Efficacy, Safety, and Patient-Reported Outcomes of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Thailand: A Multicenter Prospective Study.

PURPOSE: Atezolizumab plus bevacizumab treatment is a first-line therapy for unresectable hepatocellular carcinoma (HCC) worldwide. The efficacy, safety, and patient-reported outcomes (PROs) of HCC in Thailand have not yet been reported. This study aimed to evaluate the efficacy, safety, and PROs of atezolizumab plus bevacizumab. MATERIALS AND METHODS: From September 2020 to August 2021, 30 patients with unresectable HCC who met the inclusion criteria of atezolizumab plus bevacizumab as first-line treatment were enrolled. Analysis was assessed for progression-free survival, overall survival, adverse events (AEs), and quality of life (QoL). RESULTS: The median progression-free survival and overall survival periods were 6.7 and 10.2 months, respectively. The disease control rate was 63.3%. The frequent AEs were proteinuria, hypertension, and hepatitis. Serious AEs included gastrointestinal bleeding, but none of the patients died from serious AEs. The discontinuation rate was 23.3%, and the median number of treatment cycles was 10.5 cycles. In total, 23.3% of the patients continued treatment after 1 year of therapy. The global health status/QoL and physical function scores showed less deterioration at baseline than at 3 and 6 months (median scores = 76.7, 71.6, and 64.1 in QoL and 84.7, 79.6, and 79.0 in physical function, respectively). The HCC18 symptom score index data showed a slow progression of symptom scores from baseline to 3 and 6 months (12.7, 19.6, and 22.3, respectively). CONCLUSION: This study demonstrates that atezolizumab plus bevacizumab is effective and has a safety profile comparable with that of previous studies as first-line therapy for unresectable HCC in a real-world setting and in Thai populations. Data on PROs also demonstrate benefits in terms of patients' QoL and symptoms.

Impact of interprofessional collaborative practice in palliative care on outcomes for advanced cancer inpatients in a resource-limited setting.

BACKGROUND: Palliative care for patients with advanced cancer improves suffering symptoms, and quality of life (QoL). However, routine implementation of palliative care by specialty palliative care consultation is still an unmet need among in-patients with advanced cancer. Our study aim is to evaluate the effectiveness of a team-based approach on QoLs and readmission rate when compared to routine practice by among medical oncologists. METHODS: This study was a prospective, Quasi-Experimental design. In-patients with advanced cancer were non-randomly assigned to receive palliative care service by team-based approach or medical oncologists only. The primary endpoint was QoL. The secondary endpoint was the readmission rate at 7 and 30 days of hospital discharge. RESULTS: One hundred twenty-two in-patients were enrolled. In-patients who were assessed by a team-based approach had significantly improved change scores of subjective well-being (SWB) when compared to another group (∆ SWB: -1 [-19 - 11] vs 0 [-9 - 15], p-value = 0.043). Furthermore, patients who were assessed under a team-based approach had significantly decreased in terms of readmission rate at 7 days of hospital discharge (4.92% in the team-based approach group vs. 19.67% in the medical oncologist group, p-value = 0.013). CONCLUSIONS: Interdisciplinary collaboration is the key to success in establishing goals of care, which are supporting the best possible QoL and relieving suffering symptoms for those in-patients with advanced cancer. Furthermore, the readmission rate at 7 days of hospital discharge was significantly reduced by a team-based approach. Therefore, comprehensive palliative care assessment by interprofessional collaborative practice is required. TRIAL REGISTRATION: Thai Clinical Trials Registry (TCTR): number 20200312001. Date of first registration on 09/03/2020.

Asian Thoracic Oncology Research Group (ATORG) Expert Consensus Statement on MET Alterations in NSCLC: Diagnostic and Therapeutic Considerations.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with many oncogenic driver mutations, including de novo mutations in the Mesenchymal Epithelial Transition (MET) gene (specifically in Exon 14 [ex14]), that lead to tumourigenesis. Acquired alterations in the MET gene, specifically MET amplification is also associated with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutant NSCLC. Although MET has become an actionable biomarker with the availability of MET-specific inhibitors in selected countries, there is differential accessibility to diagnostic platforms and targeted therapies across countries in Asia-Pacific (APAC). The Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam, discussed testing for MET alterations and considerations for using MET-specific inhibitors at a consensus meeting in January 2022, and in subsequent offline consultation. Consensus recommendations are provided by the ATORG group to address the unmet need for standardised approaches to diagnosing MET alterations in NSCLC and for using these therapies. MET inhibitors may be considered for first-line or second or subsequent lines of treatment for patients with advanced and metastatic NSCLC harbouring MET ex14 skipping mutations; MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. For patients with EGFR-mutant NSCLC and MET amplification leading to EGFR TKI resistance, enrolment in combination trials of EGFR TKIs and MET inhibitors is encouraged.

