scholarly journals CTIM-30. EFFICACY OF PEMBROLIZUMAB IN PATIENTS WITH PITUITARY CARCINOMA: RESULTS FROM A PHASE II STUDY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii39-ii40
Author(s):  
Nazanin Majd ◽  
Steven Waguespack ◽  
Janku Filip ◽  
Siqing Fu ◽  
Marta Penas-Prado ◽  
...  
Keyword(s):  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Gene Mutations ◽  
Pituitary Tumors ◽  
Molecular Data ◽  
Pituitary Carcinoma ◽  
Msh6 Gene ◽  
Best Response ◽  
Pituitary Carcinomas

Abstract Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region that leads to debilitating symptoms and poor survival. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there is interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated four pituitary carcinoma patients with pembrolizumab as part of a phase II clinical trial (NCT02721732). Here, we present their clinical course and outcomes and correlate responses with available molecular data: hypermutation status, PD-L1 staining, tumor-infiltrating lymphocyte score, microsatellite status and tumor mutational burden. Patients 1 and 2, with heavily pretreated, refractory corticotroph pituitary carcinoma, had partial radiographic (60% and 32% per irRECIST, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his baseline tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor was not sampled after exposure to temozolomide, but prior somatic mutational testing was negative. Patient 3 (non-functioning corticotroph tumor) had a best response of stable disease for four months. Patient 4 (prolactin-secreting carcinoma) had progressive disease. The latter two patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. PD-L1 staining was negative in all tumors. TIL score was 2 in Patients 1 and 4, negative in Patient 3 and not available in Patient 2. All patients tolerated the treatment well with mild adverse events. Our study generates the hypothesis that an alkylating agent-induced hypermutator phenotype may be an indicator of response to CPIs in pituitary carcinomas. The role of CPI in treating patients with pituitary carcinoma and mechanisms of hypermutation in this population require further study.

scholarly journals Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

2020 ◽  
Vol 8 (2) ◽  
pp. e001532
Author(s):  
Nazanin Majd ◽  
Steven G Waguespack ◽  
Filip Janku ◽  
Siqing Fu ◽  
Marta Penas-Prado ◽  
...  
Keyword(s):  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Alkylating Agents ◽  
Evaluation Criteria ◽  
Gene Mutations ◽  
Pituitary Tumors ◽  
Pituitary Carcinoma ◽  
Tumor Patient ◽  
Pituitary Carcinomas

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.

scholarly journals Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature—“Are We There Yet?”

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 308 ◽  
Author(s):  
Lydia S. Lamb ◽  
Hao-Wen Sim ◽  
Ann I. McCormack
Keyword(s):  
Checkpoint Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Pituitary Tumors ◽  
Vascular Endothelial ◽  
Review Of The Literature ◽  
Vegf Inhibitors ◽  
Multiple Recurrences ◽  
Endothelial Growth Factor ◽  
Pituitary Carcinomas

Aggressive pituitary tumors account for up to 10% of pituitary tumors and are characterized by resistance to medical treatment and multiple recurrences despite standard therapies, including surgery, radiotherapy, and chemotherapy. They are associated with increased morbidity and mortality, particularly pituitary carcinomas, which have mortality rates of up to 66% at 1 year after diagnosis. Novel targeted therapies under investigation include mammalian target of rapamycin (mTOR), tyrosine kinase, and vascular endothelial growth factor (VEGF) inhibitors. More recently, immune checkpoint inhibitors have been proposed as a potential treatment option for pituitary tumors. An increased understanding of the molecular pathogenesis of aggressive pituitary tumors is required to identify potential biomarkers and therapeutic targets. This review discusses novel approaches to the management of aggressive pituitary tumors and the role of molecular profiling.

scholarly journals Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?

