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1.
Clin Cancer Res ; 29(10): 1906-1915, 2023 05 15.
Article in English | MEDLINE | ID: mdl-36802410

ABSTRACT

PURPOSE: The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response. PATIENTS AND METHODS: A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months. RESULTS: As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5-16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7-14.1) and 9.6 months (95% CI: 4.8-16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders. CONCLUSIONS: The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation.


Subject(s)
Head and Neck Neoplasms , Humans , Cetuximab , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/etiology , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/etiology , Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasm Recurrence, Local/drug therapy
2.
Clin Cancer Res ; 28(16): 3464-3472, 2022 08 15.
Article in English | MEDLINE | ID: mdl-35653116

ABSTRACT

PURPOSE: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection. PATIENTS AND METHODS: This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery. RESULTS: Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8-88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58-91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)-positive and PD-L1-negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083). CONCLUSIONS: Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , B7-H1 Antigen , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/surgery , Head and Neck Neoplasms/drug therapy , Humans , Neoplasm Recurrence, Local/pathology , Nivolumab/adverse effects , Squamous Cell Carcinoma of Head and Neck/therapy
3.
Clin Cancer Res ; 28(7): 1345-1352, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35338369

ABSTRACT

PURPOSE: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. PATIENTS AND METHODS: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1-3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60-66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. RESULTS: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27-80), 30% were female, 86% had stage T3-T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%-90%) in the intermediate-risk group and 66% (95% CI, 55%-84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%-77%). No new safety signals were identified. CONCLUSIONS: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.


Subject(s)
Antibodies, Monoclonal, Humanized , Head and Neck Neoplasms , Squamous Cell Carcinoma of Head and Neck , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Chemotherapy, Adjuvant , Cisplatin/therapeutic use , Female , Head and Neck Neoplasms/drug therapy , Humans , Male , Middle Aged , Neoadjuvant Therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy
4.
Cureus ; 13(4): e14448, 2021 Apr 13.
Article in English | MEDLINE | ID: mdl-34079653

ABSTRACT

INTRODUCTION:  There is very limited data comparing the accuracy of ECG to angiography in predicting reperfusion status. In this study, we will determine the accuracy of ECG change i.e. resolution of ST-segment elevation in predicting infarct-related artery (IRA) patency after thrombolysis in patients with ST-segment elevated myocardial infarction (STEMI), in comparison to angiography. METHODS: Three hundred and forty-one (n = 341) patients with acute STEMI received streptokinase, a thrombolytic agent within 12 hours of symptoms, and were enrolled in the study via consecutive convenient non-probability sampling. ECG was recorded as soon as the patient arrived in the emergency unit of cardiology. Subsequent ECG was recorded three hours after the administration of streptokinase to look for resolution of ST-segment elevation. ST-segment resolution was classified as greater/equal to 50% resolved or less than 50% resolved. Coronary angiography was performed within 24 hours of hospitalization and flow in the IRA was assessed. RESULTS: The most common site of myocardial infarction (MI) was the anterior wall (50.1%) and the commonest artery involved was the left anterior descending artery (44.2%). On ECG, ST-resolution of more than 50% was found in 242 (70.9%) participants. Thrombolysis in MI (TIMI) grade III flow in angiography was found in 211 (61.8%) participants. The sensitivity and specificity of ST-resolution to detect TIMI grade III flow was 94.79% and 67.69%, respectively, while accuracy was 84.46%. CONCLUSION: ST-resolution on ECG after streptokinase can predict IRA patency on coronary angiography with moderate to good accuracy. ECG can assist in predicting the impact of streptokinase early in the course of management and give an option of monitoring patient prognosis with a non-invasive test in patients not comfortable with angiography.

5.
Surg Innov ; 28(5): 567-572, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33228482

ABSTRACT

Background. The role of preoperative biliary stenting (PBS) before pancreaticoduodenectomy (PD) in patients with obstructive jaundice is debatable. The objective of the current study was to assess PD outcomes after upfront surgery or PBS and determine the impact of stent to surgery duration on PD outcomes. Methods. We reviewed patients who underwent PD between 2011 and 2019. Patients were grouped based on whether they underwent upfront surgery (n = 67) or PBS (n = 66). We further assessed outcomes based on stent to surgery duration. Results. There was no significant difference in 30-day mortality (3% vs. 2.9%, P = 1), 90-day mortality (7.5% vs. 4.4%, P = .4), and Grade B-C pancreatic fistula rates (7.5% vs. 4.4%, P = .4) in the PBS and upfront surgery groups, respectively. A significant increase in wound infections (22.7% vs. 7.4%, P = .01) and readmissions (10.6% vs. 0, P = .006) was seen in the PBS group. The highest rate of wound infection was seen when stent to surgery duration was 4-6 weeks (41.6%). The wound infection rates in the upfront surgery group, high-risk PBS group (4-6 weeks), and low-risk PBS group were 5/67(7.4%), 5/12(41.6%), and 7/36(19.4%), respectively (P = .008). Conclusions. PBS increases postoperative wound infections when compared with upfront surgery. Patients operated between 4 and 6 weeks after stenting have the highest rate of wound infection.


Subject(s)
Biliary Tract Surgical Procedures , Pancreatic Neoplasms , Drainage , Humans , Pancreatectomy , Pancreatic Fistula , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/surgery , Pancreaticoduodenectomy/adverse effects , Postoperative Complications/epidemiology , Preoperative Care , Retrospective Studies , Stents/adverse effects
6.
J Pak Med Assoc ; 68(3): 376-380, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29540871

ABSTRACT

OBJECTIVE: To document clinical pattern of retinoblastoma in Pakistani population. METHODS: This retrospective study, which was conducted at Department of Ophthalmology, Dow University of Health Sciences, Karachi, reviewed clinical records of patients with retinoblastoma from 1997 to 2012. Staging of disease was done by referring to retinal diagrams, RetCam images, and first magnetic resonance imaging. Ophthalmic notes, imaging reports and histopathology reports of enucleated eyes established optic nerve involvement. SPSS 21 was used for statistical analysis. RESULTS: Clinical records of 295 patients with retinoblastoma in 403 eyes were reviewed, and male to female ratio was 1.3:1. Retinoblastoma was bilateral in 106(35.93%) patients, while 118(40%) patients had hereditary pattern. Mean age at presentation was 35.98+27.63 months, while mean follow-up was 3±2 months. Leucokoria was the most common presenting feature 173(58.64%) followed by proptosis 72(24.41%). Optic nerve involvement was seen on magnetic resonance imaging or histopathology in 81(20.10%) eyes. Distant metastasis was noted in 32(10.85%) patients on first presentation. Chemotherapy with or without adjuvant treatment was given to 238(80.68%) patients. Enucleation and exentration were performed in 164(40.69%) and 12(2.98%) eyes, respectively. CONCLUSIONS: Most common presenting symptom was leucokoria followed by proptosis. Hereditary retinoblastoma was frequently seen in Pakistani children. .


Subject(s)
Neoplasms, Multiple Primary/physiopathology , Retinal Neoplasms/physiopathology , Retinoblastoma/physiopathology , Antineoplastic Agents/therapeutic use , Child, Preschool , Exophthalmos/physiopathology , Eye Enucleation , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Medical History Taking , Neoplasm Staging , Neoplasms, Multiple Primary/diagnostic imaging , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/therapy , Pakistan , Pupil Disorders/pathology , Retinal Neoplasms/diagnostic imaging , Retinal Neoplasms/pathology , Retinal Neoplasms/therapy , Retinoblastoma/diagnostic imaging , Retinoblastoma/pathology , Retinoblastoma/therapy , Retrospective Studies
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