A Pilot Study of Using Smartphone Application vs. Routine Follow-Up for Patient Care in Advanced Non-Small Cell Lung Cancer During the COVID-19 Pandemic Era.

Introduction: Cancer care monitoring should be adapted regarding COVID-19 pandemic preparedness plans. Lung Cancer Care application was a mobile application program to monitor adverse events and report outcomes. This study is aimed to invent a new mobile application evaluating patient-reported outcome (PRO) for patients with non-small cell lung cancer (NSCLC) and to evaluate the validity of a mobile application, particularly during the COVID-19 pandemic era. Methods: The validity of the application was tested, and Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaires were contained in the mobile application-based PRO. Patients were randomly assigned to use mobile application-based PRO vs. routine follow-up. The primary end point was to compare the quality of life (QoL) scores between two groups. A secondary end point was overall survival (OS) and the outcomes of progressive disease (PD) between the two groups. Results: In total, 33 patients with advanced NSCLC were enrolled. Patients in the mobile application group had higher FACT-L scores at 3 months than patients with a routine follow-up arm (106 ± 5.97 vs. 99.96 ± 5.74, p-value = 0.07). The median follow-up time was 5.43 months; patients with mobile application had an insignificant increase in median OS when compared with patients using routine follow-up (4.53 vs. 2.93 months, p-value = 0.85). The sensitivity, specificity, positive predictive value (PPV), and negative predictive (NPV) value of this application for predicting disease progression were 50, 83.3, 66.7, and 70%, respectively. Conclusion: Self-reported symptoms by Lung Cancer Care application improved QoL and were similar in monitoring outcomes to face-to-face follow-up. This tool is applicable for patients with cancer to make monitoring as safe as possible for physical distancing during the COVID-19 pandemic era.

A Double-Blind, Placebo-Controlled Randomized Phase IIa Study: Evaluating the Effect of Curcumin for Treatment of Cancer Anorexia-Cachexia Syndrome in Solid Cancer Patients.

OBJECTIVE: We aim to investigate the effect of curcumin on preventing cancer anorexia-cachexia syndrome (CACS) via through mechanism of inhibition on NF-kB signal pathway. Outcome measurement for primary end point was improvement of body tissue composition, and the secondary end points were body weight and body mass index, hand grip muscle strengthening, and safety. METHODS: This is randomized, double-blind, placebo-controlled phase ll a study, 33 patients with CACS in solid malignancy were enrolled and randomized in 1:1 to receive oral curcumin (at a dose of 800 mg twice daily) or placebo for 8 weeks. RESULTS: All parameters of body compositions were not statistically significant different between two groups, which were consist body fat mass [-1.25(SEM 0.87) vs. +0.63(SEM 0.55); p=0.119], skeletal muscle mass [-0.35(SEM 0.60) vs.+0.33(SEM 0.42); p=0.408] and percent body fat [-0.47(SEM 0.95) vs. -0.29(SEM 0.82); p=0.893] including with basal metabolic rate [-13.47(SEM 21.94) vs. +15.30(13.76); p=0.336]. The average of weight loss was also not statistically significant different between two groups. [-1.4 kg(SEM 0.89) in curcumin vs-1.12 kg(SEM 0.73), p=0.810]. Notably, patient with curcumin had less reduction of hand-grip muscle strength on both hands [Rt. handed: -2.47 in curcumin vs. -5.36 in placebo; p=0.318] [Lt. handed: -1.98 vs. -5.43; p=0.317], and basal metabolic rate than placebo group. Most adverse events were grade 1 on both groups similarly. CONCLUSION: Curcumin was not shown to be superior to placebo with regard to increasing the body composition in cancer patients with CACS. However, curcumin might show some clinical benefits, including slow progression of hand-grip muscle strength loss, and basal metabolic rate. Further investigations should be explored.

Efficacy of Curcumin on Treating Cancer Anorexia-Cachexia Syndrome in Locally or Advanced Head and Neck Cancer: A Double-Blind, Placebo-Controlled Randomised Phase IIa Trial (CurChexia).

