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Background: Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. Methods: KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. Results: Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%–49%) for pembrolizumab plus epacadostat, 21% (6%–46%) for pembrolizumab monotherapy, and 34% (19%–52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3–4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. Conclusions: Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. Trial registration: NCT03358472. Date of trial registration: November 30, 2017. [ABSTRACT FROM AUTHOR]

Background: Alpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models. Objectives: The recommended phase 2 dose (RP2D) was determined in a phase 1b dose-escalation study. Phase 2 evaluated anti-tumour activity with a randomised part in cetuximab-naïve patients and a non-randomised part in cetuximab-resistant patients. Patients and Methods: Alpelisib was administered in 28 d cycles as whole tablets, suspension from crushed tablets or suspension from dispersible tablets in patients with platinum-resistant, recurrent/metastatic HNSCC. Results: The RP2D determined for alpelisib was 300 mg/d. Alpelisib–cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, respectively. Median progression-free survival (PFS) per central review was 86 d for combination treatment and 87 d for cetuximab monotherapy (unadjusted HR 1.12; 95% CI 0.69–1.82; P > 0.05). When adjusted for baseline covariates [sum of longest diameters from central data, haemoglobin and white blood cell (WBC), the results favoured combination treatment (adjusted HR 0.54; 95% CI 0.30–0.97; P = 0.039). PFS per investigator assessment resulted in an unadjusted HR of 0.76 (95% CI 0.49–1.19; P > 0.05) favouring combination treatment. The median PFS in cetuximab-resistant patients was 3.9 months. Conclusions: The addition of alpelisib to cetuximab did not demonstrate a PFS benefit in cetuximab-naïve patients with advanced HNSCC. The alpelisib–cetuximab combination showed moderate activity in cetuximab-resistant patients, with a consistent safety profile. Clinical Trial Registration: ClinicalTrials.gov NCT01602315; EudraCT 2011-006017-34. [ABSTRACT FROM AUTHOR]

Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC. Dual PD-1 and CTLA-4 checkpoint blockade has proven effective in several cancer types. Here the authors report the results of a clinical trial of anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) in patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Posterior reversible encephalopathy syndrome (PRES) is a rare but severe neurological syndrome that may stem from the use of some medications. Although its mechanism is not well-known, hypertension and endothelial dysfunction have been mentioned in previous literature as being related. Lenvatinib serves as a neoplastic agent that inhibits the tyrosine kinase of vascular endothelial growth factor receptors (VEGFR). VEGFR inhibitors result in endothelial dysfunction and consequent hypertension by nitric oxide pathway suppression and endothelin (ET)-1 stimulation. We hypothesized that VEGFR inhibitors would cause PRES. Herein, we report the case of a 40-year-old man with olfactory neuroblastoma who developed PRES while undergoing treatment with lenvatinib, 7 months after initiation. The symptoms included loss of consciousness and seizures. Fortunately, the symptoms and presence of PRES in imaging resolved, 7 days and 1 month, respectively, after cessation of lenvatinib. [ABSTRACT FROM AUTHOR]

Background: Due to smoking, alcohol, and betel nut use, head-and-neck squamous cell carcinoma (HNSCC) is a serious public health problem in Taiwan. Materials and Methods: We performed a single-arm Phase II trial of pazopanib in patients with platinum-refractory recurrent or metastatic HNSCC in 2011. Results: We screened 43 patients in about 6 months. Thirty-three of the patients were excluded due to easy bleeding and vessel contact resulting from the advanced tumor status. The remaining ten patients were included in this study. An objective response was seen in one patient; six patients had clinical benefits, which was comparable with the outcomes of sorafenib or sunitinib in this patient group. Four patients experienced at least Grade 3 bleeding. The tumor response was usually seen in the central cavity; the rim of the cavity extended outside, reflecting peripheral invasion and future resistance. Conclusion: The early use of anti-angiogenesis treatments is necessary for better tumor control and to prevent bleeding and potential resistance. In future, vascular endothelial growth factor receptor and/or epidermal growth factor receptor tyrosine kinase inhibitors may be used in combination with immunotherapy to increase the clinical benefits and avoid the risk of hyperprogression. [ABSTRACT FROM AUTHOR]

