Clinical Cancer Research

 

A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer

Purpose: Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined. Patients and Methods: We performed a single-arm, open-label, phase...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study

Purpose: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. Patients and Methods: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B

Purpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. Patients and Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Selected Articles from This Issue

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Gastrointestinal Stromal Tumor: Challenges and Opportunities for a New Decade

Gastrointestinal stromal tumor (GIST) provides a paradigm to evaluate new molecularly targeted therapies and to identify structural and functional mechanisms for drug response and resistance. Drug development in GIST has successfully exploited the high reliance on KIT/PDGFRA oncogenic signaling as a therapeutic vulnerability. The recent arrival of avapritinib and ripretinib to the GIST arena has aimed to further improve on precision kinase inhibition and address tumor heterogeneity in imatinib-resistant...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

TIGIT Expression Is Associated with T-cell Suppression and Exhaustion and Predicts Clinical Outcome and Anti-PD-1 Response in Follicular Lymphoma

Purpose: T-cell immunoglobulin and ITIM domain (TIGIT), a member of the immune checkpoint family, is important in normal T-cell biology. However, the phenotypical profile and clinical relevance of TIGIT in follicular lymphoma is largely unknown. Experimental Design: Biopsy specimens from a cohort of 82 patients with follicular lymphoma were analyzed using mass cytometry to explore the phenotype and biological and clinical significance of TIGIT+ T cells. Results: TIGIT is highly expressed...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Current Panorama and Challenges for Neoadjuvant Cancer Immunotherapy

Immune checkpoint inhibitors (ICI) may overcome cancer cells' ability to evade the immune system and proliferate. The long-term benefit of ICI in the metastatic setting led to evaluate neoadjuvant ICI approaches in several tumor types such as melanoma, non–small cell lung cancer, and breast and bladder cancer. We summarize the current evidence for the efficacy of neoadjuvant ICI in cancer and discuss several unresolved challenges, including the role of adjuvant treatment after neoadjuvant ICI, the...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer

Purpose: 124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. Experimental Design: Adult patients with cancer...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

FDA Approval Summary: Pembrolizumab plus Lenvatinib for Endometrial Carcinoma, a Collaborative International Review under Project Orbis

On September 17, 2019, FDA granted accelerated approval to pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. The submission and review of this application was conducted through an FDA Oncology Center of Excellence initiative named Project Orbis...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial

Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)–unrelated HNSCC. Patients and Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Quest for Ideal Composite Biomarkers for Response to Immunotherapies

In the CheckMate 275 study, composite biomarkers appear to better predict response to immunotherapy over individual ones. Nevertheless, the path forward needs consensus guidelines for biomarker interpretation. Thereafter, prospective validation with real-time, serial biospecimen collection along with the development of composite biomarker models leads to the goal of personalized therapy. See related article by Galsky et al., p. 5120

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

A Diagnostic Biopsy-Adapted Immunoscore Predicts Response to Neoadjuvant Treatment and Selects Patients with Rectal Cancer Eligible for a Watch-and-Wait Strategy

Purpose: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (ISB) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watch-and-Wait"). Experimental Design: Biopsies from two independent cohorts (n1 = 131, n2 = 118) of patients with LARC treated with nT followed by radical surgery were immunostained...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Reimagining Vaccines for Prostate Cancer: Back to the Future

Given the modest clinical benefits observed with immune checkpoint blockade in advanced prostate cancer, there is a renewed interest in exploring other forms of immunotherapy. Here, the authors report the use of a novel plasmid DNA vaccine encoding the androgen receptor, called pTVG-AR, in men with metastatic hormone-sensitive prostate cancer. See related article by Kyriakopoulos et al., p. 5162

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts

Purpose: Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved. Experimental...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

AACR Cancer Progress Report 2020: Turning Science into Lifesaving Care

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

Multicenter Phase I Trial of a DNA Vaccine Encoding the Androgen Receptor Ligand-binding Domain (pTVG-AR, MVI-118) in Patients with Metastatic Prostate Cancer

Purpose: Preclinical studies demonstrated that a DNA vaccine (pTVG-AR, MVI-118) encoding the androgen receptor ligand-binding domain (AR LBD) augmented antigen-specific CD8+ T cells, delayed prostate cancer progression and emergence of castration-resistant disease, and prolonged survival of tumor-bearing mice. This vaccine was evaluated in a multicenter phase I trial. Patients and Methods: Patients with metastatic castration-sensitive prostate cancer (mCSPC) who had recently begun androgen...

