boris , Mencinger Marina , Izumi Kouji , Puente Javier , Li Jian-Ri , Mecke Almut , Mariathasan Sanjeev , Banchereau Romain , Huang Xinhui , Lee Chooi Peng , Grande Enrique
Published: March 2021

434

Background: Atezo (anti–PD-L1) monotherapy is approved for cis-ineligible pts who have locally advanced or mUC with PD-L1–expressing immune cells on ≥ 5% of the tumor area (IC2/3 per VENTANA SP142 IHC assay). The IMvigor130 primary analysis demonstrated a significant PFS benefit with atezo + platinum/gemcitabine (plt/gem) (arm A) vs placebo (pbo) + plt/gem (arm C) as 1L treatment for mUC (Galsky Lancet 2020); at that time, interim OS data for arm A vs C were encouraging but immature. OS with atezo monotherapy (arm B) could not be formally tested, but favorable efficacy was seen in IC2/3 pts. In this exploratory analysis, we assess outcomes by PD-L1 status in cis-ineligible pts. Methods: Pts were randomized 1:1:1 to arms A, B or C (Galsky Lancet 2020). Evaluation of OS (co-primary EP) was performed via a hierarchical fixed sequence procedure: arm A vs C ITT pts; then, arm B vs C ITT and IC2/3 pts. No formal testing was performed in this exploratory subgroup analyses; OS and RECIST 1.1 ORR (per investigator [secondary EP]) were descriptively evaluated. Results: Efficacy data suggested OS and ORR benefit in atezo-treated cis-ineligible IC2/3 pts (Table). In the overall safety population, all-grade treatment-related AEs (TRAEs) had occurred in 60% and 96% of arm B and C pts, respectively; grade 3-4 TRAEs occurred in 15% and 81%, respectively. Biomarker data evaluating PD-L1 biology (assessed by SP142) and associated transcriptome analysis in arms B vs C will be presented. Conclusions: This exploratory analysis of IMvigor130 pts with 1L cis–ineligible IC2/3 mUC provides additional evidence for clinical benefit with single-agent atezo, a well-tolerated treatment with a distinct safety profile vs chemo. Analyses with longer OS follow-up are warranted. Clinical trial information: NCT02807636 . Research Sponsor: F. Hoffmann-La Roche Ltd[Table: see text]
Overall survival (OS) and metastasis-free survival (MFS) by depth of prostate-specific antigen (PSA) decline in the phase III PROSPER trial of men with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with enzalutamide (ENZA).
Authors: Hussain Maha H. A. , Sternberg Cora N. , Efstathiou Eleni , Fizazi Karim , Shen Qi , Lin Xun , Sugg Jennifer , Steinberg Joyce Leta , Noerby Bettina , De Giorgi Ugo , Shore Neal D. , Saad Fred
Published: March 2021

94

Background: The PROSPER trial demonstrated prolonged MFS and OS for men with nmCRPC and rapidly rising PSA treated with ENZA vs placebo, both in combination with androgen deprivation therapy (ADT). The final survival analysis of PROSPER (Sternberg et al. NEJM 2020) recently reported a median OS of 67.0 months (95% CI, 64.0 to not reached) with ENZA and 56.3 months (95% CI, 54.4 to 63.0) with placebo (hazard ratio [HR] for death, 0.73; 95% CI, 0.61 to 0.89; P = .001). Post hoc analyses of PROSPER evaluating PSA dynamics have demonstrated longer MFS with greater PSA decline (Hussain et al. ESMO Sept 19-21, 2020. Poster 685P) and increased risk of metastases in patients with even modest PSA progression vs those without (Saad et al. Eur Urol 2020). Here we further explored the relationship between PSA dynamics and outcomes in PROSPER using uniquely defined PSA subgroups of decline. Methods: Eligible men in PROSPER had nmCRPC, a PSA level ≥ 2 ng/mL at baseline, and a PSA doubling time ≤ 10 months. Men continued ADT, were randomized 2:1 to ENZA 160 mg once daily vs placebo, and had PSA evaluation at week 17 and every 16 weeks thereafter. This post hoc analysis evaluated OS and MFS for 4 mutually exclusive subgroups defined by PSA nadir using men with PSA reduction < 50% as the reference group. The HR is based on an unstratified Cox proportional hazards analysis model. Results: 1401 men were enrolled in PROSPER; 933 were treated with ENZA and PSA data were available for 905. Measured at nadir, 38% of these men achieved PSA reduction ≥ 90% (actual nadir < 0.2 ng/mL), and another 27% achieved PSA reduction ≥ 90% (actual nadir ≥ 0.2 ng/mL). Among men in the placebo arm of PROSPER only 3/457 reported PSA reduction ≥ 90%. Median OS and MFS increased with increasing depth of PSA decline (Table). Conclusions: In men with nmCRPC and rapidly rising PSA treated with ADT plus ENZA, there was a close relationship between the degree of PSA decline and survival outcomes. Defining PSA by both percent decline and actual decline below 0.2 ng/mL revealed a previously under-appreciated relationship between these PSA metrics and highlights the importance of PSA nadir as an intermediate biomarker in nmCRPC. Clinical trial information: NCT02003924. [Table: see text]
A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281).
Authors: Fizazi Karim , George Daniel J. , De Santis Maria , Clarke Noel , Fay Andre P. , Uemura Hirotsugu , Grinsted Lynda , Rooney Claire , Verheijen Remy B , Anjum Rana , Foxley Andrew , Morris Thomas
Published: March 2021