Polatuzumab vedotin (PoV) has recently shown promising activity when combined with rituximab-bendamustine (BR) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, few studies have described the prognostic factors predicting response. Here, we aimed to evaluate the efficacy and safety profile of PoV-based chemotherapy, including regimens other than BR, as third-line or beyond treatment for patients with R/R DLBCL and to explore prognostic factors. Overall, 40 patients, including 37 with de novo and 3 with transformed DLBCL, were enrolled. The overall response rate was 52.5%, and 25% and 27.5% of patients showed a complete response and partial response, respectively. With a median follow-up of 18.8 months, the median overall survival (OS) of the total cohort was 8.5 months, and that of those receiving subsequent hematopoietic stem cell transplantation (HSCT) was 24 months. Low/intermediate risk according to the revised International Prognostic Index score at diagnosis and before PoV treatment predicted better OS. Furthermore, a normal lactate dehydrogenase level and an absolute lymphocyte count/absolute monocyte count ratio > 1.5 were favorable OS prognostic factors. The most common adverse event was cytopenia, with 42.5% of patients developing febrile neutropenia. Grade 1–3 peripheral neuropathy associated with PoV was reported in 25% of patients and resolved in most patients after the cessation of treatment. In summary, we demonstrated that PoV combined with either BR or other intensive chemotherapy is an effective and well-tolerated salvage option for patients with R/R DLBCL. Subsequent HSCT has the potential to further improve survival outcomes in this high-risk population. Clinicaltrials.gov number: NCT05006534. [ABSTRACT FROM AUTHOR]

Introduction: Histopathological characteristics of cytomegalovirus (CMV) lymphadenitis have been well described. Rare studies have reported the immune status and clinical features. Clinically, experts believed that CMV lymphadenitis develops in immunocompromised and immunocompetent patients. Infectious mononucleosis (IM)-like syndrome is the most well-known clinical presentation. Methods: We reviewed archived CMV immunohistochemical stains on lymphoid tissues. The clinicopathological features of CMV-positive cases were studied. Results: For lymph nodes, we detected CMV in 29% (5/17) allogeneic peripheral blood hematopoietic stem cell transplantation (PBSCT) recipients, 29% (4/14) post-autologous PBSCT patients, 13% (6/47) patients treated with intravenous chemotherapy, and 9% (9/96) immunocompetent patients. We detected CMV in 7% (2/24) of tonsils but not in the nasopharynx, tongue base, or spleen specimens. The patients with iatrogenic immunodeficiency ranged from 37 to 76 years old. CMV infections developed a few years after lymphoma treatment (median duration after allogeneic PBSCT, 932 days; after autologous PBSCT, 370 days; and after chemotherapy, 626 days). The most common clinical presentation was neck mass (13/25, 42%), followed by asymptomatic image finding (10/25, 40%). Positron emission tomography/computed tomography (PET/CT) scan showed increased uptake compared to the liver in all patients (11/11, 100%). Of 10 lymphoma patients, 8 (80%) had a Deauville score of 4–5; they accounted for 30% (8/27) of lymphoma patients with false-positive PET/CT scan results. All cases were self-limiting. 96% (23/25) cases had Epstein–Barr virus coinfection, and EBER-positive cells were predominantly in a few germinal centers. Conclusions: Cytomegalovirus (CMV) lymphadenitis and tonsillitis were subclinical infections, not primary CMV infection with IM-like syndrome. The lymphadenopathy typically developed a few years after lymphoma treatments in the middle-aged and the elderly. The lesions mimicked lymphoma relapse in PET scans. Therefore, recognizing CMV infection in lymphoid tissues is of clinical importance. [ABSTRACT FROM AUTHOR]

Background: The present study evaluated the 2‐year survival of the Asian population in the CheckMate 141 trial. Methods: The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed. Results: The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2‐year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment‐related adverse events (TRAEs), including skin‐related disorders, showed better OS than the patients without any TRAEs. Conclusions: Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum‐refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin‐related disorders, may be favorable prognostic factors for nivolumab efficacy. Clinical trial registration: NCT02105636. [ABSTRACT FROM AUTHOR]