Clinical Cancer Research current issue

Thu Oct 01, 2020 10:05

The BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K-mutant Solid Tumors

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K-mutant Solid Tumors:

Purpose:
This open-label, dose-finding phase Ib/II study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E–mutant solid tumors.
Patients and Methods:
In phase I, the recommended phase 2 doses (RP2D) were established (primary objective). In phase II, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated BRAF-mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma.
Results:
A total of 126 patients with BRAF-mutant solid tumors were enrolled (phase I: 47 patients; phase II: 79 patients). The RP2D was encorafenib 450 mg once daily plus binimetinib 45 mg twice daily and pharmacokinetic data suggest that drug exposures of each agent were similar in combination compared with single-agent studies. In the phase II cohorts, confirmed responses were seen in two of 11 (18%) evaluable patients with mCRC, 11 of 26 (42%) evaluable patients with BRAFi-pretreated melanoma, and 28 of 42 (67%) BRAFi-naïve patients with melanoma. The most common grade 3/4 adverse event in phase II was increased alanine aminotransferase.
Conclusions:
The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600–mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.

A Serum Protein Classifier Identifying Patients with Advanced Non-Small Cell Lung Cancer Who Derive Clinical Benefit from Treatment with Immune Checkpoint Inhibitors

A Serum Protein Classifier Identifying Patients with Advanced Non-Small Cell Lung Cancer Who Derive Clinical Benefit from Treatment with Immune Checkpoint Inhibitors:

Purpose:
Pretreatment selection of patients with non–small cell lung cancer (NSCLC) who would derive clinical benefit from treatment with immune checkpoint inhibitors (CPIs) would fulfill an unmet clinical need by reducing unnecessary toxicities from treatment and result in substantial health care savings.
Experimental Design:
In a retrospective study, mass spectrometry (MS)-based proteomic analysis was performed on pretreatment sera derived from patients with advanced NSCLC treated with nivolumab as part of routine clinical care (n = 289). Machine learning combined spectral and clinical data to stratify patients into three groups with good ("sensitive"), intermediate, and poor ("resistant") outcomes following treatment in the second-line setting. The test was applied to three independent patient cohorts and its biology was investigated using protein set enrichment analyses (PSEA).
Results:
A signature consisting of 274 MS features derived from a development set of 116 patients was associated with progression-free survival (PFS) and overall survival (OS) across two validation cohorts (N = 98 and N = 75). In pooled analysis, significantly better OS was demonstrated for "sensitive" relative to "not sensitive" patients treated with nivolumab; HR, 0.58 (95% confidence interval, 0.38–0–87; P = 0.009). There was no significant association with clinical factors including PD-L1 expression, available from 133 of 289 patients. The test demonstrated no significant association with PFS or OS in a historical cohort (n = 68) of second-line NSCLC patients treated with docetaxel. PSEA revealed proteomic classification to be significantly associated with complement and wound-healing cascades.
Conclusions:
This serum-derived protein signature successfully stratified outcomes in cohorts of patients with advanced NSCLC treated with second-line PD-1 CPIs and deserves further prospective study.

Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma Harboring HRAS Mutations

A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma Harboring HRAS Mutations:

Purpose:
To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma harboring missense HRAS mutations.
Patients and Methods:
A total of 245 adult patients with previously treated, advanced urothelial carcinoma entered the molecular screening program including HRAS. Those with missense HRAS mutations or STK11:rs2075606 received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-day treatment cycles. The primary endpoint was progression-free survival at 6 months (PFS6).
Results:
We identified 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11:rs2075606 carriers. In 21 patients enrolled in the study, 14 and 7 patients had missense HRAS mutations and STK11:rs2075606, respectively. The most frequently observed adverse events included fatigue (86%) and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as an STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. The overall response rate by intent-to-treat analysis was 24% (4 missense and one nonsense frameshift HRAS mutation); no response was observed in patients with urothelial carcinoma with wild-type HRAS tumors. Five responses were observed in 12 evaluable patients of 15 with tumors carrying HRAS mutations.
Conclusions:
Oral tipifarnib resulted in a manageable safety profile and encouraging antitumor efficacy against treatment-refractory urothelial carcinoma containing HRAS mutations.

Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma:

Purpose:
Eryaspase is composed of l-asparaginase encapsulated in erythrocytes and has demonstrated significant efficacy in a randomized phase II trial. We assessed the prognostic and predictive value of circulating tumor DNA (ctDNA) in patients, plasma included in this trial.
Experimental Design:
Samples prospectively collected pretreatment were centrally analyzed by next-generation sequencing. Prognostic values of baseline ctDNA and ctDNA early changes between day 0 and 28 were assessed in both arms combined on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS); three groups were defined: negative ctDNA (Neg), ctDNA responders (Resp), and ctDNA nonresponders (NResp). Predictive value of ctDNA for eryaspase efficacy was investigated.
Results:
ctDNA was positive at baseline in 77 patients of the 113 tested patients (68%). Detectable ctDNA was an independent negative prognostic factor for OS (4.6 vs. 8.8 months; P = 0.0025) and PFS (1.6 vs. 3.3 months; P = 0.00043). Early change in ctDNA levels was correlated with ORR (20%, 26%, 0%; P < 0.04), PFS (3.7, 3.4, 1.6 months; P < 0.0001), and OS (11.7, 6.5, 4.3 months; P < 0.0001) according to the three defined groups (Neg, Res, NResp, respectively). In patients with ctDNA detectable at baseline, eryaspase was associated with better PFS [HR = 0.53; 95% confidence interval (CI): 0.3–0.94)] and OS (HR = 0.52; 95% CI: 0.29–0.91).
Conclusions:
We confirm from a prospective randomized trial that: (i) the presence of ctDNA at baseline is a major prognostic factor, (ii) the early change of ctDNA correlates with treatment outcome, and (iii) the ctDNA could be a predictive biomarker of eryaspase efficacy.

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275:

Purpose:
We report efficacy and safety with extended follow-up, and exploratory biomarker analyses from the phase II CheckMate 275 trial to identify biomarkers of response to nivolumab in platinum-resistant metastatic or unresectable urothelial carcinoma (mUC).
Patients and Methods:
Patients received nivolumab 3 mg/kg once every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was objective response rate (ORR) per blinded independent review committee (BIRC; using RECIST v1.1) in all treated patients and by tumor PD-L1 expression. Key secondary endpoints were progression-free survival (PFS) per BIRC using RECIST v1.1 and overall survival (OS) in all patients and by PD-L1 expression. Exploratory endpoints included safety and biomarker analyses of tumor mutational burden (TMB), PD-L1, and previously identified mutational signatures.
Results:
Of 270 treated patients, 139 had evaluable TMB. With 33.7 months' minimum follow-up, ORR per BIRC, median PFS, and median OS [95% confidence interval (CI)] in all treated patients were 20.7% (16.1–26.1), 1.9 months (1.9–2.3), and 8.6 months (6.1–11.3), respectively. No new safety signals were identified. Higher TMB was associated (P < 0.05) with improved ORR [OR (95% CI): 2.13 (1.26–3.60)], PFS [HR: 0.75 (0.61–0.92)], and OS [HR: 0.73 (0.58–0.91)]. TMB combined with PD-L1 better predicted ORR, PFS, and OS than PD-L1 alone. Higher mutational signature 2 score was associated with better OS but did not improve the predictive value of TMB.
Conclusions:
These results support the durable antitumor activity of nivolumab and suggest that TMB may enrich for better response in mUC. Future studies of TMB/PD-L1 as biomarkers for response to nivolumab in randomized trials are warranted.
See related commentary by Swami et al., p. 5059

Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer

A Phase II Study of Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer:

Purpose:
This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting.
Patients and Methods:
Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8–12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms.
Results:
Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0–12.2] for Arm A and 14.7 months (95% CI, 11.6–20.0) for Arm B (HR, 1.75; P = 0.019). Using immune-related response criteria, two partial responses (5.7%) were observed in Arm A and four (13.8%) in Arm B. GVAX + ipilimumab promoted T-cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor.
Conclusions:
GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer:

Purpose:
Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues.
Experimental Design:
The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3⁺ T-cells.
Results:
Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3.
Conclusions:
This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.

