Hand Foot Research Articles

Vaccination coverage estimates and utilization patterns of inactivated enterovirus 71 vaccine post vaccine introduction in Ningbo, China

BackgroundIn China, enterovirus 71 (EV71) is the major etiological agents of hand foot mouth disease that poses severe risks to children’s health. Since 2015, three inactivated EV71 vaccines have been approved for use. Previous studies indicated the high willingness of EV71 vaccination in eastern China. However, few studies have assessed coverage and utilization patterns of EV71 vaccine in China.MethodsChildren born during 2012–2018 were sampled and their records were abstracted from Ningbo childhood immunization information management system. Descriptive statistics characterized the study population and assessed coverage and timeliness for EV71 vaccination. Simultaneous administration patterns as well as type of EV71 vaccine used were also evaluated. Bivariate and multivariable analysis was used to examine the relationship of socio-demographic characteristics with vaccination coverage and timeliness.ResultsOf 716,178 children living in Ningbo. One hundred seventy-two thousand two hundred thirty-six received EV71 vaccine with a coverage rate of 24.05% and only 8.61% received vaccination timely. 21.97% of children received the complete two dose EV71 series but only 6.49% completed timely. Vaccination coverage and timeliness increased significantly from 2012 birth cohort to 2018 birth cohort. Relatively higher coverage and timeliness were observed in resident children, Inner districts, high socioeconomic areas and large-scaled immunization clinics. Of 329,569 doses of EV71 vaccine, only 5853(1.78%) doses were administered at the same day as other vaccines.ConclusionsThere is a need for increasing EV71 vaccination coverage and timeliness as well as eliminating disparities among different populations. Our study highlights the importance of simultaneous administration to increasing coverage and timeliness of EV71 vaccination.

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study.

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady‐state exposures (area under the concentration curve from 0 to 12‐h [AUC0–>12 h]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m2/dose) or a pharmacokinetically guided dose targeting an AUC0–>12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in‐target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

A Nomogram Predicting Progression Free Survival in Patients with Gastrointestinal Stromal Tumor Receiving Sunitinib: Incorporating Pre-Treatment and Post-Treatment Parameters.

Simple SummarySunitinib has been approved as the second-line targeted treatment for gastrointestinal stromal tumor (GIST) after imatinib failure. It is thus necessary to effectively assess prognosis after sunitinib use. However, the current assessment remains insufficient for the contemporary period. We examined prognostic factors influencing progression-free survival. Furthermore, we constructed a prognostic nomogram model using these significant pre-treatment and post-treatment variables.The present study aimed to construct a prognostic nomogram incorporating pre-treatment and post-treatment factors to predict progression-free survival (PFS) after use of sunitinib in patients with metastatic gastrointestinal stromal tumors (GISTs) following imatinib intolerance or failure. From 2007 to 2018, 109 metastatic GIST patients receiving sunitinib at Chang Gung Memorial Hospital, Taiwan, were enrolled. A prognostic nomogram to predict PFS was developed. Sixty-three male and forty-six female metastatic GIST patients, with a median age of 61 years (range: 15–91 years), received sunitinib. The median PFS for 109 patients is 9.93 months. For pre-treatment factors, male gender, body mass index more than 18.5 kg/m2, no sarcopenia status, higher lymphocyte count, lower platelet/lymphocyte ratio, good performance status, higher sunitinib dose, and non-liver metastasis were significantly associated with favorable PFS. For post-treatment factors, adverse events with hypertension, hand–foot skin reaction, and diarrhea were significantly associated with favorable PFS. However, only eight clinicopathological independent factors for PFS prediction were selected for prognostic nomogram establishment. The calibration curve for probability of PFS revealed good agreement between the nomogram prediction and actual observation. High risk patients will experience the lowest PFS. A prognostic nomogram integrating eight clinicopathological factors was constructed to assist prognostic prediction for individual patients with advanced GIST after sunitinib use.

Real-world safety and effectiveness of regorafenib in metastatic colorectal cancer: the French CORRELATE cohort.