Objectives: The optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway blocker was the top compound that enhanced T-cell killing of tumor cells in a high-throughput immune-oncology screen, possibly by stimulate the antigen presentation machinery and other mechanisms. We explored the effect of combination of EGFR inhibition with a short course of anti-PD-1 therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).Method: We analyzed the effect of a short course of anti-PD-1 with continuous afatinib on the survival of a real-world cohort of R/M HNSCC patients. Patient characteristics, treatments, efficacies, and toxicities were reviewed and recorded for analysis.Results: From November 2016 to May 2018, 51 consecutive patients received pembrolizumab and afatinib. The cutoff date was June 30, 2022. The most common toxicities (all grades) were diarrhea (62.7%), skin rash (43.1%), mucositis (31.4%), and paronychia (23.5%). The objective response rate was 54.9% (95% confidence interval [CI] 40.3-68.9%). Median progression-free survival was 5.9 months (95% CI: 4.4-7.6 months), and the median overall survival was 10.5 months (95% CI: 6.8-16.5 months). The 12-month, 24-month, 36-month, and 48-month survival rate was 47.0%, 22.5%, 17.7%, and 12.6% respectively.Conclusions: This retrospective study showed that short course pembrolizumab with afatinib therapy has acceptable efficacy in R/M HNSCC patients. The durable response and long-term survival rates were similar to prospective clinical trials. Short course anti-PD-1 therapy, especially in combination with EGFR blocker, is worth for further prospective study. [ABSTRACT FROM AUTHOR]

Aim: An exploratory subgroup analysis of East Asian ( EA) patients in a phase III trial was conducted to assess efficacy and safety trends based on ethnicity. Methods: The 795 patients with recurrent or metastatic squamous cell carcinoma of the head and neck included 111 EA patients randomized to pemetrexed-cisplatin ( n = 55) and placebo-cisplatin ( n = 56) and 684 non- EA patients randomized to pemetrexed-cisplatin ( n = 343) and placebo-cisplatin ( n = 341). Treatment differences in median overall survival and progression-free survival were compared using a stratified log-rank test. Survival was estimated using the Kaplan- Meier method. Results: The median overall survival in the pemetrexed-cisplatin and placebo-cisplatin arms of the EA group (6.8 and 5.7 months, respectively [ P = 0.275]) was similar to that in the global population (7.3 and 6.3 months, respectively [ P = 0.082]); the median progression-free survival in the pemetrexed-cisplatin and placebo-cisplatin arms in the EA group (2.8 and 1.9 months, respectively [ P = 0.748]) was similar to that in the global population (3.6 and 2.8 months, respectively [ P = 0.166]). Compared to the findings in the global population, overall survival for the EA group receiving prior platinum-based therapy was longer ( P = 0.042 vs P = 0.065). There was no significant interaction between treatment arms and ethnicity. Conclusion: Consistent with findings in the global population, pemetrexed-cisplatin did not improve survival compared with placebo-cisplatin for the EA group. However, in a subgroup analysis, pemetrexed-cisplatin showed an overall survival advantage in EA patients receiving prior platinum-based therapy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum-based chemotherapy is often a first-line treatment. Pemetrexed has shown single-agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed-cisplatin for SCCHN. METHODS: In a double-blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2; n = 398) or placebo plus cisplatin (75 mg/m2; n = 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed-cisplatin arm and 6.3 months in the placebo-cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75-1.02; P = .082). Median progression-free survival (PFS, months) was similar in both treatment arms (pemetrexed-cisplatin, 3.6; placebo-cisplatin, 2.8; HR, 0.88; 95% CI, 0.76-1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed-cisplatin (n = 347) led to longer OS and PFS than placebo-cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed-cisplatin (n = 86) resulted in longer OS and PFS than placebo-cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed-cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed-cisplatin compared with placebo-cisplatin did not significantly improve survival for the intent-to-treat population. However, in a prespecified subgroup analysis, pemetrexed-cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Capecitabine is an oral fluoropyrimidine with single-agent activity in metastatic nasopharyngeal carcinoma (NPC). This multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus cisplatin as a first-line treatment for metastatic NPC. Methods Patients with metastatic NPC received cisplatin 100 mg/m2 day 1 plus capecitabine 1000 mg/m2 twice daily on days 1 to 14 every 3 weeks for 6-8 cycles. The primary endpoint was overall response rate. Results Forty-four patients were enrolled; 39 patients were evaluable for efficacy. The overall response rate was 53.8% (95% confidence interval [CI], 37%-70%), including 1 complete response. Median time to tumor progression was 7.3 months (95% CI, 5.6-9.9 months) and median overall survival was 28.0 months (95% CI, 14.5 months-not reached). Common grade 3/4 adverse events were neutropenia (50%), vomiting (11%), thrombocytopenia (9%), and nausea (7%). Conclusions Capecitabine plus cisplatin is an active first-line combination in metastatic NPC that requires a short hospital stay. © 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Background This study was designed to compare 201Tl single photon emission computed tomography (SPECT)/CT with 18-fluoro-2-deoxyglucose (18F-FDG) PET/CT in diagnosing recurrent skull base nasopharyngeal carcinoma (NPC). Methods Twenty-seven patients were recruited. Both 201Tl SPECT/CT and 18F-FDG PET/CT for each patient were performed at least 4 months later after initial therapy. Results The sensitivity and specificity for 201Tl SPECT/CT were 66.7% and 100%, and those for 18F-FDG PET/CT were 86.7% and 75.0%. Lesion/background ratios were obtained for the 10 lesions that were both SPECT and PET true positive. For the 8 patients with recurrences in nasopharyngeal regions, PET lesion/background ratios were all higher than SPECT lesion/background ratios. For the 2 patients with intracranial metastases, SPECT lesion/background ratios were higher than PET lesion/background ratios. Conclusion 201Tl SPECT/CT is as effective as 18F-FDG PET/CT in detecting recurrent NPC. For intracranial recurrence, 201Tl SPECT, because of its high intracranial lesion/background ratio, is probably better than 18F-FDG PET. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [ABSTRACT FROM AUTHOR]