Radical external beam re‐irradiation in the treatment of recurrent head and neck cancer: Critical review

Radical external beam re‐irradiation in the treatment of recurrent head and neck cancer: Critical review:

Abstract

Management of patients with recurrent head and neck cancer remains a challenge for the surgeon as well as the treating radiation oncologist. Even in the era of modern radiotherapy, the rate of severe toxicity remains high with unsatisfactory treatment results. Intensity‐modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and heavy‐ion irradiation have all emerged as highly conformal and precise techniques that offer many radiobiological advantages in various clinical situations. Although re‐irradiation is now widespread in clinical practice, little is known about the differences in treatment response and toxicity using diverse re‐irradiation techniques. In this review, we provide a comprehensive overview of the role of radiation therapy in recurrent or second primary head and neck cancer including patient selection, therapeutic outcome, and risk using different re‐irradiation techniques. Critical review of published evidence on IMRT, SBRT, and heavy‐ion full‐dose re‐irradiation is presented including data on locoregional control, overall survival, and toxicity.

Endoscopic transoral nasopharyngectomy

Endoscopic transoral nasopharyngectomy:

Abstract

Background

A minimal access technique for the management of nasopharyngeal tumors extending below the palatal plane and laterally beyond the pterygoid musculature is yet to be developed. In this study we demonstrate the feasibility of endoscopic transoral nasopharyngectomy (ETON) for resection of large nasopharyngeal lesions as a natural orifice alternative to traditional approaches.

Methods

ETON was completed in three latex‐injected specimens. Surgical freedom (SF) and angles of attack (AoA) were calculated along the internal carotid artery (ICA).

Results

An endoscopic transoral approach was successfully used to identify the parapharyngeal ICA and subsequently perform a complete nasopharyngeal resection. SF and AoA (sagittal) were found to be the greatest at the anterior genu of the ICA.

Conclusions

ETON is feasible. It provides wide exposure of the skull base and proximal control of the ICA. It may be indicated for the management of nasopharyngeal tumors with inferolateral extension, involving the ICA.

Impact of 23‐valent pneumococcal polysaccharide vaccination on the frequency of pneumonia‐related hospitalization and survival in elderly patients with prostate cancer: A seven‐year nationwide matched cohort study

Impact of 23‐valent pneumococcal polysaccharide vaccination on the frequency of pneumonia‐related hospitalization and survival in elderly patients with prostate cancer: A seven‐year nationwide matched cohort study:

Background

The 23‐valent pneumococcal polysaccharide vaccine (PPSV23) is indicated for adults who have a high risk of pneumonia; however, its effectiveness in patients with prostate cancer who are at a risk of pneumonia because of age and cancer treatments, including androgen‐deprivation therapy, is unknown.

Methods

Between 2000 and 2010, 38,735 patients with prostate cancer were diagnosed in Taiwan. After exclusions and exact matching for age, previous pneumonia, and influenza vaccination, 2188 vaccinated patients and 2188 unvaccinated patients were recruited. The incidence density of all‐cause bacterial pneumonia hospitalizations was analyzed.

Results

Over 7 years of follow‐up, patients who received the PPSV23 had a significantly lower incidence density, with 142.8 per 1000 person‐years versus 162.0 per 1000 person‐years for unvaccinated patients. More patients in the vaccinated cohort were never hospitalized for pneumonia compared with those in the unvaccinated cohort (64.2% vs 62.2%, respectively). After adjusting for the Charlson comorbidity index, cancer treatment modalities, and socioeconomic levels, the risk of pneumonia‐related hospitalization in the PPSV23 vaccination cohort was 0.48 times lower than that in the unvaccinated cohort (adjusted incidence rate ratio, 0.48; P = .046). For patients who received the influenza vaccination, subgroup analysis demonstrated that PPSV23 vaccination significantly decreased the risk (adjusted incidence rate ratio, 0.45; P < .001). Compared with unvaccinated controls, PPSV23‐vaccinated patients had a lower cumulative incidence for the first occurrence of pneumonia‐related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% and 42.3%, respectively; P < .001).