Aim: We report real-world evidence with regorafenib in previously treated metastatic colorectal cancer from the French cohort of the international, prospective, observational CORRELATE study. Patients & methods: Patients receiving regorafenib according to French health authority approval were included. The primary end point was treatment-emergent adverse events. Overall survival and progression-free survival were secondary end points. Results: Two hundred and forty-two patients (61% male, median age: 66years) were enrolled. The most common grade ≥3 drug-related treatment-emergent adverse events were hand-foot skin reaction (10.3%), asthenia/fatigue (9.9/1.2%) and hypertension (6.2%). Median overall survival and progression-free survival were 6.8 (95% CI: 6.3-7.6) and 2.8months (95% CI: 2.6-3.0), respectively. Conclusion: The real-world safety and effectiveness data of regorafenib in metastatic colorectal cancer in France align with findings from Phase III clinical trials and the global CORRELATE population.

Adjuvant capecitabine in locoregionally advanced nasopharyngeal carcinoma: A multicenter randomized controlled phase III trial.

6005 Background: We conducted a multicenter, randomized controlled phase III clinical trial (NCT02143388) to investigate the efficacy and toxicity of adjuvant capecitabine (AC) in addition to concurrent cisplatin and radiotherapy (CCRT) compared to CCRT alone in high-risk locoregionally advanced nasopharyngeal carcinoma (LANPC) patients. Methods: Eligibility criteria included AJCC/UICC 7th ed TNM stage III-IVb and one of the following features: T3-4N2 or T1-4N3 or pre-treatment plasma EBV DNA concentration of >20,000 copy/ml or gross primary tumor volume (GTVnx) of >30 cm3 or a maximum standard uptake value (SUVmax) of >10.0 by 18FDG PET-CT within the primary tumor or multiple neck node metastases, with any larger than 4 cm. All patients were randomly assigned in a 1:1 ratio to receive CCRT (3-weekly cisplatin at 100 mg/m2 for 2-3 cycles) followed by AC (1000 mg/m2 bi-daily for 14 days every 21-day cycle for 8 cycles), or CCRT alone. The prescribed radiation doses were 68-72 Gy/30-32 fractions to the PTVnx, 60-68 Gy/30-32 fractions to PTVnd, 60-64Gy/30-32 fractions to PTVhigh-risk, 54-58Gy/30-32 fractions to PTVlow-risk. Primary end point was failure-free survival (FFS). Results: Between Mar 2014 to Jul 2018, 180 patients were recruited (90 patients in CCRT+AC arm and 90 in CCRT alone arm). All patients completed RT and ≥2 cycles of concurrent cisplatin in both treatment arms (cumulative dose intensities for cisplatin were 200 mg/m2 in both arms). 85 (94.4%) patients went on to receive AC, with 71 (78.9%) patients completing 8 cycles; 19 (22.4%) patients had dose reduction of AC. With a median follow-up of 44.8 mo, the 3-y FFS was significantly superior in the CCRT+AC arm than the CCRT arm for the intention-to-treat cohort (87.7% vs 73.3%; HR: 0.52 [95% CI: 0.29-0.77], P = 0.037). 3-year overall, distant metastasis-free and locoregional relapse-free survival were 92.6% vs 88.9% (HR [95% CI]: 0.66 [0.28-1.59]), 88.8% vs. 81.1% (HR: 0.67 [0.33-1.33]) and 91.5% vs 80.0% (HR: 0.50 [0.25-1.00]), respectively. Incidences of G3-4 acute toxicities were 57.8% (52 of 90) in CCRT+AC arm and 51.1% (46 of 90) in CCRT alone arm, with a higher incidence of hand foot syndrome (3.5% vs 0%), xerostomia (11.1% vs 3.3%), mucositis (23.3% vs 16.7%), and anemia (5.6% vs 2.2%) in the CCRT+AC arm. G3-4 late toxicities occurred in 13.3% (12 of 90) and 9.0% (8 of 89), respectively. Conclusions: The addition of capecitabine to CCRT conferred a superior disease control than CCRT alone in high-risk LANPC. Survivals in ITT and PP set. Clinical trial information: NCT02143388. [Table: see text]

Apatinib in combination with camrelizumab, a humanized immunoglobulin G4 monoclonal antibody against programmed cell death-1, in patients with metastatic acral melanoma.