TPS178

Background: In metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone combined with androgen deprivation therapy (ADT) is highly effective in improving patient outcomes. However, around 20% of patients progress to castration-resistant disease within 12 months of treatment; these patients have shorter survival and limited treatment options. Aberrant activation of the PI3K/AKT pathway, predominately due to PTEN loss, is common in prostate cancer, especially in later-stage disease. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated such as that inhibition of one leads to upregulation of the other. Therefore, combining abiraterone therapy with AKT inhibition may be beneficial in patients with mHSPC who have PTEN deficiency. In preclinical studies, capivasertib, a selective oral pan-AKT inhibitor, inhibited proliferation of models of hormone-sensitive and castration-resistant prostate cancer with PTEN loss. The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. CAPItello-281 (NCT04493853) is a global, multicenter, phase 3 trial to evaluate capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. Methods: Eligible patients for this double-blind, randomized trial are men aged 18 years or older with confirmed newly diagnosed previously untreated metastatic hormone-sensitive prostate adenocarcinoma with immunohistochemically confirmed PTEN deficiency and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Following screening, approximately 1000 patients will be randomized 1:1 to receive either capivasertib (400 mg) or placebo (twice daily; 4 days on, 3 days off) in combination with abiraterone (1000 mg once daily) and ADT until radiographic progression or intolerable toxicity. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020. Acknowledgments: We thank Julia Grigorieva, PhD, of Oxford PharmaGenesis, Philadelphia, USA, for providing medical writing assistance. Funding: The CAPItello-281 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04493853.
A phase I/II study of combination olaparib and radium-223 in men with metastatic castration-resistant prostate cancer with bone metastases (COMRADE): A trial in progress.
Authors: Shaya Justin , Xie Wanling , Saraiya Biren , Parikh Mamta , Folefac Edmund , Olson Adam C. , Choudhury Atish Dipankar , Einstein David Johnson , Heath Elisabeth I. , Parikh Rahul Atul , Kunos Charles , Ivy S. Percy , LoRusso Patricia , Kurzrock Razelle , Shapiro Geoffrey , McKay Rana R.
Published: March 2021

TPS182

Background: Radium-223 is an α-emitting radioisotope that induces DNA double-stranded breaks leading to cell death and has demonstrated improvement in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. PARP inhibitors, including olaparib and rucaparib, inhibit repair of DNA single-stranded beaks and have demonstrated clinical efficacy in mCRPC patients harboring alterations in the homologous recombination repair (HRR) pathway. In extensive preclinical cancer models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the clinical hypothesis that the combination of radium-223 with olaparib will demonstrate anti-tumor activity in patients with mCRPC irrespective of underlying HRR deficiency status. Methods: This is an open label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of olaparib in combination with radium-223 in men with mCRPC with bone metastases. Patient must have 2 or more bone metastases and at least 1 bone metastasis that has not been treated with prior radiation therapy. Key exclusion criteria include the presence of visceral metastases or malignant lymphadenopathy exceeding 4 cm and prior therapy with radium-223 and/or PARP inhibitors. The phase 1 component of the study uses a 3+3 dose escalation design to determine the recommended phase 2 dose of olaparib in combination with standard of care dosing of Radium-223. The primary endpoint of the phase 1 component is safety. The phase 2 component of the study is an open-label, randomized study evaluating the combination of olaparib and radium-223 compared to radium-223 alone. The primary endpoint of the phase 2 component is radiographic progression-free survival as defined by Prostate Cancer Working Group 3 guidelines for bone metastases and RECIST v1.1 for non-bone metastases. Secondary endpoints include time to PSA progression, PSA response, time to subsequent therapy, time to first skeletal event, overall survival, and safety. Exploratory endpoints include stratification of response based on HRR alterations, whole exome sequencing of plasma cell free DNA both at baseline, on treatment, and at progression, and evaluation of changes in the tumor immune microenvironment with therapy. As of October 1, 2020, the phase 1 component has completed accrual and we anticipate opening the phase 2 component by December 2020. Clinical trial information: NCT03317392.
A phase I, dose-expansion cohort study on the safety of a cannabidiol for biochemical recurrence in prostate cancer patients.
Authors: Myint Zin , St Clair William H. , Strup Stephen , Wang Peng , James Andrew Callaway , Yan Donglin , Allison Derek B. , Ellis Carleton Scott , Otto Danielle E. , Kolesar Jill , DiPaola Robert S.
Published: March 2021

