Institutional experience with nab-sirolimus in patients with malignancies harboring TSC1 or TSC2 mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3111-3111
Author(s):  
Mark Andrew Dickson ◽  
Vinod Ravi ◽  
Kristen N. Ganjoo ◽  
Gopa Iyer
Keyword(s):  
Response Rate ◽  
Xenograft Model ◽  
Low Frequency ◽  
Mtor Pathway ◽  
Serious Adverse Events ◽  
Improved Outcomes ◽  
S 100 ◽  
Institutional Experience ◽  
Tumor Accumulation ◽  
Tumor Types

3111 Background: TSC1/ TSC2 genes are tumor suppressors in the mTOR pathway; mutated at low frequency across tumor types (̃1–2%). Retrospective analyses of patients (pts) with mTOR pathway mutations treated with everolimus did not show improved outcomes vs the wild type (Voss et al. Clin Cancer Res 2019. PMID 30327302). In NCT02201212, pts with TSC1/TSC2 mutations treated with everolimus had a 7% (2/30) response rate. In the AMPECT study, pts with advanced PEComa treated with a novel mTOR inhibitor (mTORi), nab-sirolimus ( nab-S, ABI-009), the subset of pts with TSC1/TSC2 mutations had a response rate of 64% (9/14) (Wagner et al. CTOS 2020. #3463014). In a xenograft model, nab-S showed significantly higher tumor accumulation, target suppression (pS6) and antitumor activity vs everolimus or sirolimus (Hou et al. AACR 2019. #348). In an expanded access program (NCT03817515), pts with advanced tumors bearing TSC1/ TSC2 mutations were treated with nab-S and outcomes in pts with malignancies other than PEComa are reported herein. Methods: Eligible pts (ECOG 0–2) received nab-S 100 mg/m2 IV, once weekly for 2 of every 3 weeks at 3 US sites between 7/2019 and 11/2020. Results: 7 pts with TSC1/ TSC2 mutations have been consecutively enrolled and are reported here. 6/7 pts had multiple prior therapies including 2 pts previously progressing on an mTORi. 4/7 pts had partial response (PR), all in mTORi naïve pts. 2/7 pts had stable disease (SD). In 2 pts previously treated with an mTORi, 1 had SD and 1 came off treatment after 1 cycle (CA125 ↑) with no follow-up scan. Treatment-related serious adverse events (SAEs; hyperglycemia and infection) and dose reduction were reported in 1 pt with metastatic angiosarcoma; SAEs resolved and the pt continued Rx. No other SAE or dose limiting event was reported Conclusions: Patients with various malignancies bearing TSC1 or TSC2 mutations, most with progression on multiple prior therapies, showed evidence of response and manageable toxicities during treatment with nab-S. A basket trial of nab-S in malignancies with TSC1/ TSC2 mutations is planned. Clinical trial information: NCT03817515. [Table: see text]

474 Multiple combinational strategies of immunotherapy for esophageal squamous cell carcinoma: one institutional experience in Taiwan since 2016

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A505-A505
Author(s):  
Jo-Pai Chen ◽  
Wei-Chen Lu ◽  
Ruey-Long Hong
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Clinical Benefit ◽  
Response Rate ◽  
University Hospital ◽  
List Type ◽  
Duration Of Response ◽  
Institutional Experience

BackgroundEsophageal squamous cell carcinoma is still a health burden in Taiwan. In R/M setting, the prognosis becomes worse. ESCC is still an immunogenic cancer. In randomized 2nd line ATTRACTION-3 study(nivolumab vs taxane after PF failure), median OS improved from 8.4 months in chemotherapy to 10.9 months in nivolumab(HR, 0.77; 95% CI, 0.62–0.96; p =0.019). The median duration of response was 3.9 months and 6.9 months. Nivolumab is a new 2nd line option for ESCC.MethodsFrom early 2016 to early 2020, 15 advanced ESCC patients had ever received immunotherapy-containing regimens in Yun-lin Branch of National Taiwan University Hospital and were analyzed.ResultsThe overall response to immunotherapy-containing regimens was 60%(9/15) and clinical benefit was 80%(12/15). 2nd line nivolumab was given in 3 cases; response rate was33% and clinical benefit was 67%. 2nd line afatinib combined with anti-PD1 was given in 9 case; response rate was 67% and clinical benefit was 78%. The response rate of 2nd line afatinib & pembrolizumab was 75%(3/4); however, Gr. III pneumonitis & Gr. II hepatitis were noted in the patient with progression. The response rate of 2nd line afatinib & nivolumab was 60%(3/5) and clinical benefit was 80%(4/5); skin rash and diarrhea were often found. 1st line afatinib combined with anti-PD1 was given in 3 patients; response rate was 67% and clinical benefit was 100%. The response rate of 1st line afatinib & nivolumab was 100%(2/2).ConclusionsEGFR TKIs have multiple immuno-modulatory effects and may increase immunotherapy benefits in ESCC. Anti-PD1 and anti-CTLA4, another possible rationale, could bring more benefits maybe in 1st line CheckMate649 study.AcknowledgementsNilTrial RegistrationN/AEthics ApprovalN/AConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferencesNil

scholarly journals Increasing molar activity by HPLC purification improves 68Ga-DOTA-NAPamide tumor accumulation in a B16/F1 melanoma xenograft model

PLoS ONE ◽  
2019 ◽  
Vol 14 (6) ◽  
pp. e0217883
Author(s):  
Jan Lennart von Hacht ◽  
Sarah Erdmann ◽  
Lars Niederstadt ◽  
Sonal Prasad ◽  
Asja Wagener ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Hplc Purification ◽  
Molar Activity ◽  
Melanoma Xenograft ◽  
Tumor Accumulation

scholarly journals Cognitive therapy training for psychiatrists: impact on individual clinical practice

2004 ◽  
Vol 28 (4) ◽  
pp. 117-119 ◽  
Author(s):  
G. Swift ◽  
I. Durkin ◽  
C. Beuster
Keyword(s):  
Clinical Practice ◽  
Cognitive Therapy ◽  
Response Rate ◽  
Postal Questionnaire ◽  
Clinical Implications ◽  
Previous Survey ◽  
Therapy Training ◽  
Training And Supervision ◽  
Improved Outcomes ◽  
Therapy Sessions

Aims and MethodWe aimed to survey how psychiatrists with in-depth training in cognitive therapy use these skills. A postal questionnaire based on a previous survey was sent to all psychiatrists who are accredited members of the British Association for Behavioural and Cognitive Psychotherapies.ResultsThere was a 94% response rate. Psychiatrists in non-psychotherapy posts used formal cognitive therapy, with an average of 20% of new patients compared with 65% for those in psychotherapy posts, and were less satisfied with the extent to which they were able to use their skills (20%v. 80%). A total of 85% of respondents described themselves as being involved in teaching, training and supervision of cognitive therapy.Clinical ImplicationsUnless psychiatrists are planning on working in specialised psychotherapy posts, they are unlikely to use cognitive therapy training in formal therapy sessions. Further research is needed to determine whether cognitive therapy training for psychiatrists translates into improved outcomes for patients.

scholarly journals Attitudes of psychiatrists to evidence-based guidelines

2002 ◽  
Vol 26 (11) ◽  
pp. 421-424 ◽  
Author(s):  
Harvey Rees ◽  
Attila Sipos ◽  
Matthew Spence ◽  
Glynn Harrison
Keyword(s):  
Response Rate ◽  
Postal Questionnaire ◽  
Clinical Implications ◽  
Evidence Based ◽  
Previous Survey ◽  
Health Partnership ◽  
Improved Outcomes ◽  
Actual Use ◽  
Evidence Based Guidelines ◽  
Improving Patient Care

Aims and MethodWe aimed to survey clinicians' attitudes on using evidence-based guidelines. A postal questionnaire based on a previous survey of general practitioners was sent to 105 psychiatrists working within Avon and Western Wiltshire Mental Health Partnership NHS Trust.ResultsThere was a 91% response rate. Respondents were generally in favour of clinical guidelines, with scores indicating a positive attitude to guidelines in 13 of the 18 statements. The majority felt that guidelines were effective in improving patient care, could be used flexibly to suit individual patients and did not impinge on their clinical judgement.Clinical ImplicationsPsychiatrists welcomed the increasing use of guidelines. Further research is needed to determine whether this will translate into actual use and improved outcomes for patients.

scholarly journals Waning Humoral Response 3 to 6 Months after Vaccination with the SARS-COV-2 BNT162b2 mRNA Vaccine in Dialysis Patients

2021 ◽  
Vol 11 (1) ◽  
pp. 64
Author(s):  
Noa Berar-Yanay ◽  
Sarit Freiman ◽  
Maʹanit Shapira ◽  
Amer Saffoury ◽  
Ameer Elemy ◽  
...  
Keyword(s):  
Response Rate ◽  
Vaccine Dose ◽  
Humoral Response ◽  
Albumin Level ◽  
High Response Rate ◽  
Control Group ◽  
Dialysis Patients ◽  
Serious Adverse Events ◽  
Antibody Levels