9539 Background: Patients(pts) with metastatic acral melanoma respond poorly to anti–PD-1 monotherapy. Apatinib, a vascular endothelial growth factor (VEGF) inhibitor, is a kind of anti-angiogenic drugs which have shown synergistic therapeutic effects in combination with PD-1 blockade. We conducted this single-center, open label phase trial to evaluate the safety and efficacy of camrelizumab in combination with apatinib in advanced treatment-naïve acral melanoma pts. Methods: Eligible participants were adult pts (aged 18 to 75) with histologically confirmed unresectable stage or distant metastatic acral melanoma. Exclusion criterion included unknown primary melanoma, brain metastatic disease or previous use of anti PD-1 ab. Pts received camrelizumab at 200mg intravenous infusion every 2 weeks, in combination with apatinib 250 mg orally once a day. The primary endpoint was ORR according to RECIST 1.1 criteria, and the secondary endpoints were safety and RFS. Results: Thirty pts were enrolled from April 2019 to January 2021. Basic characteristics: the mean age was 56.7 years, 22 pts were at stage, 33.3% had an elevated LDH level. Median tumor burden was 45mm (10-187). Gene mutation: Nras 4, cKit 3, Braf 2. Up to January 2021, 27 pts could be evaluated, in which 2 pts got CR, 4 pts achieved PR, and 63% experienced tumor shrinkage. The ORR and DCR were 22.2% and 77.8%, respectively. With a median follow up time of 8.3 months, the median PFS was 8.0 months (95% CI, 3.68, 10.19), the one-year durable response rate was 83.3% and the duration of response time was still not reached. Univariate analysis showed high LDH level was negatively associated with PFS. Whole exome data of baseline tumor biopsies revealed a positive correlation between high copy number variation (CNV) plus high mutational load (TMB) and efficacy，and all of the 4pts with MDC1 gene mutation got tumor shrink and 2 got PR. 96.7% pts experienced treatment-related AEs (TRAEs), including hand foot syndrome in 40%, proteinuria in 40%, liver dysfunction in 36.7%, and hypothyroidism in 30%. The grade 3-4 TRAEs were 33.3%. AE-related permanent discontinuation occurred in only 13.3% pts. 6 pts had delays of treatment due to the COVID-19 epidemic. No dose-limiting toxicities and suspected unexpected AEs were observed in the combination. Conclusions: The combination of apatinib plus camrelizumab was tolerable and showed promising antitumor activities and PFS improvement in pts with treatment-naïve metastatic acral melanoma. The survival is still in follow up. Clinical trial information: NCT03955354.

Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC).

e15016 Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4. Capecitabine (X) at optimal dose of 7 days on and 7 days off schedule (7/7) is well-tolerated with low rates of ≥ grade (G3) diarrhea. Methods: We conducted phase Ib/II study of N with X (7/7) with loperamide and colestipol prophylaxis in patients (pts) with pretreated HER2+ MBC (NCT03377387). Eligible pts had normal left ventricular ejection fraction (≥ 50%), any and < 4 prior chemotherapy-based treatments in phase Ib and II, respectively. Primary endpoint of phase Ib is maximum tolerated dose (MTD) and phase II is response rate. Secondary endpoints are safety, tolerability, and progression-free survival. Exploratory endpoint is to quantify cell-free DNA (cfDNA), correlating with response. Phase Ib follows traditional 3+3 design with 4 dose levels. In phase II, if > 3/9 respond, study is expanded to 24. If > 10/24 respond, study is deemed successful. Results: As of 2-4-2021, 10 pts were enrolled in phase Ib. 4 pts were treated at dose level 1 (X at 1500 mg BID at 7/7 and N at 240 mg daily); 2/4 pts experienced with G3 diarrhea during cycle 1. Six pts were treated at dose level -1 (X at 1000 mg BID 7/7 and N at 240 mg daily); 1 (17%) developed G3 diarrhea. The MTD is X at 1000 mg BID 7/7 and N at 240 mg daily. Twenty-two of 24 pts have been enrolled in phase II. Of 22 pts, data show 6 with partial response, 8 with stable disease, 3 with progressive disease, and 5 have not been assessed radiographically. Overall, 6/22 (27.3%) and 1/22 (4.5%) had all G and G3 diarrhea, respectively. Other significant toxicities at MTD included G2 hand foot syndrome (n = 1, 4.5%), G1 fatigue (n = 1, 4.5%) and G1 nausea (n = 4, 18%). Conclusions: The MTD is X at 1000 mg BID at 7/7 and N at 240 mg daily. This combination is safe and well tolerated with G3 diarrhea rate of 4.5%, which is significantly lower than the X 14/7 schedule in NALA study. The phase II portion of the study is near completion and updated result will be presented. Analysis of cfDNA, to correlate with response for phase II portion, is ongoing. Clinical trial information: NCT03377387.

Planned drug holiday in a cohort study exploring the effect of lenvatinib on differentiated thyroid cancer.

