Precision Medicine in Cholangiocarcinoma: Past, Present, and Future.

Cholangiocarcinoma (CCA), or biliary tract cancer, has a poor prognosis. The median survival time among patients with CCA is under 2 years from diagnosis, and the global 5-year survival rate is only 10%. First-line therapy with chemotherapeutic agents, gemcitabine plus cisplatin, has traditionally been used to treat unresectable advanced CCA. In recent years, precision medicine has become a mainstream cancer treatment due to innovative next-generation sequencing technology. Several genetic alterations, including mutations, gene fusions, and copy number variations, have been found in CCA. In this review, we summarized the current understanding of genetic profiling in CCA and targeted therapy in CCA. Owing to the high heterogeneity of CCA, tumor microenvironmental factors, and the complexity of tumor biology, only pemigatinib, infigratinib, ivosidenib, larotrbctinib, and entrectinib are currently approved for the treatment of CCA patients with fibroblast growth factor receptor 2 gene (FGFR2) fusion, isocitrate dehydrogenase gene (IDH1) mutation, and neurotrophin receptor tyrosine kinase gene (NRTK) fusion, respectively. Additional targeted therapies, including other FGFR2 inhibitors, PI3K/AKT/mTOR inhibitors, and BRAF-directed targeted therapy, have been discussed for the management of CCA, and immune checkpoint inhibitors, particularly pembrolizumab, can be administered to patients with high microsatellite instability tumors. There is a further need for improvement in precision medicine therapies in the treatment of CCA and discuss the approved and potential targeted therapies for CCA.

Association of prior fluoroquinolone treatment with survival outcomes of immune checkpoint inhibitors in Asia.

WHAT IS KNOWN AND OBJECTIVE: Gut microbiota plays an important role in shaping immune responses. Several studies have reported that antibiotics may alter gut microbiota diversity and compromise the therapeutic response to immune checkpoint inhibitors (ICIs). Nevertheless, the impact of a specific class of antibiotics on ICIs therapy is still not known. The aim of this study was to analyse the influence of antibiotics on the clinical outcomes of non-small cell lung cancer (NSCLC) patients treated with ICIs and to compare the effects of fluoroquinolones vs. other broad-spectrum antibiotics. METHODS: This retrospective cohort study (n = 340) analysed data from Chang Gung Research Database, which comprises work from seven medical institutions in Taiwan. Patients with NSCLC who received ICIs between January 2016 and March 2019 were evaluated. The data of patients who received antibiotics (ie fluoroquinolone) within 30 days prior to ICIs therapy were analysed. Overall survival (OS) was the goal of our study and was calculated from the time the ICIs therapy start. Survival analysis was estimated using the Kaplan-Meier and Cox statistics. RESULTS: A total of 340 patients were identified for analysis. Of the 340 patients, only over one third (38%) of patients received antibiotics 30 days prior to ICI therapy. These patients exhibited a shorter OS compared with those not receiving antibiotics (median OS, 266 days vs. 455 days; hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.1-8.1, p = 0.003). In this study, 127 out of 128 patients who were exposed to antibiotics had received at least one broad-spectrum antibiotic. We observed patients who had received fluoroquinolone had a shorter OS compared with those receiving other broad-spectrum antibiotics (median OS, 121 days vs. 370 days; HR, 1.582; 95% CI 1.007-2.841; p = 0.047). WHAT IS NEW AND CONCLUSION: Antibiotic treatment, especially fluoroquinolone, prior to ICIs therapy was associated with poorer clinical efficacy in NSCLC patients. Antibiotics should not be withheld when there is a clear need for them despite the possibility of interfering with the microbiome, which may, in turn, adversely affect the ICI's effectiveness. However, one should consider avoiding the use of fluoroquinolones antibiotics.

The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies.