Background. A phase II study was conducted to evaluate the safety and efficacy of a gemcitabine plus vinorelbine combination (GV) for patients with cisplatin-resistant nasopharyngeal carcinoma (NPC). Methods. Thirty-nine eligible patients received vinorelbine, 20 mg/m2, followed by gemcitabine, 1000 mg/m2, on days 1 and 8 of each 21-day cycle. Results. Grade 3/4 neutropenia and thrombocytopenia occurred in 44% and 18% of patients, respectively, but there was only one episode of febrile neutropenia. Nonhematologic toxicities were mild and did not lead to any treatment withdrawal. The overall response rate was 36% (95% confidence interval [CI], 20% to 52%) in an intent-to-treat analysis, with one complete response (3%) and 13 partial responses (33%). The median response duration, progression-free survival, and overall survival were 5.1, 5.6, and 11.9 months, respectively. Conclusion. Given the moderately high activity and favorable toxicity profile, GV is a reasonable choice for patients with cisplatin-resistant NPC. © 2005 Wiley Periodicals, Inc. Head Neck28: XXX–XXX, 2005 [ABSTRACT FROM AUTHOR]

Background. There is a lack of effective treatment for metastatic adenoid cystic carcinoma (ACC), a usually indolent tumor. We studied the efficacy of imatinib mesylate, a potent inhibitor of KIT tyrosine kinase, in patients with KIT-positive metastatic ACC. Methods. Five patients with lung metastasis were treated in a pilot study with imatinib 400 mg by mouth twice a day. Mutations of c-kit and platelet-derived growth factor receptor (PDGFR)-α in tumors from these patients were analyzed. Results. Disease progression was noted in three of five patients during the short treatment periods, ranging from 2 to 3 weeks. Three patients died of disease within 6 months. No detectable mutations were found in c-kit and PDGFR-α. Conclusion. We observed an unexpected high progression rate of metastatic ACC within short periods during imatinib treatment. Use of imatinib to treat cancers without c-kit or PDGFR-α mutation should be approached with caution. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX–XXX, 2005 [ABSTRACT FROM AUTHOR]