6070 Background: Lenvatinib is now available for unresectable radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). However, toxicities are considerable and require frequent dose interruption and modification. Recently, planned drug holidays, which are dose interruptions in accordance with the timing of severe or intolerable adverse events, have been proposed to avoid severe adverse events due to lenvatinib (Tahara M.ESMO Open 2018). Our retrospective study demonstrated that progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who used planned drug holidays than those who did not (Matsuyama C et.al, 2020 Annual Meeting of the Japan Association of Endocrine Surgeons). Methods: In this prospective observational study, patients with curatively unresectable and progressive RAI-refractory DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities were permitted. Primary endpoint was OS, and secondary endpoints were time to treatment failure (TTF), time to failure of strategy (TFS), PFS with clinical progressive disease, response rate, quality of life, safety, and patient reports. This study was registered with UMIN Clinical Trials Registry (UMIN000022243). Results: 262 patients were accrued. Of 255 evaluable, 153 were female; median age was 70 (range 27.0-88.0); histology was papillary thyroid carcinoma/follicular thyroid carcinoma/poorly DTC in 204/45/4; previous therapy was surgery/RAI/molecular targeted drug in 246/164/14; reason for initiation of lenvatinib was disease progression/unsuitable for RAI in 241/4. 1-year OS was 85.6% (95%CI: 80.6-89.4%); 1-year TTF rate was 74.9% (95%CI: 69.1-79.8%); 1-year TFS rate was 80.8% (95%CI: 75.4-85.2%); and 1-year PFS rate was 84.4% (95%CI: 79.3-88.4%). Overall response by RECIST was 3 (1.2%) in CR and 151 (61.9%) in PR. Most common grade 3 or 4 toxicities were hypertension (61.4%), hand foot syndrome (10.2%), fatigue (9.1%), anorexia (8.3%) and diarrhea (4.7%). Grade 5 toxicities occurred in 4 patients (fistula, hypoxia, respiratory failure, trachea stenosis). Of 253 patients evaluable for efficacy, 73 used planned drug holidays. TTF, TFS and PFS were significantly longer in patients who used planned drug holiday than those who did not (Table). Conclusions: Planned drug holiday for lenvatinib demonstrated significantly better clinical outcomes, including TTF, TFS and PFS, than daily oral administration. These data further support use of a planned drug holiday in RAI-refractory DTC patients receiving lenvatinib. Clinical trial information: 000022243. [Table: see text]

Successful treatment of pulmonary lymphangitic carcinomatosis by anlotinib in 14 Chinese patients with advanced non-small cell lung cancer.

e21064 Background: Pulmonary lymphangitic carcinomatosis (PLC) occurs in 6%-8% of intrathoracic metastases among malignant tumor. The median survival was only 2.0 months from time of pulmonary symptoms to death in cases during 2000-2018, which is a poor prognosis. Effective interventions were needed besides standard chemotherapy and symptomatic support. Anlotinib showed a critical effect on lymphangiogenesis, and lymphatic metastasis in mouse models of lung adenocarcinoma, it might be a therapeutic option for tumor lymphatic metastasis. In this study, we retrospectively analyzed the efficacy and safety of anlotinib for PLC in patients with Non-small Cell Lung Cancer (NSCLC). Methods: We retrospectively investigated NSCLC patients with PLC at our hospital between May 2018 and November 2020, who received anlotinib monotherapy or combined therapy for PLC. Data were analyzed for progression-free survival (PFS), overall survival (OS), objective response rate(ORR), disease control rate(DCR) and adverse events (AE). The impact of clinical and genomic factors on PFS and OS were also assessed. Results: A total of 14 patients were enrolled with a median age of 64 years. 10(71.4%) were male, 4(28.6%) has smoking history, 10(71.4%) of patients had a performance status of 2-3. 9, 3, 2 patients had TP53 mutation, EGFR mutation, ALK fusion respectively. 9(64.3%) patients received anlotinib monotherapy. Of 14 patients, 8 achieved partial response (PR), 5 presented stable disease (SD), 1 had progressed disease. The ORR and DCR were 57.1% and 92.9% respectively. The median PFS was 3.1 months (95% CI: 2.0-4.2), the median OS for 1, 2, ≥3 line were 13 months, 7.2 months, 5.2 months, respectively. Median PFS and OS (≥3 line) were significantly longer for patients with TP53-mutant tumors compared with those with TP53–wild-type tumors (median PFS: 7 vs. 1.1 months, median OS (≥3 line): 6.8 vs. 1.9 months). No difference of PFS and OS (≥3 line) was found between EGFR or ALK alteration and the corresponding wild type patients. The most frequently reported AEs were high blood pressure (11, 78.6%), hand foot syndrome (6, 42.9%), diarrhea (5, 35.7%), fatigue (4, 28.6%), hoarseness (3, 21.4%), proteinuria (2, 14.3%) and stomatitis (2, 14.3%). Conclusions: Anlotinib presented favorable efficacy in patients with pulmonary lymphangitic carcinomatosis and conferred considerable survival benefit compared with previous studies, especially in patients harboring TP53 mutations. The AEs were manageable. These indicated that anlotinib can be a promising therapeutic treatment of PLC. More clinical data is needed to validate this finding.