Background: Cancer anorexia-cachexia syndrome (CAS) is a significant comorbidity among all patients with cancer, increasing the mortality rate. Almost all patients with head and neck cancer experience this syndrome. CAS causes increased energy expenditure by increasing systemic inflammation and decreasing energy consumption due to anorexia. It leads to skeleton muscle breakdown and reduces the quality of life. Nutritional interventions and primary cancer treatment are the mainstays to manage this situation. However, a vicious cycle causes CAS to persist, especially in head and neck cancer, where tumour location and its treatment interfere with nutritional interventions. Curcumin shows anti-inflammatory effects, including modulated CAS in animal and in vitro studies. Objective: The study aimed to determine the effect of curcumin to treat cancer anorexia-cachexia syndrome among current patients with locally advanced or advanced head and neck cancer. Methods: This constitutes a randomised, double-blind, placebo-controlled phase IIa study. Twenty patients with CAS in locally advanced or advanced head and neck cancer adequately nourished via a feeding tube were enrolled and randomised in a 1 : 1 ratio to receive oral curcumin (at a dose of 4000 mg daily) (n = 10) or placebo (n = 10) for 8 weeks. The primary endpoint was body composition (muscle mass, body fat mass, and basal metabolic rate). The secondary endpoints were handgrip muscle strength, body mass index, absolute lymphocyte count, and safety and toxicity. Result: There was a statistically significant benefit from curcumin on improving muscle mass compared with placebo (2.16% [95% confidence interval; CI, -0.75 to 5.07] vs. -3.82% [95% CI, -8.2 to 0.57]; P=0.019). The other parameters of body composition were not significant but tended to favour curcumin benefit. The body fat mass (-0.51 [95% CI, -21.89 to 20.86] vs. -8.97% [95% CI, -19.43 to 1.49]; P=0.432) and percentage of mean change in the basal metabolic rate were noted (BMR) (0.54% [95% CI, -1.6 to 2.67] vs. -1.61% [95% CI, -4.05 to 0.84]; P=0.153). Notably, patients treated with curcumin exhibited less reduction in handgrip muscle strength and absolute lymphocyte count but was not significant. Similarly, most adverse events were grade 1 in both groups. Conclusion: The curcumin add-on resulted in a significant increase in muscle mass than standard nutritional support. Furthermore, it may improve and delay a decrease in the other body composition parameters, handgrip strength, and absolute lymphocyte count. Curcumin was safe and well tolerated. This constitutes an unmet need for clinical trials. This trial is registered with NCT04208334.

The Effect of Intravenous Mannitol Combined With Normal Saline in Preventing Cisplatin-Induced Nephrotoxicity: A Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: Nephrotoxicity is a major dose-limiting toxicity among patients with cancer who were treated with cisplatin. Although no standard approach is available to prevent cisplatin-induced nephrotoxicity, administering intravenous isotonic saline is recommended. Additionally, mannitol combined with hydration has been evaluated, but none of them have been established. Our study aimed to determine the efficacy of mannitol combined hydration to prevent cisplatin-induced nephrotoxicity. PATIENTS AND METHODS: This study was a phase II, randomized, placebo-controlled design. All patients with solid cancers who were treated with cisplatin (n = 48) were randomly assigned to receive either placebo (n = 25) or 20 g of mannitol (n = 23) after completing 2 L of prehydration and receiving cisplatin. Serum creatinine, blood urea nitrogen, electrolyte, and glomerular filtration rate (GFR) were measured at baseline and days 2 and 7. Moreover, GFR was calculated based on the 24-hour urine creatinine clearance rate to assess renal function at baseline and 48 hours after receiving cisplatin. Severity of nausea and vomiting was evaluated using Common Terminology Criteria for Adverse Events. RESULTS: No difference was found regarding baseline characteristics between the two groups. Seven of 23 patients (37.4%) in the mannitol group and 10 of 25 patients (40%) in the placebo group increased serum creatinine level ≥ 0.3 mg/dL at 48 hours after intervention (P value = .48). Patients receiving mannitol exhibited significantly lower incidence of 24-hour urine GFR below 60 mL/min/1.73 m than those in the placebo group (13.6% v 48.0% in the placebo group; P value = .012). Univariate analysis showed the greatest benefit for administering mannitol among patients receiving cisplatin > 80 mg/m2, or patients receiving concomitant radiation. CONCLUSION: Mannitol combined with hydration significantly prevented cisplatin-induced nephrotoxicity. Additionally, mannitol should be particularly considered among patients with cancer, treated with cisplatin > 80 mg/m2, or patients receiving concomitant radiation.