2021 ◽  
Vol 184 (1) ◽  
pp. K1-K5 ◽  
Author(s):  
Bastiaan Sol ◽  
Jeroen M K de Filette ◽  
Gil Awada ◽  
Steven Raeymaeckers ◽  
Sandrine Aspeslagh ◽  
...  
Keyword(s):  
Case Report ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Pituitary Carcinoma ◽  
Disease Stabilization ◽  
Checkpoint Inhibitor Therapy ◽  
Promising Treatment ◽  
Acth Secreting

Background Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report. Case We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy. Discussion Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma. Conclusion ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.

Pituitary Carcinoma Diagnosis and Survival Improvement, with Affordable Care Act Correlation: A SEER Database Study

2021 ◽  
Author(s):  
Nathan J. Wallace ◽  
Anand K. Devaiah
Keyword(s):  
Affordable Care Act ◽  
Access To Health Care ◽  
Demographic Data ◽  
Pituitary Tumors ◽  
Pituitary Carcinoma ◽  
Seer Database ◽  
Patient Access ◽  
Case Review ◽  
Retrospective Case ◽  
Pituitary Carcinomas

Abstract Background Pituitary carcinomas are challenging tumors to diagnose and treat due to their rarity and limited data surrounding their etiology. Traditionally, these patients have exhibited poor survival. Over the last several decades, our understanding of pituitary carcinomas has dramatically increased, and there have been recent initiatives to improve patient access to health care, including the Affordable Care Act (ACA). This study investigates whether there were any changes in incidence and treatment outcomes of pituitary carcinoma that correlated with these advances. Methods A retrospective case review was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Those with primary site pituitary tumors with noncontiguous metastases were identified from 1975 to 2016. Demographic data, overall, and cause-specific outcomes were obtained. The data were analyzed using SPSS to generate 5-year Kaplan–Meier curves. Results The incidence of pituitary carcinoma pre- and post-ACA was 0.31 and 2.14 diagnoses/year, respectively. This represents a significant increase (Chi-square, p < 0.00002). In addition, 1-, 2-, and 5-year overall survival of these patients was determined to be 88.2, 74.0, and 66.6% which was significantly improved compared with prior studies. Cause-specific survival of these patients follow similar trends exhibiting 94.1, 79.0, 71.1% after 1, 2, and 5 years, respectively. Conclusion The survival for pituitary carcinoma has improved significantly which signals a change in how practitioners should counsel their patients. There is a significant surge in the number of cases in the post-ACA timeline, which suggests that improving patient access has played a part in wider recognition and treatment initiation for this disease.

scholarly journals Pituitary carcinoma: a review of the literature

2004 ◽  
Vol 16 (4) ◽  
pp. 1-9 ◽  
Author(s):  
Brian T. Ragel ◽  
William T. Couldwell
Keyword(s):  
Pituitary Tumor ◽  
English Literature ◽  
Treatment Options ◽  
Latency Period ◽  
Pituitary Tumors ◽  
Distant Metastases ◽  
Pituitary Carcinoma ◽  
Future Studies ◽  
Additional Surgery ◽  
Pituitary Carcinomas

Pituitary carcinomas, defined as distant metastases of a pituitary neoplasm, are rare; fewer than 140 reports exist in the English literature. The initial presenting pituitary tumor is usually a secreting, invasive macroadenoma, with adrenocorticotropic hormone (ACTH)– and prolactin (PRL)–secreting tumors being the most common. The latency period between the diagnosis of a pituitary tumor and the diagnosis of a pituitary carcinoma is 9.5 years for ACTH-producing lesions and 4.7 years for PRL-secreting tumors. Survival after documentation of metastatic disease is poor; 66% of patients die within 1 year. Treatment options include additional surgery, radiotherapy, and chemotherapy, all of which are associated with poor results. Future studies will focus on identifying those invasive pituitary tumors most likely to metastasize and treating them aggressively before they progress to pituitary carcinomas.

scholarly journals Immunotherapy in Corticotroph and Lactotroph Aggressive Tumors and Carcinomas: Two Case Reports and a Review of the Literature