Outcomes of tyrosine kinase inhibitors after immunotherapy in advanced hepatocellular carcinoma: A multi-center study.

e16181 Background: Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are widely adopted in contemporary advanced HCC (aHCC) treatment algorithms. Nevertheless, the optimal strategy for treatment after ICI exposure is unknown. We evaluated the pattern of use, response, survival and safety of TKIs in aHCC patients who previously received ICIs. Methods: We performed an international, multi-centre study of aHCC patients who received TKIs after prior treatment with ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and adverse events (AE) were assessed. Results: Between January 2015 and December 2020, one-hundred and forty-eight patients were included. The median age was 63 (range 29-84) and 78.4% were of Child-Pugh Grade A. 75.7% had hepatitis-B related HCC. 64.9% received TKI as single agent and 35.1% received TKI in combination with other agents. 75% who received TKI combinations had concomitant ICIs. 48.6% had prior TKIs. The median follow-up was 23.3 months. For single agent TKI patients, the ORR was 14.6%, DCR was 38.5%, median TTP was 3.9 months (95% C.I. 3.3-4.5) and median OS was 8.6 months (95% C.I. 5.8-11.4). For patients receiving TKI combinations, the ORR was 25%, DCR was 38.5%, median TTP was 3.5 months (95% C.I. 1.7-5.2) and median OS was 15.1 months (95% C.I. 5.7-24.5). There were no significant differences in ORR, DCR and median OS between patients who had primary resistance to prior ICI compared to those with acquired ICI resistance and between those who were TKI-naive compared to those who were TKI-exposed. Notably, patients who received TKI-ICI combinations had significantly superior survival compared to single agent TKI patients (median OS 15.1 months (95% C.I. 6.7-23.5) vs. 8.6 months (95% C.I. 5.6-11.7), p = 0.011) but not significantly superior ORR, DCR or TTP. Amongst patients who received single agent TKI and were naive to both sorafenib and lenvatinib, those who received lenvatinib had significantly superior DCR, TTP and OS compared to those who received sorafenib (DCR 51.5% vs 25.8%, p = 0.035; median TTP 6.3 months (95% C.I. 3.0-9.7) vs. 1.8 months (95% C.I. 0-3.6), p = 0.003; median OS 12.0 months (95% C.I. 7.0-17.0) vs. 5.9 months (95% C.I. 1.9-10.0), p = 0.008). 70.3% and 15.5% of all patients, and 77.1% and 15.6% of patients who received single agent TKI experienced all grade and grade ≥3 AEs respectively. The most common AEs were hand foot syndrome, skin rash and diarrhea. Conclusions: TKIs can achieve encouraging anti-tumour response and survival outcomes with acceptable safety in prior ICI-treated aHCC patients. Moreover, TKI-ICI combinations were associated with better survival than single agent TKIs. Notably, among patients who received single agent TKIs, lenvatinib had significantly better responses and survival results than sorafenib.