Single dose dexamethasone prophylaxis of postembolisation syndrome after chemoembolisation in hepatocellular carcinoma patient: A randomised, double-blind, placebo-controlled study.

BACKGROUND: Even in the immuno-oncology era, transcatheter arterial chemoembolisation (TACE) is the most effective way to treat intermediate stage hepatocellular carcinoma (HCC). Postembolisation syndrome (PES) is the most common side effect from TACE and there is still no standard prevention guideline. AIM: To evaluate the efficacy of single dose intravenous dexamethasone regimen to prevent PES after TACE among patients with HCC. METHODS: This study enrolled patients with HCC who had eligible indication for TACE without macrovascular invasion/extrahepatic metastasis. Patients were randomly assigned to either an intravenous single dose of dexamethasone 8 mg or placebo one hour before TACE. The primary outcome was a negative result of PES at 48 h after TACE, which was defined as score < 2 of Southwest Oncology Group toxicity coding criteria using fever, nausea, vomiting and pain to calculated. And the secondary end point was duration of admission between two groups. RESULTS: One hundred patients were randomly assigned 1:1. Under intention-to-treat analysis, 49 patients were randomly assigned to the dexamethasone and 51 to the placebo groups. Both groups were similar for baseline characteristics. The negative PES rate was significantly higher in the dexamethasone group than in the placebo group (63.3% vs 29.4%; P = 0.005). Mean Southwest Oncology Group toxicity coding PES was 2.14 (95%CI: 1.41-2.8) vs 3.71 (95%CI: 2.97-4.45) between the dexamethasone and placebo groups, respectively. Cumulative incidence of fever was significantly lower in dexamethasone group with P < 0.001, pain, nausea and vomiting were also lower in the dexamethasone group compared with the placebo group (P = 0.16, P = 0.11, and P = 0.49). The dexamethasone regimen was generally well tolerated by patients with HCC patients including those with hepatitis B virus infection and well-controlled diabetes mellitus. CONCLUSION: Single dose dexamethasone was effective at preventing PES among patients with HCC treated with TACE. The study showed no adverse events of special interest related to dexamethasone.

Extremely high alpha-fetoprotein-producing adrenal hepatoid adenocarcinoma.

Hepatoid adenocarcinoma (HAC) is a rare tumour that produces an alpha-fetoprotein (AFP) mimicking hepatocellular carcinoma (HCC). Adrenal HAC is exceedingly rare. Here we report extremely high AFP-producing adrenal HAC, the first case in Thailand. A 47-year-old man presented with left flank pain and weight loss for 2 months. A palpably huge left flank mass was observed on physical examination. CT revealed a 7 cm enhanced mass involving the left adrenal gland and multiple contrast-enhanced hypodense masses in both liver lobes. The largest was a 3.7 cm at liver segment-VII without cirrhotic background, with an AFP level of 321 495 ng/mL. Both adrenal and liver biopsies were performed. This patient received a diagnosis of advanced adrenal HAC. Unfortunately, the tumour progressed, causing massive upper gastrointestinal bleeding and death. Adrenal HAC is challenging to diagnose, which multifocal HCC, pheochromocytoma and adrenocortical carcinoma should be excluded. Surgical resection is preferred among resectable patients. However, no systemic therapy has been standardised.

Aberrant RL2 O-GlcNAc antibody reactivity against serum-IgA1 of patients with colorectal cancer.

O-GlcNAcylation, a single attachment of N-acetylglucosamine (GlcNAc) on serine and threonine residues, plays important roles in normal and pathobiological states of many diseases. Aberrant expression of O-GlcNAc modification was found in many types of cancer including colorectal cancer (CRC). This modification mainly occurs in nuclear-cytoplasmic proteins; however, it can exist in some extracellular and secretory proteins. In this study, we investigated whether O-GlcNAc-modified proteins are present in serum of patients with CRC. Serum glycoproteins of CRC patients and healthy controls were enriched by wheat germ agglutinin, a glycan binding protein specifically binds to terminal GlcNAc and sialic acid. Two-dimensional gel electrophoresis, RL2 O-GlcNAc immunoblotting, affinity purification, and mass spectrometry were performed. The results showed that RL2 O-GlcNAc antibody predominantly reacted against serum immunoglobulin A1 (IgA1). The levels of RL2-reacted IgA were significantly increased while total IgA were not different in patients with CRC compared to those of healthy controls. Analyses by ion trap mass spectrometry using collision-induced dissociation and electron-transfer dissociation modes revealed one O-linked N-acetylhexosamine modification site at Ser268 located in the heavy constant region of IgA1; unfortunately, it cannot be discriminated whether it was N-acetylglucosamine or N-acetylgalactosamine because of their identical molecular mass. Although failed to demonstrate unequivocally it was O-GlcNAc, these data indicated that serum-IgA had an aberrantly increased reactivity against RL2 O-GlcNAc antibody in CRC patients. This specific glycosylated form of serum-IgA1 will expand the spectrum of aberrant glycosylation which provides valuable information to cancer glycobiology.