2020 ◽  
Vol 10 (3) ◽  
pp. 88 ◽  
Author(s):  
Camille Duhamel ◽  
Mirela Diana Ilie ◽  
Henri Salle ◽  
Adjoa Sika Nassouri ◽  
Stephan Gaillard ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Progressive Disease ◽  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Therapeutic Option ◽  
Pituitary Tumors ◽  
Pituitary Mass ◽  
Radiological Response ◽  
Aggressive Tumors ◽  
Pituitary Carcinomas

Once temozolomide has failed, no other treatment is recommended for pituitary carcinomas and aggressive pituitary tumors. Recently, the use of immune checkpoint inhibitors (ICIs) has raised hope, but so far, only one corticotroph carcinoma and one aggressive corticotroph tumor treated with immunotherapies have been reported in the literature. Here, we present two cases, one corticotroph carcinoma and one aggressive prolactinoma (the first one reported in the literature) treated with ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) every three weeks, followed by maintenance treatment with nivolumab (3 mg/kg every 2 weeks) in the case of the corticotroph carcinoma, and we compare them with the two previously reported cases. Patient #1 presented a biochemical partial response (plasma ACTH decreased from 13,813 to 841 pg/mL) and dissociated radiological response to the combined ipilimumab and nivolumab—the pituitary mass decreased from 37 × 32 × 41 to 29 × 23 × 42 mm, and the pre-existing liver metastases decreased in size (the largest one from 45 to 14 mm) or disappeared, while a new 11-mm liver metastasis appeared. The maintenance nivolumab (21 cycles) resulted in a stable disease for the initial liver metastases, and in progressive disease for the newly appeared metastasis (effectively treated with radiofrequency ablation) and the pituitary mass. Patient #2 presented radiological and biochemical progressive disease after two cycles of ICIs—the pituitary mass increased from 38 × 42 × 26 to 53 × 57 × 44 mm, and the prolactin levels increased from 4410 to 9840 ng/mL. In conclusion, ICIs represent a promising therapeutic option for aggressive pituitary tumors and carcinomas. The identification of subgroups of responders will be key.

scholarly journals The Role of Checkpoint Inhibitors in Adults with Classical Hodgkin Lymphoma; A Systematic Review and Meta-Analysis of Phase II and III Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Yazan Samhouri ◽  
Muhammad Yasir Anwar ◽  
Ali Younas Khan ◽  
Urwat Til Vusqa ◽  
Iqraa Ansar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Classical Hodgkin Lymphoma ◽  
Programmed Death ◽  
Phase Ii And Iii

