Update on Emerging Therapies for Advanced Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is projected to increase by 3.2 million new cases and account for 1.6 million deaths by 2040. Mortality is largely due to limited treatment options for patients who present with advanced disease. Thus, the development of effective and tolerable therapies is crucial. Chemotherapy has been the backbone of systemic treatment of advanced CRC, but utility has been limited because of invariable resistance to therapy, narrow mechanisms of action, and unfavorable toxicity profile. Tumors that are mismatch repair-deficient have demonstrated remarkable response to immune checkpoint inhibitor therapy. However, most CRC tumors are mismatch repair-proficient and represent an unmet medical need. Although ERBB2 amplification occurs only in a few cases, it is associated with left-sided tumors and a higher incidence of brain metastasis. Numerous combinations of HER2 inhibitors have demonstrated efficacy, and antibody-drug conjugates against HER2 represent innovative strategies in this area. The KRAS protein has been classically considered undruggable. Fortunately, new agents targeting KRAS G12C mutation represent a paradigm shift in the management of affected patients and could lead the advancement in drug development for the more common KRAS mutations. Furthermore, aberrant DNA damage response is present in 15%-20% of CRCs, and emerging innovative combinations with poly (ADP-ribose) polymerase (PARP) inhibitors could improve the current therapeutic landscape. Multiple novel biomarker-driven approaches in the management of patients with advanced CRC tumors are reviewed in this article.

Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis.

BACKGROUND: Patients with decompensated cirrhosis are excluded or underrepresented in clinical trials of systemic therapies for hepatocellular carcinoma (HCC) and comparisons of available therapies are lacking. We aimed to compare overall survival for patients with HCC and Child-Pugh B cirrhosis treated with nivolumab or sorafenib as first systemic treatment. METHODS: We performed a retrospective cohort study in patients with HCC and Child-Pugh B cirrhosis treated at Veterans Affairs medical centers to compare overall survival, adverse events, and reason for discontinuation of therapy between patients treated with nivolumab or sorafenib as first systemic treatment. All statistical tests were 2-sided. RESULTS: Of those meeting inclusion criteria, 431 patients were treated with sorafenib and 79 with nivolumab. Median OS was 4.0 months (95% CI 3.5-4.8) in the sorafenib cohort and 5.0 months (95% CI 3.3-6.8) in the nivolumab cohort. In the multivariable Cox proportional hazards model, nivolumab was associated with a significantly reduced hazard of death compared to sorafenib (HR 0.69; 95% CI 0.52-0.91; p = 0.008). In a secondary analysis using propensity score methods, results did not reach statistical significance (HR 0.77; 95% CI 0.55-1.06; p = 0.11). Treatment was discontinued due to toxicity in 12% of patients receiving nivolumab compared to 36% receiving sorafenib (p = 0.001). CONCLUSION: In patients with HCC and Child-Pugh B cirrhosis, nivolumab treatment may be associated with improved overall survival and improved tolerability compared to sorafenib and should be considered for the first systemic treatment in this population.

PARPis and Other Novel, Targeted Therapeutics in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a mere ∼10% of patients in the United States surviving 5 years from the time of diagnosis. Until recently, the treatment for advanced PDAC differed little based on patient or tumor characteristics. However, recent breakthroughs have identified subgroups of patients who benefit from novel, biomarker-driven therapies. We review the data and role for PARP inhibitors and for other biomarker-directed therapies, including for patients with NTRK fusions, NRG1 fusions, mismatch repair deficiency, and KRAS p.G12C mutations.

Multianalyte Prognostic Signature Including Circulating Tumor DNA and Circulating Tumor Cells in Patients With Advanced Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC. MATERIALS AND METHODS: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone. RESULTS: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681). CONCLUSION: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

Evolving standards of care for neoadjuvant and adjuvant therapy in esophageal, gastroesophageal junction, and gastric cncer.

Multimodality therapy, which can include systemic therapy, radiation therapy, and surgery, is the preferred approach for most localized, clinical T2 to T4, and/or node-positive esophageal, gastroesophageal junction, and gastric cancers. The optimal content and sequence of perioperative treatment of patients with different sites of disease and tumor histologic types continue to evolve. This review highlights the current standard-of-care approaches and areas of ongoing clinical research, including biomarker-directed therapy, pertaining to the treatment of esophageal, gastroesophageal junction, and gastric cancers in patients who are candidates for therapy with curative intent.