Glycoproteomic Analysis Reveals Aberrant Expression of Complement C9 and Fibronectin in the Plasma of Patients with Colorectal Cancer.

Colorectal cancer (CRC) is a major cause of cancer mortality. Currently used CRC biomarkers provide insufficient sensitivity and specificity; therefore, novel biomarkers are needed to improve the CRC detection. Label-free quantitative proteomics were used to identify and compare glycoproteins, enriched by wheat germ agglutinin, from plasma of CRC patients and age-matched healthy controls. Among 189 identified glycoproteins, the levels of 7 and 15 glycoproteins were significantly altered in the non-metastatic and metastatic CRC groups, respectively. Protein-protein interaction analysis revealed that they were predominantly involved in immune responses, complement pathways, wound healing and coagulation. Of these, the levels of complement C9 (C9) was increased and fibronectin (FN1) was decreased in both CRC states in comparison to those of the healthy controls. Moreover, their levels detected by immunoblotting were validated in another independent cohort and the results were consistent with in the study cohort. Combination of CEA, a commercial CRC biomarker, with C9 and FN1 showed better diagnostic performance. Interestingly, predominant glycoforms associated with acetylneuraminic acid were obviously detected in alpha-2 macroglobulin, haptoglobin, alpha-1-acid glycoprotein 1, and complement C4-A of CRC patient groups. This glycoproteomic approach provides invaluable information of plasma proteome profiles of CRC patients and identification of CRC biomarker candidates.

Survival in Response to Multimodal Therapy in Anaplastic Thyroid Cancer.

Context: Historical outcomes in anaplastic thyroid cancer (ATC) have been dismal. Objective: To determine whether an initial intensive multimodal therapy (MMT) is associated with improved ATC survival. Design: MMT was offered to all patients with newly diagnosed ATC treated at the Mayo Clinic from 2003 through 2015; MMT vs care with palliative intent (PI) was individualized considering clinical status and patient preferences. Outcomes were retrospectively analyzed by American Joint Committee on Cancer stage and treatments compared with patient cohort data from 1949 through 1999. Patients: Forty-eight patients (60% male; median age, 62 years); 18 treated with PI, 30 with MMT. Main Outcome Measure: Overall survival (OS) and progression-free survival determined by Kaplan-Meier method. Results: Median OS and 1-year survival for the later cohort were 9 months [95% confidence interval (CI), 4 to 22 months] and 42% (95% CI, 28% to 56%) vs 3 months and 10% for the earlier cohort. Median OS was 21 months compared with 3.9 months in the pooled MMT vs PI groups for the later cohort [hazard ratio (HR), 0.32; P = 0.0006]. Among only patients in the later cohort who had stage IVB disease, median OS was 22.4 vs 4 months (HR, 0.12; 95% CI, 0.03 to 0.44; P = 0.0001), with 68% vs 0% alive at 1 year (MMT vs PI). Among patients with stage IVC cancer, OS did not differ by therapy. Conclusion: MMT appears to convey longer survival in ATC among patients with stage IVA/B disease.

Effects of Animal Venoms and Toxins on Hallmarks of Cancer.

Animal venoms are a cocktail of proteins and peptides, targeting vital physiological processes. Venoms have evolved to assist in the capture and digestion of prey. Key venom components often include neurotoxins, myotoxins, cardiotoxins, hematoxins and catalytic enzymes. The pharmacological activities of venom components have been investigated as a source of potential therapeutic agents. Interestingly, a number of animal toxins display profound anticancer effects. These include toxins purified from snake, bee and scorpion venoms effecting cancer cell proliferation, migration, invasion, apoptotic activity and neovascularization. Indeed, the mechanism behind the anticancer effect of certain toxins is similar to that of agents currently used in chemotherapy. For example, Lebein is a snake venom disintegrin which generates anti-angiogenic effects by inhibiting vascular endothelial growth factors (VEGF). In this review article, we highlight the biological activities of animal toxins on the multiple steps of tumour formation or hallmarks of cancer. We also discuss recent progress in the discovery of lead compounds for anticancer drug development from venom components.