Introduction The ability of the neoplastic cells to escape from immune surveillance has been considered as a hallmark of cancer. The upregulation of programmed death-1 (PD-1) and programmed death ligand-1/2 (PDL-1) axis is a major immune escape pathway in multiple malignancies including classical hodgkin lymphoma (cHL). Disruption of PD1-PDL1/2 pathway using checkpoint inhibitors (CPIs) leads to reactivation of immune cells to attack malignant cells. CPIs have been studied in cHL in different settings. Here in, we did a systematic review and meta-analysis of phase II and III clinical trials that looked at the efficacy of CPIs in cHL Methods We did a comprehensive literature search, using 4 major databases (pubmed, embase, chocrane, and clinialtrials.gov). We used MeSH terms and related keywords that included all CPIs in generic and trade names, and cHL. We included phase II and III prospective clinical trials in patients &gt; 18 year-old. We excluded case reports, case series, review articles, retrospective and observational studies, and phase I clinical trials. Initial search resulted in 1647 articles. After applying the inclusion and exclusion criteria, we had 13 articles that we explored in details. We stratified the articles according to CPIs and did a pooled-analysis of the complete response (CR) rate. Medcalc was used to do the statistical analysis. Results Of those 13 clinical trials, we had 12 phase II trials and 1 phase III trial. Nivolumab was studied in 7 trials (n=568), pembrolizumab in 5 trials (n=427), and camrelizumab in 1 trial (n=86). Table 1 shows the characteristics of these trials. (table 1) Four studies evaluated the efficacy of nivolumab in the relapsed/refractory (RR) setting. Armand et al (2018) evaluated the efficacy of nivolumab after autologous hematopoietic stem cell transplantation (auto-HSCT), the cohort in this study was divided into 3 groups: patients who received brentuximab vedotin (BV) after auto-HSCT, patients who are BV naïve, and patients who received BV before and/or after auto-HSCT. Overall response rate (ORR) and CR were 68% and 13%, 65% and 29%, 73% and 12%, respectively. Maruyama et al (2017) reported ORR and CR of 81.3% and 25%, in 16 Japanese patients received nivolumab in combination with BV. The ORR and CR in the remaining 2 trials were: 82% and 59%, and 85% and 67%. In the frontline setting, nivolumab showed ORR and CR of 84% and 67% (Ramchandren et al, 2019), 96%-100% and 53-85% (Brockelmann et al, 2019 in 2 different dosing regimens), and 100% and 72% (Yasenchack et al, 2019). Pooled analysis of all nivolumab trials showed CR rate of 47.4 % (95% CI 29.0-66.1) (figure 1) Pembrolizumab was evaluated in 4 clinical trials in the RR setting. Armand et el (2019) reported CR rate of 83% in 25 patients. Chen et al (2019) reported ORR and CR of 76.8 % and 26.1% in patients who relapsed after auto-HSCT and BV, 66.7% and 25.9% in patients ineligible for HSCT, and 73.3% and 31.7% in patients who relapsed after auto-HSCT with no prior exposure to BV. In combination with gemcitabine, vinorelbone , and doxorubicin, pembrolizumab showed ORR and CR of 100% and 93%, respectively. The only phase III clinical trial compared pembrolizumab vs BV in the RR setting showed ORR of 65.6% vs 54% and CR of 24.5% vs 24%, respectively. Only one study evaluated pembrolizumab in the frontline setting, ORR and CR of 100% in 30 patients received 3 cycles of pembolizumab followed by 4-6 cycles of doxorubicin, vinblastine, and dacarbazine. Pooled analysis of all pembrolizumab trials showed CR rate of 54.4% (95% CI 32.6-77.2) (figure 2) Only one trial evaluated the role of camrelizumab as monotherapy or in combination with decitabine. The combination regimen showed ORR and CR of 95% and 71% in CPIs naïve patients, and 52% and 28% in patients previously received CPIs. Camrelizumab monotherapy showed ORR and CR of 90% and 32% in CPIs naïve patients. Conclusion CPIs in cHL have showed high rates of response in the frontline and RR settings, with fairly acceptable toxicity profile. Their efficacy was studied post HSCT and BV, in BV naïve patients, and in HSCT-ineligible patients. Pembrolizumab and nivolumab were the 2 most studied CPIs. Future direction should focus on more studies in the frontline setting, the role of combined CPIs with other CPIs or with novel agents, to spare this relatively young population the long term toxicity of chemotherapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.Fazal:Jansen:Speakers Bureau;Jazz Pharma:Consultancy, Speakers Bureau;Stemline:Consultancy, Speakers Bureau;Glaxosmith Kline:Consultancy, Speakers Bureau;Gilead/Kite:Consultancy, Speakers Bureau;Amgen:Consultancy, Speakers Bureau;Novartis:Consultancy, Speakers Bureau;Agios:Consultancy, Speakers Bureau;BMS:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene:Speakers Bureau;Karyopham:Speakers Bureau;Incyte Corporation:Consultancy, Honoraria, Speakers Bureau;Takeda:Consultancy, Speakers Bureau.