Background and objectives: The short-term reported antibody response to SARS-COV-2 vaccination in dialysis patients is high, with a seroconversion response rate up to 97%. Data on the long-term durability of this response are scarce. Our objective was to characterize the long-term anti-spike antibody level in dialysis patients. Design, setting, participants, and measurements: In an observational study, we measured SARS-COV-2 anti-spike antibody levels in dialysis patients who completed 2 doses of the BNT162b2 mRNA SAR S-COV-2 vaccine at 1, 3 and 6 months after the second vaccine dose. We compared the response to dialysis patients who were infected with COVD-19 and to a control group of healthcare-employees. Results: One hundred and forty-two dialysis patients who had been vaccinated (ages 64 ± 11.9 years, 61% male), 33 dialysis patients who had COVID-19 infection (ages 54 ± 14.3 years, 55% male) and 104 individuals in the control group (ages 50 ± 12.2 years, 44% male) were included. The response rate in the vaccinated dialysis patients was 94%, 78% and 73% at 1, 3 and 6 months after the second vaccine dose. In the COVID-19 infected dialysis group and in the control group, the response rate remained at 100% over 6 months. The percentage of change in antibody levels between one and 6 months was −66% in the vaccinated dialysis group, −28% in the control group (p < 0.001) and +48% in dialysis patients who had been infected with COVID-19 (p < 0.001). A non-responder status at 6 months was associated with a lower albumin level. No serious adverse events following vaccination were reported. In conclusion: the initially high response rate to the BNT162b2 vaccine in dialysis patients decreases rapidly. Our results indicate that an early booster (3rd) dose, at three months after the second dose, may be advised for this population to preserve the humoral immunity.

scholarly journals Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 406
Author(s):  
Quang Loc Bui ◽  
Léo Mas ◽  
Antoine Hollebecque ◽  
David Tougeron ◽  
Christelle de la Fouchardière ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Immune Checkpoints ◽  
Repair Deficiency ◽  
Improved Outcomes ◽  
Number Of Patients ◽  
Tumor Types

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

scholarly journals Silencing VEGF enhances the radiosensitivity of the radioresistant human nasopharyngeal carcinoma cell line CNE-2R by inhibiting autophagy through the activation of mTOR pathway

2020 ◽  
Author(s):  
Li Chen ◽  
Guoxiang Lin ◽  
Kaihua Chen ◽  
Fangzhu Wan ◽  
Yongchu Sun ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Carcinoma ◽  
Cell Line ◽  
Western Blotting ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Angiogenic Factor ◽  
Cell Counting

Abstract Background: Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced to the radioresistance of tumors. The purpose of our study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma radioresistant cell line CNE-2R and the underlying mechanisms.Methods: The radiosensitivity of CNE-2R cells after silencing VEGF was detected by cell counting kit 8 (CCK-8) and clonogenic assay, cell cycle and apoptosis was subjected to flow cytometry. DNA damage and autophagy were observed by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation analysis. In vivo, the effect of VEGF on radiosensitivity of NPC cells was investigated through xenograft model, furthermore, immunohistochemistry and TUNEL assay were used to further verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion.Results: Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of CNE-2R cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in CNE-2R cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through the activation of mTOR pathway.Conclusion: VEGF depletion increased radiosensitivity of NPC radioresistant cell CNE-2R by suppressing autophagy via the activation of mTOR pathway.

Final results of phase 1 evaluation of the safety and clinical activity of sapanisertib in combination with serabelisib and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5569-5569
Author(s):  
David Starks ◽  
Luis Alexander Rojas-Espaillat ◽  
Nandini Dey ◽  
Pradip De ◽  
Brian Leyland-Jones ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Phase 1 ◽  
Endometrial Adenocarcinoma ◽  
Mtor Pathway ◽  
Clinical Activity ◽  
Open Label ◽  
Serious Adverse Events ◽  
Positive Effects ◽  
Taxane Resistance ◽  
Heavily Pretreated