A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer.

e16268 Background: The multi-kinase inhibitor sorafenib (S) and HDAC inhibitor vorinostat (V) demonstrated synergism against preclinincal pancreatic cancer (PaCa) models. The combination of S & V also potently radiosensitized pancreatic cancer cells and enhanced the activity of gemcitabine (G). This led to a phase 1 trial to determine the doses and schedule appropriate for phase 2 study of S & V with weekly G and intensity modulated radiotherapy (IMRT) as neoadjuvant treatment of PaCa following chemotherapy. Methods: Using a 3+3 dose-escalation design, adult patients with resectable, borderline resectable, unresectable, and lymph node positive PaCa were enrolled to 6 dose levels. Enrolled patients had completed at least 8w of neoadjuvant chemotherapy prior to IMRT. The schedule of administration was weekly 200mg/m2 G weekly during IMRT, S & V were dosed either 3x or 5x weekly during IMRT. Primary endpoint was to identify the dose and schedule for S & V with G based chemoradiation. Key secondary endpoints included antitumor activity, R0 resection rate, OS. Correlative studies to evaluate a variety of biomarkers and Nanostring expression analysis on pre- and post-therapy tumor specimens were also performed. Results: 22 patients were enrolled and 21 treated at 6 dose levels. Due to thrombocytopenia limiting drug exposure, the trial was modified to reduce G to 200mg/m2/wk and S & V to 3 d/wk instead of 5 d/wk. 13 patients were eligible for surgery, and 9 had R0 resections. Conclusions: Our findings indicate that the study regimen was well tolerated, typical toxicities of S (hand foot syndrome) were not observed with intermittent dosing. Uncomplicated cytopenias limited drug exposure, which was improved with intermittent S&V dosing. The RP2D of the combination is S (400mg po BID 3d/wk), V (200mg po qd 3d/wk), G 200mg/m2 IV weekly, with IMRT (50.4 Gy over 28 fractions, 5d/wk). Antitumor activity was observed across dose levels, with an encouraging R0 resection rate. These results warrant further investigation of combining S and V with G and IMRT as neoadjuvant treatment of PaCa following chemotherapy. Analyses of correlative studies and OS are underway. Clinical trial information: NCT02349867. [Table: see text]

Apatinib plus vinorelbine versus vinorelbine for advanced triple-negative breast cancer with failed first or second-line treatment: The NAN trial.

1075 Background: No standard treatment exists for triple negative breast cancer (TNBC) with failure of multi-line therapies. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for TNBC. We aimed to evaluate the safety and efficacy of adding apatinib to chemotherapy in patients with metastatic TNBC with failed first/second-line treatment. Methods: This randomized, open-label, phase 2 trial recruited patients with advanced TNBC who failed to receive first or second-line treatment. A total of 66 patients were randomly assigned, in a 1:1 ratio, to receive vinorelbine 25 mg/m2 (days 1, 8, 15) or vinorelbine 20 mg/m2 (days 7, 14, 21) with apatinib (250 mg once daily, days 1-5, 8-12, 15-19, if tolerable, the second cycle started with 500 mg per day) in 28-day cycles. The efficacy was evaluated every two treatment cycles (8 weeks ± 3 days). According to the RECIST criterion, patients with CR, PR and SD continued treatment until disease progression or unacceptable toxicity or withdrawal of consent. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rate (ORR) and safety. Results: Between Sep 14, 2017 and Dec 08, 2020, 66 patients underwent randomization. Median follow-up was 21.3 months. 33 received apatinib plus vinorelbine and 32 received vinorelbine (1 was withdrawal of consent). Median PFS was significantly longer in the apatinib plus vinorelbine group than in the vinorelbine group (3.8 months vs. 1.9 months; hazard ratio for disease progression or death, 1.76; 95% confidence interval [CI], 1.02 to 3.05; P= 0.039). Median OS was 14.6 months with apatinib plus vinorelbine and 14.1 months with vinorelbine (HR,1.34; 95% CI, 0.60 to 3.00; P= 0.469). The ORR was 48.5% in the apatinib plus vinorelbine group and 31.3% in the vinorelbine group ( P= 0.156). The most common treatment-related hematologic grade 3–4 adverse events in those treated with apatinib plus vinorelbine versus vinorelbine, respectively, were leukopenia (42.4% vs. 34.4%), granulocytopenia (57.6% vs. 28.1%), anemia (9.1% vs. 12.5%) and thrombocytopenia (3.1% vs. 3.0%). The most frequent grade 3 nonhematologic toxicities were hand–foot syndrome (21%), proteinuria (9%), hypertension (9%) and increased ALT (9%) and which only occurred in apatinib plus vinorelbine group. No treatment-related nonhematologic grade 4 adverse events or treatment-related deaths were observed. Conclusions: Collectively, among patients with advanced TNBC with failed first/second-line treatment, apatinib plus vinorelbine show a promising benefit in PFS compared to vinorelbine monotherapy. Apatinib plus vinorelbine regimen shows promising efficacy and manageable toxicity, which might be a previously unappreciated therapeutic option for advanced TNBC. Clinical trial information: NCT03254654 .