Pituitary Carcinoma Occurring as Middle Ear Tumor

1982 ◽  
Vol 90 (5) ◽  
pp. 665-666 ◽  
Author(s):  
David F. Wilson
Keyword(s):  
Medical Treatment ◽  
Pituitary Gland ◽  
Middle Ear ◽  
Pituitary Tumors ◽  
Pituitary Carcinoma ◽  
Glandular Tissue ◽  
Pituitary Fossa ◽  
Slow Growing ◽  
Pituitary Carcinomas

Pituitary gland tumors are most commonly adenomas of the glandular tissue. They are benign, slow-growing tumors confined to the pituitary fossa region. Pituitary tumors that become aggressive, involving contiguous bony structures and brain, as well as metastasizing out of the confines of the skull, are referred to as pituitary carcinomas. This case of pituitary carcinoma is the first reported in the literature occurring as a middle ear tumor. The literature documents many cases of pituitary carcinoma. The history and medical treatment of this case are presented.

scholarly journals Cervical Nodal Metastatic Pituitary Carcinoma: A Case Report

2020 ◽  
pp. 014556132094464
Author(s):  
Matthew M. Kwok ◽  
Jagdeep S. Virk ◽  
Michael Michael ◽  
Madeleine McKinley ◽  
Matthew J. R. Magarey
Keyword(s):  
Needle Biopsy ◽  
Cervical Vertebra ◽  
Pituitary Tumors ◽  
Needle Aspiration ◽  
Pituitary Carcinoma ◽  
Aspiration Cytology ◽  
Fine Needle ◽  
Needle Aspiration Cytology ◽  
Sites Of Metastases ◽  
Pituitary Carcinomas

Pituitary carcinomas are rare tumors with only 170 cases reported in the literature.1 They form a very small proportion of pituitary tumors, which are commonly benign adenomas. Metastatic disease diagnosed by fine needle aspiration cytology is extremely rare and has only been reported in 6 patients,2-5 3 of whom had cervical nodal metastases, with other sites of metastases being the liver and cervical vertebra. We report a case of cervical metastatic pituitary carcinoma diagnosed by core needle biopsy.

scholarly journals Clinical and Molecular Data Define a Diagnosis of Arrhythmogenic Cardiomyopathy in a Carrier of a Brugada-Syndrome-Associated PKP2 Mutation

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 571
Author(s):  
Simone Persampieri ◽  
Chiara Assunta Pilato ◽  
Elena Sommariva ◽  
Angela Serena Maione ◽  
Ilaria Stadiotti ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Gene Mutations ◽  
Diagnostic Algorithm ◽  
Ventricular Myocardium ◽  
Molecular Data ◽  
Arrhythmogenic Cardiomyopathy ◽  
Plakophilin 2 ◽  
The Right ◽  
Early Phases

Plakophilin-2 (PKP2) is the most frequently mutated desmosomal gene in arrhythmogenic cardiomyopathy (ACM), a disease characterized by structural and electrical alterations predominantly affecting the right ventricular myocardium. Notably, ACM cases without overt structural alterations are frequently reported, mainly in the early phases of the disease. Recently, the PKP2 p.S183N mutation was found in a patient affected by Brugada syndrome (BS), an inherited arrhythmic channelopathy most commonly caused by sodium channel gene mutations. We here describe a case of a patient carrier of the same BS-related PKP2 p.S183N mutation but with a clear diagnosis of ACM. Specifically, we report how clinical and molecular investigations can be integrated for diagnostic purposes, distinguishing between ACM and BS, which are increasingly recognized as syndromes with clinical and genetic overlaps. This observation is fundamentally relevant in redefining the role of genetics in the approach to the arrhythmic patient, progressing beyond the concept of “one mutation, one disease”, and raising concerns about the most appropriate approach to patients affected by structural/electrical cardiomyopathy. The merging of genetics, electroanatomical mapping, and tissue and cell characterization summarized in our patient seems to be the most complete diagnostic algorithm, favoring a reliable diagnosis.

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