BACKGROUND: The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. METHODS: We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, the patients who experienced grade 1-2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27-0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24-1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21-0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17-0.69, p = 0.003) than patients without any of these irAEs. CONCLUSIONS: Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1-2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Immune Checkpoint Inhibitors for Advanced Melanoma: Experience at a Single Institution in Taiwan.

Background: Immune checkpoint inhibitors (ICIs) have significantly changed the current approach to cancer treatment. Although the use of ICIs has become the standard of care for advanced melanoma, reports of ICI use among Asian populations with melanoma are limited. Therefore, we conducted this retrospective study to assess the efficacy and safety of ICI use in Taiwanese patients. Patients: Patients with histologically confirmed melanoma treated with ICIs at Linkou Chang Gung Memorial Hospital from January 2014 to July 2019 were retrospectively reviewed. Univariant and multivariant analyses were performed to identify possible prognostic factors. Results: Among 80 patients, 45 were treatment-naïve (56.3%), and 35 received prior systemic drugs other than ICIs. Regarding treatment regimens, patients were treated with ipilimumab (n = 9), nivolumab (n = 33), pembrolizumab (n = 16), or combination drugs (n = 22). Nine patients achieved either a complete (n = 2) or partial (n = 7) response and 13 patients were stable, with a resulting response rate of 11.3% and disease control rate of 27.5%. As of the last follow-up in January 2020, patients treated with combination drugs had longer median progression-free survival (PFS) of 5.6 (95% confidence interval [CI]: 1.6-9.6) months than nivolumab (2.9 months, 95% CI: 1.9-3.9 months), pembrolizumab (3.2 months, 95% CI: 2.6-3.8 months), and ipilimumab (2.6 months, 95% CI: 2.4-2.8 months; p = 0.011). No significant differences in overall survival (OS) among the four regimens (p = 0.891) were noted. In the multivariate analysis, combination treatment, disease control, and performance ≤ 1 were independent prognostic factors for PFS. Liver metastases and no disease control were independent unfavorable prognostic factors for OS. The most common factor was skin toxicity (45%), followed by endocrine toxicity (18.8%). Patients undergoing combination treatment experienced more frequent and serious adverse events than patients undergoing monotherapy. Conclusion: ICIs demonstrated efficacy and safety in Taiwanese patients with melanoma. Combination treatment showed the greatest efficacy, but this was also accompanied by greater toxicity among the four regimens. In addition, we identified important prognostic factors, such as liver metastases, performance status, and tumor response, for both PFS and OS. These findings could provide physicians with more information to justify clinical outcomes observed in Asian patients with advanced melanoma.

Response evaluation for immunotherapy through semi-automatic software based on RECIST 1.1, irRC, and iRECIST criteria: comparison with subjective assessment.

BACKGROUND: Pseudoprogression is difficult to diagnose in patients undergoing immunotherapy. Subjective response assessment is still common in clinical practice. PURPOSE: To evaluate the differences between response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), immune-related response criteria (irRC), and modified RECIST 1.1 for immunotherapy (iRECIST) through semi-automatic software, and to compare iRECIST-based response evaluation with subjective assessment. MATERIAL AND METHODS: The best overall response of each patient based on RECIST 1.1, irRC, and iRECIST was determined on CT scans through semi-automatic software and the differences between the criteria were evaluated. Criteria-based response evaluation through semi-automatic software was compared with subjective assessment on radiology report by correlating the best overall response to overall survival. RESULTS: A total of 21 patients were included (five patients with melanoma, 12 patients with non-small-cell lung cancer, and four patients with hepatocellular carcinoma). Two patients with progressive disease by RECIST 1.1 but non-progressive disease by irRC and iRECIST eventually experienced tumor response and had favorable outcomes, indicating pseudoprogression. The survival difference between patients with non-progressive disease and progressive disease was better stratified through iRECIST-based response evaluation (P = 0.078) than that through subjective assessment (P = 0.501). CONCLUSION: Pseudoprogression in immunotherapy may be captured through semi-automatic software utilizing irRC or iRECIST criteria. iRECIST-based response evaluation may provide a better survival stratification compared with subjective assessment.

