Concurrent Regimen Research Articles

Primary Hypothyroidism in Patients Exposed to Therapeutic External Beam Radiation: Non-randomized Comparative Study.

Background Cancer patients are not routinely assessed for thyroid function after external beam radiotherapy (EBRT) to the neck, despite hypothyroidism being a known side effect of EBRT. So, this study aimed to assess the incidence of hypothyroidism after therapeutic external beam radiotherapy to the neck and to determine the time for the development of hypothyroidism. Methodology A non-randomized prospective comparative study was done at a tertiary care center from April 2018 to September 2020. Any cancer patients who were euthyroid before radiotherapy and are planned to receive EBRT to the neck were included as cases, whereas controls were selected from the patients who were euthyroid before radiotherapy and were planned to receive EBRT to the site other than the neck. A total of 100 participants in each case and control group were selected. Data were collected on participants' age, gender, primary tumor site, treatment modality, total radiation dose along with concurrent chemoradiation regimens. Details of blood chemistry including thyroid hormone levels were collected during the pre-radiation phase and post-radiation phase. After the completion of radiotherapy, both the patients and controls were followed up periodically at three months, six months, nine months, 12 months, and finally at 15 months post-radiation. Data were analyzed and interpreted to pursue defined objectives by using tables and graphs using Microsoft Excel and IBM SPSS, version 26.0 (Armonk, NY: IBM Corp.). The chi-square test was applied to find out the association of different variables with the development of hypothyroidism. P-values<0.05 were considered significant throughout. Results According to our findings, the incidence of hypothyroidism following external beam radiotherapy to the neck where radiation portals included a portion or the entire thyroid gland was 16% and 4%, when the radiation given to sites other than neck region.The difference in incidence between the case and control groups was found to be statically significant (p<0.05). However, it was found that age, gender, the primary tumor site, total radiation dose, and treatment modality had no significant effects on hypothyroidism development. The median time duration to become hypothyroid after EBRT was 12 months. Conclusions The monitoring of thyroid function should become a part of routine follow-up procedures in all cancer patients who receive neck radiation as part of their treatment.

Sequential Hypofractionated versus Concurrent Twice-Daily Radiotherapy for Limited-Stage Small-Cell Lung Cancer: A Propensity Score-Matched Analysis.

Simple SummaryAlthough twice-daily concurrent chemoradiotherapy for limited-stage small-cell lung cancer (LS-SCLC) is still the standard treatment, this regimen is inconvenient and not universally adopted across different institutions. Therefore, the optimal radiation dose and fractions are still under investigation. A once-daily hypofractionated schedule may be suitable for LS-SCLC patients, and more and more hypofractionated schedule studies are being performed. However, few studies have investigated the efficacy and toxicities of sequential chemotherapy and hypofractionated radiotherapy compared with the concurrent twice-daily schedule. Our evaluation of sequential hypofractionated and twice-daily concurrent chemoradiotherapy schedules before and after propensity score-matched analysis (PSM) for LS-SCLC revealed a comparable survival and less toxicity. The sequential hypofractionated schedule may be used as an alternative to concurrent twice-daily regimens.Background: As there are no randomized trials comparing twice-daily with sequential hypofractionated (sequential hypo) radiotherapy regimens for limited-stage small-cell lung cancer (LS-SCLC). This study aimed to compare these two regimens for LS-SCLC by propensity score-matched analysis (PSM). Methods: We retrospectively analyzed 108 LS-SCLC patients between January 2015 and July 2019. All patients received concurrent twice-daily or sequential hypo radiotherapy. The survival, failure patterns, and toxicities were evaluated before and after PSM. Results: Before PSM, multivariate analysis showed that patients treated with sequential hypo had a significantly better overall survival (OS) and distant metastasis-free survival (DMFS) (HR = 0.353, p = 0.009; HR = 0.483, p = 0.039, respectively). Total radiotherapy time ≥ 24 days and stage III (HR = 2.454, p = 0.004; HR = 2.310, p = 0.004, respectively) were poor prognostic indicators for OS. Patients with a total radiotherapy time ≥ 24 days and N2–3 were more likely to recur than others (HR = 1.774, p = 0.048; HR = 2.369, p = 0.047, respectively). N2–3 (HR = 3.032, p = 0.011) was a poor prognostic indicator for DMFS. After PSM, being aged ≥65 years was associated with poorer OS, relapse-free survival (RFS) and DMFS (p < 0.05). A total radiotherapy time of ≥24 days was a poor prognostic indicator for OS and RFS (HR = 2.671, p = 0.046; HR = 2.370, p = 0.054, respectively). Although there was no significant difference, the patients in the sequential hypo group had a trend towards a better OS. The failure pattern between the two groups showed no difference. More patients had grade 1–2 esophagitis in the twice-daily group (p = 0.001). Conclusions: After propensity matching, no difference was shown in survival and failure. The sequential hypo schedule was associated with comparable survival and less toxicity and may be used as an alternative to concurrent twice-daily regimens.