Conclusions

Vaccination of elderly patients who have prostate cancer with the relatively common and inexpensive PPSV23 can decrease the risk of pneumonia and prolong survival.

Cognitive rehabilitation program to improve cognition

Cognitive rehabilitation program to improve cognition of cancer patients treated with chemotherapy: A 3‐arm randomized trial:

Background

There is no treatment for cancer‐related cognitive impairment, an important adverse effect that negatively impacts quality of life (QOL). We conducted a 3‐arm randomized controlled trial to evaluate the impact of computer‐assisted cognitive rehabilitation (CR) on cognition, QOL, anxiety, and depression among cancer patients treated with chemotherapy.

Methods

Patients who reported cognitive complaints during or after completing chemotherapy were randomly assigned to 1 of 3 12‐week CR programs: computer‐assisted CR with a neuropsychologist (experimental group A), home cognitive self‐exercises (active control group B), or phone follow‐up (active control group C). Subjective cognition was assessed by the Functional Assessment of Cancer Therapy–Cognitive Function (FACT‐Cog), objective cognition was assessed by neuropsychological tests, QOL was assessed by the FACT‐General, and depression and anxiety were assessed by psychological tests. The primary endpoint was the proportion of patients with a 7‐point improvement in the FACT‐Cog perceived cognitive impairment (PCI) score.

Results

Among the 167 enrolled patients (median age, 51 years), group A had the highest proportion of patients with a 7‐point PCI improvement (75%), followed by groups B (59%) and C (57%), but the difference was not statistically significant (P = .13). Compared with groups B and C, the mean difference in PCI score was significantly higher in group A (P = .02), with better perceived cognitive abilities (P < .01) and a significant improvement in working memory (P = .03). Group A reported higher QOL related to cognition (FACT‐Cog QOL) (P = .01) and improvement in depression symptoms (P = .03).

Conclusions

These results suggest a benefit of a computer‐based CR program in the management of cancer‐related cognitive impairment and complaints.

Intraductal Lithotripsy in Sialolithiasis Using the Calculase III™ Ho:YAG Laser: First Experiences

Intraductal Lithotripsy in Sialolithiasis Using the Calculase III™ Ho:YAG Laser: First Experiences:

Background and Objectives

To report the first experiences with a newly available Ho:YAG laser system for the treatment of salivary stones.

Study Design/Materials and Methods

A retrospective study in a tertiary referral center was conducted. Patients diagnosed with sialolithiasis were treated in Erlangen using the Calculase III™ Ho:YAG laser (Karl Storz, Tuttlingen, Germany). Preset parameters had a frequency of 4 Hz and energy of 0.8–1.2 J, resulting in 3.2–4.8 W. Following total fragmentation, one to two serial sialendoscopies were performed to achieve complete fragment clearance.

Results

A total of 55 stones in 49 patients were treated; 17 stones in 15 submandibular glands and 38 in 34 parotids. In total, 61 laser lithotripsies (range 1–3 per stone) were performed using various modes (long, short, and burst) and with preset parameters of 4 Hz and energy of 0.8–1.2 J, resulting in effective power of 3.2–4.8 W. Complete fragmentation was achieved in all the accessible stones. Sialendoscopes, fibers, or the mode used had no significant influence on success rates. A multimodal therapy concept was employed to treat stones in 12.24% of the cases; 95.92% of the patients were ultimately stone‐free, and all became symptom‐free. All glands were preserved.

Conclusions

The new Calculase III™ Ho:YAG laser was effective in the treatment of sialolithiasis with no increased risk of complications in the patients or damage to the sialendoscopes. Clinical factors such as the type of gland involved, or the location and size of stones had a greater impact on success rates than the technical or preset parameters. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection

Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection:

Background and Objectives

PD‐L1 is a tumor ligand that binds to the PD‐1 receptor on immune cells, thereby inhibiting the antitumor immune response. The antibody nivolumab is a PD‐1 inhibitor, Food and Drug Administration approved for systemic treatment of several aggressive cancer types. Topically applied nivolumab may hold potential as a future strategy to treat keratinocyte cancer, but its molecular properties preclude unassisted topical uptake. The aim of this study was to investigate uptake and biodistribution of topically delivered nivolumab, assisted by two physical enhancement techniques with different delivery kinetics; ablative fractional laser (AFL) and electronically controlled pneumatic injection (EPI).