5569 Background: Evidence suggests that activation of the PI3K/AKT/mTOR pathway by paclitaxel may play a role in the development of taxane resistance. Conversely, PI3K inhibitors have been shown to sensitize tumors to the effects of paclitaxel. Therefore, the link between taxane resistance and activation of the PI3K/AKT/mTOR signaling pathway suggests inhibition of this pathway in combination with antimitotic drugs like paclitaxel may improve treatment outcomes in many malignancies. To further investigate this hypothesis we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial of heavily pretreated patients to determine the safety, efficacy, and RP2D. Methods: This is an open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. A traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts was used. All 5 cohorts plus an expansion cohort are presented. Results: Enrollment has been completed and the overall results are summarized. Nineteen patients were enrolled; the majority were heavily pretreated with the average number of prior regimens exceeding 4. Based upon ITT, the ORR is 37%. The ORR is 47% in patients that completed at least 3 cycles. The clinical benefit rate is 73% and the PFS currently stands at approximately 11 months. Two patients with endometrioid endometrial adenocarcinoma achieved a complete response. All patients received comprehensive genomic profiling and 7 patients received prior mTOR inhibitor. Overall, the combination was well tolerated, except by patients in cohort 5. One DLT occurred in the last patient enrolled. The most common non-laboratory AEs were nausea (6%), fatigue (5%), and mucositis (5%). There were 45 (9%) grade 3 or 4 events, and the most common were decreased WBC and non-febrile neutropenia. Hyperglycemia was common in patients with a history of diabetes mellitus. Conclusions: Overall, the combination of sapanisertib, serabelisib, and paclitaxel was safe and efficacious throughout the first 4 cohorts. There were few serious adverse events, and most side effects were managed with routine supportive care interventions. Preliminary clinical results appear very promising, especially for patients with PI3K/AKT/mTOR pathway mutations. The positive effects of the combination were routinely seen in the lowest dosing cohorts and clinical benefit was even seen in patients that had previously failed everolimus or temsirolimus. All patients were either resistant or refractory to paclitaxel at time of enrollment, so further exploration of this combination to elucidate the mechanism of benefit is warranted. Clinical trial information: NCT03154294.

scholarly journals Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia

2020 ◽  
Vol 38 (10) ◽  
pp. 1006-1018 ◽  
Author(s):  
Kim-Hien T. Dao ◽  
Jason Gotlib ◽  
Michael M.N. Deininger ◽  
Stephen T. Oh ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Symptom Assessment ◽  
Complete Response ◽  
Serious Adverse Events ◽  
Chronic Neutrophilic Leukemia ◽  
Atypical Chronic Myeloid Leukemia ◽  
Grade 3

PURPOSE Colony-stimulating factor-3 receptor ( CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status. METHODS We conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival. RESULTS ORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed. CONCLUSION Ruxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.

scholarly journals MNAT1 promotes proliferation and the chemo-resistance of osteosarcoma cell to cisplatin through regulating PI3K/Akt/mTOR pathway

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Chensheng Qiu ◽  
Weiliang Su ◽  
Nana Shen ◽  
Xiaoying Qi ◽  
Xiaolin Wu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Regulation Mechanism ◽  
Osteosarcoma Cell ◽  
Migration Ability ◽  
Mouse Xenograft Model

Abstract Background MNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, highly expressed in diverse cancers and was involved in cancer molecular pathogenesis. However, its deliverance profile and biological function in osteosarcoma (OS) remain unclear. Methods The expression of MNAT1 in OS was detected by western blot (WB) and immunohistochemistry (IHC). The potential relationship between MNAT1 molecular level expression and OS clinical expectations were analyzed according to tissues microarray (TMA). Proliferation potential of OS cells was evaluated in vitro based on CCK8 and OS cells colony formation assays, while OS cells transwell and in situ tissue source wound healing assays were employed to analyze the OS cells invasion and migration ability in vitro. A nude mouse xenograft model was used to detect tumor growth in vivo. In addition, ordinary bioinformatics analysis and experimental correlation verification were performed to investigate the underlying regulation mechanism of OS by MNAT1. Results In this research, we found and confirmed that MNAT1 was markedly over-expressed in OS tissue derived in situ, also, highly MNAT1 expression was closely associated with bad clinical expectations. Functional studies had shown that MNAT1 silencing could weaken the invasion, migration and proliferation of OS cells in vitro, and inhibit OS tumor growth in vivo. Mechanism study indicated that MNAT1 contributed to the progression of OS via the PI3K/Akt/mTOR pathway. We further verified that the MNAT1 was required in the regulation of OS chemo-sensitivity to cisplatin (DDP). Conclusions Taken together, the data of the present study demonstrate a novel molecular mechanism of MNAT1 involved in the formation of DDP resistance of OS cells.

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