Fifty Taiwanese patients with relapsed and/or refractory multiple myeloma (MM) were treated with thalidomide on a dose-escalation schedule, commencing with 100 mg/d nightly and incremented either to the maximally tolerated dose or 800 mg/d. Twenty-two patients (44%) responded, with 10 (45.5%) classified as partial remission and 12 (54.5%) minimal response (MR). Complete response did not occur. Of the 28 non-responders, 14 were progressive disease and 14 stable. The median time from commencement of thalidomide treatment to initial achievement of MR was 29 days (range, 8~155), and the corresponding thalidomide dose was 200 mg/d (range, 100~500). The median tolerated dose of thalidomide for the entire sample was 400 mg/d (range, 100~800), with only two (4%) able to tolerate 800 mg/d. Comparing responsive and non-responsive patients, statistically significant differences were not demonstrated for any characteristics except for CRP level and percentage cytogenetic change, which was slightly higher in the latter group relative to the former. Of particular interest, 18 of the 22 responders experienced transient reduction of leukocyte count preceding the attainment of significant reduction in M-proteins in comparison to only four of the 28 non-responders (82% vs. 14%; p<0.001). The median time from commencement of thalidomide treatment to attainment of minimal leukocyte count was 28 days (range, 7~150), with a mean of 2.19×109/l (range, 0.96~3.35×109/l). Leukopenia was generally transient, with rapid recovery despite subsequent continuation of thalidomide. Levels of other non-hematologically adverse effects attributed solely to thalidomide were generally acceptable. For 25 patients, thalidomide treatment was supplemented with low-dose dexamethasone (4 mg, every other day). Of these, 11 had relapsed from and 14 were primarily refractory to thalidomide treatment. Nine of the 25 dexamethasone-supplemented patients were responders (36%). Of particular note were the unusual events noted with this thalidomide-dexamethasone combination, including vascular thrombosis, acute cholecystitis, idiopathic interstitial lung disease and sudden cardiac death. Our results suggest that thalidomide is also effective for Taiwanese patients with refractory and/or relapsed MM. Importantly, the transient reduction in leukocyte count after commencement of thalidomide treatment may serve as a clinical predictor for response. Adverse effects should be carefully monitored when combining thalidomide and dexamethasone, however. [ABSTRACT FROM AUTHOR]

Purpose. Chemotherapy of advanced hepatocellular carcinoma (HCC) is frequently limited by unacceptable toxicity. Long-circulating polyethylene glycol-coated (PEGylated) liposomal doxorubicin (PLD) has low systemic toxicity. Its safety and efficacy in patients with advanced HCC and the relationship between hepatic function and pharmacokinetics were investigated in this phase II study. Methods. Patients were given 30 mg/m2 PLD every 3 weeks and the dose was escalated to 45 mg/m2 from the third course if the toxicity was deemed tolerable. The plasma level of doxorubicin was determined with fluorometry. Results. A total of 40 patients were recruited into this phase II study. The toxicities were usually mild but unexpectedly, three cirrhotic patients died of infection without neutropenia. Four had a partial response (response rate 10%, confidence interval 0–20%). The median duration of response was 5.6 months. The median time to tumor progression and the median survival of all patients was only 2 and 3 months, respectively. Patients with advanced HCC had lower initial serum concentration, larger volume of distribution and more rapid clearance than patients with other malignancies and normal liver function. However, the pharmacokinetic parameters correlated with neither toxicity nor response. Conclusions. The disposition of PLD in patients with liver dysfunction was not hampered, but it did not exhibit higher activity compared with free drug, and the risk of infection must be watched closely especially in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