Study Design/Materials and Methods

In vitro porcine skin was exposed to CO₂ AFL (20 mJ/mb, 5% density), followed by passive diffusion of nivolumab in a Franz cell (1 mg/ml, 18 hours, n = 6) or treated with EPI (4 bar) for immediate delivery of nivolumab (1 mg/ml, 10 minutes, n = 6). The resulting nivolumab skin concentrations were quantified by enzyme‐linked immunosorbent assay (ELISA) at three skin depths (100, 500, and 1500 µm), comparing the uptake from assisted delivery with intact skin. Biodistribution of nivolumab in the skin for all interventions was visualized by laser ablation‐inductively coupled plasma‐mass spectrometry (LA‐ICP‐MS) and fluorescence microscopy.

Results

Delivery of nivolumab by AFL‐assisted passive diffusion and immediate EPI both resulted in significantly enhanced uptake of nivolumab in all skin depths compared with intact skin (P < 0.05). With AFL, nivolumab concentrations reached 86.3 µg/cm³ (100 µm), 105.8 µg/cm³ (500 µm), and 19.3 µg/cm³ (1500 µm), corresponding to 2–10% of the applied concentration, with the highest deposition in the mid dermis. Immediate EPI delivered 429.4 µg/cm³ (100 µm), 584.9 µg/cm³ (500 µm), and 295.9 µg/cm³ (1500 µm) into the skin, corresponding to 29–58% of the applied nivolumab concentration. From qualitative visualization of the biodistribution, it appeared that nivolumab distributed in a horizontal and continuous homogenous band in the upper and mid dermis through AFL‐exposed skin, whereas EPI‐delivery showed a deep focal deposition extending into the deep dermis.

Conclusions

AFL‐assisted passive diffusion and immediate EPI‐assisted delivery show the potential to deliver therapeutic antibodies locally. Future in vivo and pharmacokinetic studies would reveal the full potential for topical antibody delivery by energy‐based devices. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

Radiotherapy‐Induced Oral Mucositis...Photobiomodulation on Nitrite and Inflammatory Activity

The Effect of Photobiomodulation on Nitrite and Inflammatory Activity in Radiotherapy‐Induced Oral Mucositis: A Randomized Clinical Trial:

Background and Objectives

To investigate pro‐ and anti‐inflammatory cytokines and nitrite salivary levels in patients with head and neck cancer receiving photobiomodulation therapy (PBMT) associated with a Preventive Oral Care Program (POCP), for prevention and control of oral mucositis (OM) during radiotherapy (RT) associated or not with chemotherapy protocol.

Study Design/Materials and Methods

In this randomized double‐blinded clinical trial, 48 patients were randomly assigned to two groups: PBMT (n = 25) and Control (n = 23). In the PBMT group, patients were submitted to PBMT associated with the POCP. In the Control group, patients were submitted only to the POCP. Saliva samples were collected in the 1st (baseline), 7th, 14th, 21st, and 30th sessions of RT, and the levels of interleukin‐6 (IL‐6), IL‐8, IL‐10, IL‐12p70, IL‐1β, and tumoral necrosis factor‐α (TNF‐α) were measured using the cytometric bead array. Nitrite levels were measured by colorimetric method. OM was assessed using the World Health Organization and the National Cancer Institute scales.

Results

Patients in the PBMT group presented less severe OM. PBMT tended to stabilize nitrite concentration levels during the RT regimen. The IL‐1β concentration was associated with higher OM scores. PBMT promoted an increase in IL‐12p70, TNF‐α, and IL‐10 concentration.

Conclusion

PBMT was effective in the prevention and control of severe OM, and its mechanism of action may be related to a better balance of inflammatory response that may favor injury control. Lasers Surg. Med. © 2020 Wiley Periodicals LLC