Peripheral blood IRF1 expression as a marker for glucocorticoid sensitivity.

OBJECTIVE: Despite of the common usage of glucocorticoids (GCs), a significant portion of asthma patients exhibit GC insensitivity. This could be mediated by diverse mechanisms, including genomics. Recent work has suggested that measuring changes in gene expression may provide more predictive information about GC insensitivity than baseline gene expression alone, and that expression changes in peripheral blood may be reflective of those in the airway. METHODS: We performed in silico discovery using gene expression omnibus (GEO) data that evaluated GC effect on gene expression in multiple tissue types. Subsequently, candidate genes whose expression levels are affected by GC were examined in cell lines and in primary cells derived from human airway and blood. RESULTS: Through gene expression omnibus analysis, we identified interferon regulator factor 1 (IRF1), whose expression is affected by GC treatment in airway smooth muscle cells, normal human bronchial epithelial (NHBE) cells, and lymphoblastoid cell lines (LCLs). Significant IRF1 downregulation post GC exposure was confirmed in two cultured airway epithelial cell lines and primary NHBE cells (P<0.05). We observed large interindividual variation in GC-induced IRF1 expression changes among primary NHBE cells tested. Significant downregulation of IRF1 was also observed in six randomly selected LCLs (P<0.05), with variable degrees of downregulation among different samples. In peripheral blood mononuclear cells obtained from healthy volunteers, variable downregulation of IRF1 by GC was also shown. NFKB1, a gene whose expression is known to be downregulated by GC and the degree of downregulation of which is reflective of GC response, was used as a control in our study. IRF1 shows more consistent downregulation across tissue types when compared with NFKB1. CONCLUSION: Our results suggest that GC-induced IRF1 gene expression changes in peripheral blood could be used as a marker to reflect GC response in the airway.

Differentiating arytenoid dislocation and recurrent laryngeal nerve paralysis by arytenoid movement in laryngoscopic video.

OBJECTIVE: To present a new method of quantifying arytenoid movement during inspiration and determine if it can be used to distinguish arytenoid dislocation from vocal fold paralysis. STUDY DESIGN: Case series with chart review. SETTING: Retrospective study conducted in a university laboratory based on university hospital data. SUBJECTS AND METHODS: Endoscopic videos from 8 patients with dislocation and 5 patients with vocal fold paralysis diagnosed by electromyography were included. Vector analysis measured cuneiform movement, an indirect measurement of arytenoid movement, during 1 inspiration. Measurements normalized and not normalized to vocal fold length were evaluated. Interrater reliability (2 raters) and intrarater reliability (1 rater performing the analysis twice) were evaluated using intraclass correlation coefficient (ICC) analysis. Raters were blinded to subject group during analysis. RESULTS: Pixel-valued cuneiform movement was 81.16 ± 25.62 for dislocation and 30.22 ± 23.60 for paralysis (P = .019). Unitless cuneiform movement was 0.58 ± 0.17 for dislocation and 0.24 ± 0.18 for paralysis (P = .030). Interrater ICC was 0.942 for pixel-valued measurements and 0.962 for unitless measurements. Intrarater ICC was 0.909 for pixel-valued measurements and 0.881 for unitless measurements. CONCLUSIONS: Both pixel-valued and unitless measures of arytenoid movement were significantly greater in arytenoid dislocation than vocal fold paralysis. Pixel-valued measurements were included to demonstrate the ability to make quantitative comparisons across subjects without precise knowledge of camera precision, provided position is approximately stable, as each measurement is inherently normalized by vocal tract length. Future studies will apply this new method of evaluating vocal fold immobility disorders on a larger scale and incorporate a more diverse group of etiologies.

Assessment of vision-related quality of life in dry eye patients.