Hepatic Arterial Infusion Chemotherapy of Oxaliplatin, Fluorouracil, and Leucovorin With or Without Sorafenib as Initial Treatment for Advanced Hepatocellular Carcinoma.

PurposeOur previous study showed that hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) plus sorafenib provided a significant survival benefit over sorafenib for advanced hepatocellular carcinoma. However, it is unclear whether the survival benefit should be attributed to the synergism between HAIC and sorafenib or just HAIC alone. We aim to compare HAIC using FOLFOX plus sorafenib with HAIC alone in patients with advanced hepatocellular carcinoma.Materials and MethodsThis was a retrospective study including 225 eligible patients treated with HAIC using FOLFOX (HAIC alone group, n=126, oxaliplatin 85 mg/m², leucovorin 400 mg/m², fluorouracil bolus 400 mg/m² and 2400 mg/m² for 46 hours, every 3 weeks) alone or HAIC plus sorafenib (soraHAIC group, n=99, sorafenib 400 mg twice daily). Survival curves were calculated by the Kaplan-Meier method, and propensity-score matching was used to reduce bias.ResultsThe soraHAIC group showed a longer overall survival (12.9 [95% CI, 10.4-15.4] vs. 10.5 [95% CI, 9.5-11.5] months, HR=0.71 [95% CI, 0.53-0.96]; P=0.025), a better progression free survival (7.0 [95% CI, 5.3-8.8] vs. 5.3 [95% CI, 3.5-7.1] months, HR=0.76 [95% CI, 0.58-0.99]; P=0.046), and a higher disease control rate (RECIST 1.1: 74.8% vs. 61.1%, P=0.030) than the HAIC alone group. In multivariate analysis, soraHAIC was an independent favor factor for survival. In terms of the grade 3/4 adverse event, hand–foot skin reaction was more frequent in the soraHAIC group than the HAIC alone group. In the propensity-score matched cohorts (93 pairs), the overall survival, the progression free survival and disease control rates in the soraHAIC group were also better than those in the HAIC group (P<0.05).ConclusionHAIC plus sorafenib may improve overall survival and progression free survival compared with HAIC alone as initial treatment for advanced hepatocellular carcinoma.

Health System Barriers and Facilitators to Delivering Additional Vaccines through the National Immunisation Programme in China: A Qualitative Study of Provider and Service-User Perspectives.

In China, there are two categories of vaccines available from the Chinese Center for Disease Control and associated public health agencies. Extended Program of Immunization (EPI) vaccines are government-funded and non-EPI vaccines are voluntary and paid for out-of-pocket. The government plans to transition some non-EPI vaccines to EPI in the coming years, which may burden public health system capacity, particularly in terms of budget, workforce, supply chains, and information systems. Our study explored vaccinator and caregiver perspectives on introducing non-EPI vaccines into routine immunization and perceived facilitators and barriers affecting this transition. We conducted a qualitative study from a realist perspective, analysing semi-structured interviews with 26 vaccination providers and 160 caregivers in three provinces, selected to represent regional socioeconomic disparities across Eastern, Central, and Western China. Data were analysed thematically, using deductive and inductive coding. Most participants were positive about adding vaccines to the national schedule. Candidate EPI vaccines most frequently recommended by participants were varicella, mumps vaccine, and hand–foot–mouth disease. Providers generally considered existing workspaces, cold-chain equipment, and funding sufficient, but described frontline staffing and vaccine information systems as requiring improvement. This is the first qualitative study to explore interest, barriers, and facilitators related to adding vaccines to China’s national schedule from provider and caregiver perspectives. Findings can inform government efforts to introduce additional vaccines, by including efforts to retain and recruit vaccine programme staff and implement whole-process data management and health information systems that allow unified nationwide data collection and sharing.

Classifications of split hand foot malformation (SHFM) should include transverse deficiencies: Why Maisels was correct

Classifications of split hand foot malformation (SHFM) should include transverse deficiencies: Why Maisels was correct

Tolerability of Molecular-targeted Agents for Hepatocellular Carcinoma Treatment in Haemophiliacs.