TPS263

Background: Cannabinoids, widely used in pain control, as an appetite stimulant, and anti-emetic in cancer patients, may play role as an anti-carcinogenic agent. A preclinical study demonstrated that cannabinoid receptors (CB1 and CB2) were highly expressed in human androgen-responsive prostate cancer (PCa) cells (LNCaP) as compared to normal prostate epithelial cells (PrEC). When these two cell lines were treated with a potent cannabinoid receptor agonist, PCa cells showed a decrease in prostate-specific antigen (PSA) protein expression and increased apoptosis in a dose and time-dependent manner with no effect seen in PrEC cells. An FDA-approved cannabidiol (CBD) agent, is derived from Cannabis sativa L. plants. Extracts from these plants are processed to yield pure CBD and contain less than 0.5% THC. We will expand these preclinical studies with a phase I trial. Methods: This trial is an open-label, single-center, phase I dose escalation study followed by dose expansion to evaluate acute toxicity, long-term safety and tolerability, and preliminary antitumor activity of cannabidiols in patients with biochemically recurrent (BCR) PC after primary definitive local therapy and prostate-specific antigen doubling time ≤ 12 months. The dose escalation will be determined by a Bayesian Optimal Interval design and the target dose-limiting toxicity rate is set at 30%. An additional 6-9 patients will be enrolled as an expansion cohort once the maximum tolerated dose is determined. Patients will be treated for a total 90 days with a 10 day taper. The primary objective is to evaluate the acute toxicity and long-term safety and tolerability of cannabidiols in patients with BCR. The secondary objective includes measuring changes in serial PSA levels, PSA velocity, and testosterone levels and to assess health-related quality of life (EORTC QLQ-C30 and QLQ-PR 25) from baseline throughout the treatment period. CB receptor 1 and 2 expression levels by immunohistochemistry staining will be evaluated from archival prostatectomy specimens if available as an exploratory objective. This trial opened on 7.28.2020 and has started enrollment. Clinical trial information: NCT04428203.
Insights on Droplet Digital PCR–Based Cellular Kinetics and Biodistribution Assay Support for CAR-T Cell Therapy
Authors: Sugimoto Hiroshi , Chen Susan , Minembe Jean-Pierre , Chouitar Johara , He Xingyue , Wang Haiqing , Fang Xiaodong , Qian Mark G.
Published: March 2021

Characterizing in vivo cellular kinetics and biodistribution of chimeric antigen receptor T (CAR-T) cells is critical for toxicity assessment, nonclinical and clinical efficacy studies. To date, the standardized assay to characterize CAR-T cell distribution, expansion, contraction, and persistence profiles is not readily available. To overcome this limitation and increase comparability among studies, we have established a universal protocol for analysis. We established a duplexing ddPCR protocol for the CAR-T transgene and reference gene to normalize the genomic DNA input prepared from mouse blood and tissues. The high-throughput gDNA extraction method enabled highly reproducible gDNA extraction while eliminating labor-intensive steps. The investigational CAR-T cells were intravenously injected into immunodeficient mice bearing human colorectal cancer xenografts. The blood and tissue samples were collected to measure the cellular kinetics by ddPCR and flow cytometry. The standard curves were linear throughout the calibration range with acceptable intra- and inter-day precision and accuracy. The gDNA recovery study performed by spiking in the exo-gene plasmid DNA or CAR-T cells revealed that the recovery ranged from 60 to 100% in blood and tissue homogenates. The use of both units of copy/μg gDNA and copy/μL blood met the current regulatory requirement and allowed for a systematic understanding of CAR-T cell expansion and a direct comparison with the flow cytometry data. A standardized ddPCR assay, including automated gDNA extraction procedures, has been established for evaluating cellular kinetics and biodistribution in CAR-T cell therapies.