PURPOSE: To determine vision-related quality of life (QoL) measured with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) and the Ocular Surface Disease Index (OSDI) in dry eye patients, and establish potential correlations with the Zung Self Rating Anxiety Scales (SAS), the Zung Self Rating Depression Scales (SDS), ocular surface parameters, and sociodemographic measures. METHODS: The comparative study included 87 dry eye patients and 71 healthy volunteers who visited the department of ophthalmology, Eye and Ear Nose and Throat (EENT) Hospital of Fudan University, Shanghai, China, between June 2009 and December 2009. Surveys were administered to participants to evaluate their sociodemographic characteristics and disease-related factors. Data collected from the NEI-VFQ and OSDI survey instruments were analyzed to identify potential differences between the dry eye group and the control group. Correlations with sociodemographic characteristics, clinical parameters, and psychological status were evaluated. RESULTS: Compared with the control group, our patient group had lower (worse) NEI-VFQ scores for the subscales of general health, general vision, ocular pain, short distance vision activities, long distance vision activities, vision related social function, vision related mental health, vision related role difficulties, vision related dependency, and driving (all P < 0.05), and higher (worse) OSDI composite and subscale scores of ocular symptoms, vision-related function, and environmental triggers (all P < 0.001). Significant correlations were found between QoL scores and patient anxiety and depression levels. CONCLUSIONS: Vision-related QoL in dry eye patients was impaired and was correlated with anxiety and depression, further implicating this condition as an important public health problem deserving increased attention and resources.

Optimal arytenoid adduction based on quantitative real-time voice analysis.

HYPOTHESIS: The optimal degree of arytenoid rotation for arytenoid adduction (AA) can be determined using quantitative real-time voice analysis. STUDY DESIGN: Repeated measures with each larynx serving as its own control. METHODS: Unilateral vocal fold paralysis (VFP) was modeled in five excised canine larynges. Medialization laryngoplasty (ML) was performed, followed by AA. The optimal degree of arytenoid rotation was determined using real-time measurements of vocal efficiency (V(E) ), percent jitter, and percent shimmer. After the optimal degree of rotation was determined, the arytenoid was hypo- and hyperrotated 10% ± 2% of the optimal angle to mimic hypoadducted and hyperadducted states. Aerodynamic, acoustic, and mucosal wave measurements were recorded. RESULTS: Mean optimal angle of arytenoid adduction was 151.4 ± 2.5°. V(E) differed significantly across experimental conditions (P = .003). Optimal AA produced the highest V(E) of any treatment, but this value did not reach that produced in the normal condition. Percent jitter (P < .001) and percent shimmer (P < .001) differed across groups and were lowest for optimal AA. Mucosal wave amplitude of the normal (P = .001) and paralyzed fold (P = .043) differed across treatments. Amplitude of both folds was highest for optimal AA. CONCLUSIONS: V(E) and perturbation parameters were sensitive to the degree of arytenoid rotation. Using real-time voice analysis may aid surgeons in determining the optimal degree of arytenoid rotation when performing AA. Testing this method in patients and determining if optimal vocal outcomes are associated with optimal respiratory and swallowing outcomes will be essential to establishing clinical viability.

Comparison of labial and mechanical interruption for measurement of aerodynamic parameters.

OBJECTIVES/HYPOTHESIS: To directly compare the mechanical and labial interruption techniques of measuring subglottal pressure (P(s)), mean flow rate (MFR), and laryngeal resistance (R(L)). METHODS: Thirty-four subjects performed 10 trials with both mechanical and labial interruption. P(s) and MFR were recorded, whereas R(L) was calculated by dividing P(s) by MFR. Coefficients of variation were calculated to compare intrasubject precision. A subset of 10 subjects performed the tasks twice with 30 minutes between sessions. Bland-Altman plots were used to determine intrasubject repeatability for each of the methods. RESULTS: Mechanical interruption produced coefficients of variation for P(s), MFR, and R(L) of 0.0995, 0.127, and 0.129, respectively. Labial interruption produced coefficients of variation of 0.102, 0.147, and 0.169, respectively. P values were 0.824 for P(s), 0.159 for MFR, and 0.043 for R(L). The Bland-Altman plots revealed comparable repeatability between the two methods. The 95% confidence intervals of the Bland-Altman plots for mechanical interruption were (-0.050, 0.072), (-0.543, 1.832), and (-2.498, 10.528) for MFR, P(s), and R(L). Confidence intervals for labial interruption were (-0.018, 0.031), (0.057, 2.442), and (-3.267, 10.595) for MFR, P(s,) and R(L). CONCLUSIONS: Mechanical interruption produced higher precision when measuring R(L) because of more reliable airflow measurements. Mechanical and labial interruption showed comparable repeatability. Further research into using mechanical interruption clinically is warranted.