Objective: Nasopharyngeal carcinoma (NPC) is one of the dominant cancers in South China and Taiwan. Although NPC is highly chemosensitive, the use of chemotherapy for treating patients with recurrent or metastatic NPC has not been very successful. The emergence of drug resistance may be one of the major reasons. However, the mechanisms of drug resistance of NPC have never been addressed before. In this study, we sought to clarify the role of classical drug resistance markers in predicting the chemosensitivity and the prognosis of patients with advanced NPC. Methods: In a cohort of 202 consecutive patients diagnosed at the Department of Pathology of the National Taiwan University Hospital, 44 patients with adequately preserved pretreatment tumor tissues and complete clinical information regarding the details of chemotherapy and tumor response were identified. The expression of multidrug resistance (MDR1), glutathione-S-transferase-π (GSTπ), and p53 were determined by immunohistochemistry. Tumor response to chemotherapy and survival of the patients were the endpoints of this analysis. Results: Thirty-four patients received cisplatin-based regimens, and 28 of them were enrolled in a prospective trial using a doxorubicin-containing regimen. The overall response rate was 70%. Expression of MDR1 was seen in only 5 cases (11%) and was associated with a significantly worse overall survival, yet did not appear to predict chemoresistance to the doxorubicin-containing regimen. Overexpression of p53 was seen in 22 patients, and surprisingly, was correlated with chemoresponse and a trend towards better survival. GSTπ expression was demonstrated in 13 cases (30%) and was not correlated with chemoresistance to cisplatin-containing regimens and overall survival. Conclusion: In this relatively small cohort, positive MDR1 immunostaining predicted a poor overall survival for recurrent or metastatic NPC patients receiving chemotherapy. Overexpression of p53 by immunohistochemical staining, however, was associated with a better response rate to systemic chemotherapy and a trend towards better survival.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We have previously shown that emodin suppresses tyrosine kinase activity of HER-2/neu-encoded p185neu receptor tyrosine kinase. In this study, we examine the relationship between the chemical structure and the activity of emodin and nine derivatives, and identified that one methyl, one hydroxy, and one carbonyl functional groups are critical for the biological activities of emodin. We also found that one of the derivatives 10-(4-acetamidobenzylidene)-9-anthrone (DK-V-47) is more effective than emodin in repressing the tyrosine phosphorylation of p185neu and in inhibiting the proliferation and transformation of HER-2/neu-overexpressing human breast cancer cells. Using mutation-activated HER-2/neu transformed 3T3 cells, we also investigated whether emodin and DK-V-47 can inhibit malignant transformation induced solely by the HER-2/neu oncogene. We found that DK-V-47 is more potent than emodin in suppressing transformation phenotypes of activated HER-2/neu transformed 3T3 cells including anchorage-dependent and -independent growth, metastasis-associated properties. These results clearly indicate that the inhibition of p185neu tyrosine kinase by both emodin and DK-V-47 is capable of suppressing the HER-2/neu associated transformed phenotypes including the ability to induce metastatic potential. Our results also support the chemotherapeutic implications of the use of either emodin or DK-V-47 to target HER-2/neu-overexpressing cancer cells. [ABSTRACT FROM AUTHOR]

Long-circulating PEG-modified liposome has been shown to improve pharmacokinetic properties and reduce systemic toxicity in cancer treatment. However, drug bioavailability from liposome remains a major challenge to the improvement of its therapeutic efficacy. Previously, we designed a PEGylated dual-effect liposome (named as PL-Dox-Ce6) with chlorin e6 incorporated in the lipid bilayer and Doxorubicin encapsulated in the interior. In this study, another dual-effect liposome with cisplatin encapsulated in the interior was further developed. The pharmacokinetics of these two dual-effect liposomes were studied in tumor-bearing mice. Based on the kinetic data of tumor and plasma, light irradiation was applied onto the tumors at different time points after drug administration to compare the therapeutic efficacy. We demonstrated that a single dose of the dual-effect liposomes combined with two doses of light irradiation can completely eradicate over 90% of the tumor in mice alone with significant survival rate and no toxicity. Thus, this study established a platform that utilizes the dual-effect liposome which combines photodynamic therapy and chemotherapy to improve the therapeutic outcomes of tumors. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal chondrosarcoma (MCS) is a rare malignant variant of chondrosarcoma with a high tendency of recurrence and metastasis. Intradural extramedullary spinal MCS is exceedingly rare and usually found in pediatric patients. Herein, we present an elderly patient with primary intradural extramedullary spinal MCS. Relevant literatures are reviewed to disclose characteristics of intradural extramedullary spinal MCS.Case Presentation: A 64-year-old female presented with urinary difficulty and tightness of upper back preceding progressive weakness of right lower extremity. Magnetic resonance imaging revealed an intradural extramedullary tumor at the level of 3rd thoracic vertebra. This patient underwent total tumor resection and then received adjuvant radiotherapy. Histopathological examination showed that the tumor composed of spindle and round cells with high nucleocytoplasmic ratio accompanied by scattered eosinophilic chondroid matrix. Along with immunohistochemical findings and the existence of HEY1-NCOA2 fusion transcript, the diagnosis of MCS was confirmed. Neurologic deficit recovered nearly completely after surgery. No evidence of local recurrence or distant metastasis was found 5 years after treatments. Including the current case, a total of 18 cases have been reported in the literature with only one case with local recurrence and one case of mortality. The current case was the eldest patient diagnosed with primary intraspinal MCS in the literature.Conclusions: MCS rarely appears in the intradural space of the spine. In contrast to classic MCS, treatment outcome of primary intradural extramedullary spinal MCS is usually excellent as total tumor resection is commonly achievable. Adjuvant radiotherapy may reduce local recurrence and chemotherapy may be associated with fewer recurrences especially for unresectable tumors. [ABSTRACT FROM AUTHOR]