HLA associations and clinical implications in T-cell mediated drug hypersensitivity reactions: an updated review.

T-cell mediated drug hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to drug hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with drug hypersensitivity.

An ultrasensitive tool exploiting hydration dynamics to decipher weak lipid membrane-polymer interactions.

We introduce a newly developed tool, (1)H Overhauser Dynamic Nuclear Polarization (ODNP), to sensitively explore weak macromolecular interactions by site-specifically probing the modulation of the translational dynamics of hydration water at the interaction interface, in the full presence of bulk water. Here, ODNP is employed on an illustrative example of a membrane-active triblock copolymer, poloxamer 188 (P188), which is known to restore the integrity of structurally compromised cell membranes. We observe a distinct change in the translational dynamics of the hydration layer interacting with the lipid membrane surface and the bilayer-interior as P188 is added to a solution of lipid vesicles, but no measurable changes in the dynamics or structure of the lipid membranes. This study shows that hydration water is an integral constituent of a lipid membrane system, and demonstrates for the first time that the modulation of its translational diffusivity can sensitively report on weak polymer-membrane interactions, as well as mediate essential lipid membrane functions. ODNP holds much promise as a unique tool to unravel molecular interactions at interfaces even in the presence of bulk water under ambient conditions.

Cisplatin-induced acute hyponatremia leading to a seizure and coma: a case report.

We report a rare case of cisplatin-induced acute hyponatremia leading to a seizure and coma. A 66-year-old woman with breast cancer received adjuvant chemotherapy with docetaxel and cisplatin. She had no nausea, vomiting, or diarrhea during or after chemotherapy administration. She had an acute onset of a generalized seizure and coma on the fourth day after chemotherapy. On arrival in the emergency department, she was unconscious with a Glasgow Coma Score of 6 (eyes 1, verbal 1, motor 4). Computed tomography of the brain did not show any lesions. She had no underlying diseases except breast cancer. The laboratory studies showed severe hyponatremia (Na 113 mmol/L) with low plasma osmolality, and elevation of both urinary sodium and urinary osmolality. In addition, polyuria (about 4 L/day) was also noted. Her consciousness level gradually improved the next day with a rise in serum sodium after 3% NaCl infusion. She recovered fully with no sequelae. Assessment using the Naranjo probability scale suggested that cisplatin was the probable cause for the adverse event. The mechanism of hyponatremia induced by cisplatin in our case was thought to be renal salt wasting syndrome (RSWS). In conclusion, cisplatin-induced acute hyponatremia leading to seizures and coma is seen rarely. When RSWS is suspected, hypertonic saline should be administered.

Molecular wheels as nanoporous materials: differing modes of gas diffusion through Ga10 and Ga18 wheels probed by hyperpolarized 129Xe NMR spectroscopy.

The study of crystals of molecular wheels as nanoporous materials is reported. Hyperpolarized (129)Xe NMR spectroscopy has been used to characterize the mode of molecular diffusion and Xe interactions within the supramolecular nanochannels formed upon crystallization of the molecular wheels [Ga(10)(OMe)(20)(O(2)CMe)(10)] and [Ga(18)(pd)(12)(pdH)(12)(O(2)CMe)(6)(NO(3))(6)](NO(3))(6). In agreement with expectations based on the collision diameter of the Xe atom relative to the differing internal diameters of the two types of gallium wheels, single-file diffusion occurs in the Ga(10) channels, whereas in the Ga(18) system the data are consistent with normal, Fickian diffusion. Information about the electronic environment inside the channels was probed by the Xe chemical shift. The interaction of the gas with the channel walls is found to be substantially stronger than the interaction in organic nanotubes and zeolites. The results establish the ability of crystals of molecular wheel compounds to function as a new class of porous nanotubular materials, and ones of a known and variable diameter, for studying the channel diameter dependence of molecular exchange and unidirectional diffusion on the micrometer length scale.