Anxiety and depression in patients with dry eye syndrome.

PURPOSE: This study aimed to determine whether patients with dry eye syndrome [DES] have more symptoms of anxiety and depression than controls without DES. METHODS: In this case-control study, the sample consisted of 89 DES subjects (13 diagnosed with Sjögren's syndrome [SS]) and 73 control subjects. Each subject was diagnosed as having DES or was chosen as a control subject by an ophthalmologist. The Zung Self Rating Anxiety Scales (SAS), Zung Self Rating Depression Scales (SDS), and Ocular Surface Disease Index (OSDI) were administered to all subjects. Scores of SAS and SDS, measuring level of anxiety and depression symptoms, were compared between the DES group and the control group. Correlations with other health status measures were conducted. RESULTS: The SAS and SDS scores of the DES group were significantly higher than the control group (P < 0.001, P < 0.001). The prevalence of DES subjects with anxiety or depression symptoms was significantly higher than in the control group (P = 0.003, P < 0.001). In the DES group, SAS scores were found to be correlated with OSDI and educational level. SDS scores were found to be correlated with OSDI. Neither SAS nor SDS scores were correlated with age, sex, household income, tear break up time (BUT), Schirmer Test 1 (S1T), corneal fluorescein staining (FL), or visual acuity. CONCLUSION: Anxiety and depression are correlated with DES, demonstrating that DES is an important public health problem that merits increased attention and research.

Clinical curative effect of acupuncture therapy on xerophthalmia.

This study observes changes in symptoms of xerophthalmia pre- and post-acupuncture therapy and compares the results of the acupuncture therapy (AT) group and the artificial tear control (ATC) group. Parallel comparative studies were carried out on 44 patients with xerophthalmia, who were divided into the AT group (n = 20) and the ATC group (n = 24). A 10-session acupuncture therapy program was performed for the AT group while Dextran 70 was used for the ATC group with each course of treatment lasting 21 day. Examinations were made on the day when a patient was chosen to join the study, 1 hour after completion of treatment, and 3 weeks after stopping treatment. There was no statistically significant difference in terms of the reduction of the symptoms and sign score (SSS) 1 hour after completion of treatment between the AT group and the ATC group. Three weeks after completion of treatment, the reduction of SSS for the AT group was larger than that of the ATC group, with the difference achieving statistical significance. Both acupuncture therapy and artificial tear therapy have an immediate positive effect on the symptoms of xerophthalmia, but acupuncture therapy has a longer continuous effect than that of artificial tears.

Multiparameter comparison of injection laryngoplasty, medialization laryngoplasty, and arytenoid adduction in an excised larynx model.

OBJECTIVES/HYPOTHESIS: Evaluate the effect of injection laryngoplasty (IL), medialization laryngoplasty (ML), and ML combined with arytenoid adduction (ML-AA) on acoustic, aerodynamic, and mucosal wave measurements in an excised larynx setup. STUDY DESIGN: Comparative case study using ex vivo canine larynges. METHODS: Measurements were recorded for eight excised canine larynges with simulated unilateral vocal fold paralysis before and after vocal fold injection with Cymetra. A second set of eight larynges was used to evaluate medialization laryngoplasty using a Silastic implant without and with arytenoid adduction. RESULTS: IL and ML led to comparable decreases in phonation threshold flow (PTF), phonation threshold pressure (PTP), and phonation threshold power (PTW). ML-AA led to significant decreases in PTF (P = .008), PTP (P = .008), and PTW (P = .008). IL and ML led to approximately equal decreases in percent jitter and percent shimmer. ML-AA caused the greatest increase in signal-to-noise ratio. ML-AA discernibly decreased frequency (P = 0.059); a clear trend was not observed for IL or ML. IL significantly reduced mucosal wave amplitude (P = 0.002), whereas both ML and ML-AA increased it. All procedures significantly decreased glottal gap, with the most dramatic effects observed after ML-AA (P = 0.004). CONCLUSIONS: ML-AA led to the greatest improvements in phonatory parameters. IL was comparable to ML aerodynamically and acoustically, but caused detrimental changes to the mucosal wave. Incremental improvements in parameters recorded from the same larynx were observed after ML and ML-AA. To ensure optimal acoustic outcome, the arytenoid must be correctly rotated. This study provides objective support for the combined ML-AA procedure in tolerant patients.