Hepatocellular carcinoma (HCC) is considered a leading cause of death in patients with haemophilia. Recent advances in the treatment of unresectable HCC with molecular-targeted agents (MTAs) have led to better clinical outcomes. However, the tolerability of MTAs by haemophilic patients with HCC remains unclear. This study aimed to compare the tolerability of MTAs in such patients. From January 2011 to October 2020, five haemophilic patients with HCC were treated with MTAs. Adverse events were assessed in comparison with 265 non-haemophilic patients with HCC. The prevalence of hand-foot skin reaction was not higher in the haemophiliacs than in the non-haemophiliacs, whereas the rate of haemorrhagic events was higher in the haemophiliacs (6.0% versus 40.0%, p=0.037). Haemophiliacs tolerate long-term MTA use, without the occurrence of life-threatening complications. However, careful observation and prevention are needed for MTA-related gastrointestinal bleeding in haemophiliacs.

Motor processing modulates word comprehension

We evaluated whether movement modulates the semantic processing of words. To this end, we used homograph words with two meanings, one associated with hand movements (e.g., 'abanico', 'fan' in Spanish) or foot movements ('bota', 'boot' in Spanish), and the other not associated with movement ('abanico', 'range' in Spanish; 'bota', 'wineskin' in Spanish). After the homograph, three words were presented, and participants were asked to choose the word related to one of the two homograph meanings. The words could be either related to the motor meaning of the homograph ('fan-heat'), to the non-motor meaning of the homograph ('range-possibility') or unrelated ('fan-phone'). The task was performed without movement (simple condition) or by performing hand (Experiment 1) and foot (Experiment 2) movements. Compared with the simple condition, the performance of movement oriented the preference towards the motor meaning of the homograph. This pattern of results confirms that movement modulates word comprehension.

Apatinib-Induced Hand-Foot Skin Reaction in Chinese Patients With Liver Cancer.

Apatinib, an anti-tumor drug selectively targeting VEGFR2 (Vascular Endothelia Growth Factor Recpetor-2), has been proven effective in Chinese patients with liver cancer. Generally, treatment with apatinib achieves 16.1% of the overall objective remission rate (ORR) and 55.83% of the disease control rate (DCR) in Chinese patients with liver cancer. However, the prevalence of apatinib-induced hand–foot skin reaction (AI-HFSR) is noticeably high. The incidence of AI-HFSR is about 50.5%, of which Grades 1/2 and 3 are 38.8 and 11.6%, respectively. In addition, potential molecular mechanisms underlying the development of AI-HFSR are poorly understood and urgently needed to be investigated histologically. In this review, we summarize and review the current efficacy of apatinib and the prevalence of AI-HFSR in Chinese patients with liver cancer. Besides, we postulate the potential mechanisms underlying the development of AI-HFSR and discuss the optimal clinical management for this unwanted cutaneous side effect.

Caregivers: the potential infection resources for the sustaining epidemic of hand, foot, and mouth disease/herpangina in Guangdong, China?

BackgroundAlthough several measures have been taken to control hand foot and mouth disease (HFMD) and herpangina (HA), these two diseases have been prevalent in China for 10 years with high incidence. We suspected that adults’ inapparent infection might be the cause of the continued prevalence of HFMD/HA infection in mainland China.MethodsTo explore the role of adults (especially caregivers) in the transmission process of HFMD/HA among children, 330 HFMD/HA cases and 330 healthy children (controls) were selected for a case–control study. Then, data were analyzed by logistic regression.ResultsSingle-variable analyses revealed that caregivers who tested positive for enterovirus was a significant risk factor of HFMD/HA transmission to children (adjusted odds ratio (OR) = 9.22; 95% CI, 1.16 to 73.23). In the final multivariable model, caregiver behavior, such as cooling children’s food with mouth (OR = 1.85; 95% CI, 1.11 to 3.08) and feeding children with their own tableware (OR = 2.19; 95% CI, 1.07 to 4.45), significantly increased the risk of transmitting HFMD/HA to children. On the contrary, washing hands before feeding children reduced such risk.ConclusionsThese results implied that the caregivers might be the infectious source or carriers of enterovirus. Therefore, preventing or treating the caregivers’ enterovirus infection and improving their hygiene habits, especially when they are in contact with children, could provide a breakthrough for the effective control of HFMD/HA.

Clinical study on blood routine and dynamic changes, condition and prognosis of hand foot and mouth disease (EV71)

<strong>Background:</strong> The Indian Association for the prevention and control of rabies estimates that 80, 00, 000 individuals receive the treatment for dog bites each year. The matter with dog rabies in India is that dogs are asymptomatic in each human establishment.