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

The combination regimen of trastuzumab (Tras) plus Nab-paclitaxel (Nab) is recommended to treat HER2-positive (HER2+) cancers. However, they exert effects in different mechanisms: Tras need to stay on cell membranes, while Nab need to be endocytosed, therefore the concurrent combination regimen may not be the best one in HER2+ tumors treatment. Caveolin-1 (Cav-1) is a key player in mediating their endocytosis and is associated with their efficacy, but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy. Herein, we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+ Cav-1High tumor treatment. In the regimen, lovastatin (Lova) was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression, increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+ Cav-1High cells but not in HER2+ Cav-1Low cells. Therefore, by exchanging the dosing sequence of Nab and Tras, and by adding Lova at appropriate time points, the precise three-drug-sequential regimen (PTDS, Nab(D1)-Lova(D2)-Lova & Tras(D2+12 h)) was established. Compared with the concurrent regimen, the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+ Cav-1High tumors, which might be a promising combination regimen for these patients in clinics.

Revisiting the therapeutic potential of tocotrienol.

The therapeutic potential of the tocotrienol group stems from its nutraceutical properties as a dietary supplement. It is largely considered to be safe when consumed at low doses for attenuating pathophysiology as shown by animal models, in vitro assays, and ongoing human trials. Medical researchers and the allied sciences have experimented with tocotrienols for many decades, but its therapeutic potential was limited to adjuvant or concurrent treatment regimens. Recent studies have focused on targeted drug delivery by enhancing the bioavailability through carriers, self‐sustained emulsions, nanoparticles, and ethosomes. Epigenetic modulation and computer remodeling are other means that will help increase chemosensitivity. This review will focus on the systemic intracellular anti‐cancer, antioxidant, and anti‐inflammatory mechanisms that are stimulated and/or regulated by tocotrienols while highlighting its potent therapeutic properties in a diverse group of clinical diseases.

A network meta-analysis for efficacies and toxicities of different concurrent chemoradiotherapy regimens in the treatment of locally advanced non-small cell lung cancer

BackgroundConcurrent chemoradiotherapy (CCRT) has become the cornerstone of treatment for patients with locally advanced non-small cell lung cancer (LA-NSCLC). The aim of this study was to compare the efficacies and toxicities of different CCRT regimens in the treatment of LA-NSCLC by adopting a network meta-analysis (NMA).MethodsAn exhaustive search of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted to identify relevant studies from inception to October 1, 2020. Direct and indirect evidence was combined to calculate the odds radios (ORs) and 95% confidence intervals (CIs), as well as to plot the surface under the cumulative ranking (SUCRA) curves. Cluster analyses were adopted to compare the efficacies and toxicities of different CCRT regimens according to the similarity of 2 variables. Publication bias was detected by comparison-adjusted funnel plots.ResultsTwenty-two studies were enrolled in this NMA, including 18 regimens: CCRT (cisplatin + etoposide), CCRT (carboplatin + paclitaxel), CCRT (pemetrexed + carboplatin), CCRT (pemetrexed + cisplatin), CCRT (docetaxel + cisplatin), CCRT (S-1 + cisplatin), CCRT (mitomycin + vindesine + cisplatin), CCRT (cisplatin + vinorelbine), CCRT (cisplatin), CCRT (etoposide + cisplatin + amifostine), RT, CCRT (5-FU), CCRT (paclitaxel + cisplatin), CCRT (irinotecan + carboplatin), CCRT (nedaplatin), CCRT (carboplatin + etoposide), CCRT (paclitaxel), and CCRT (carboplatin). The results indicated that the regimens with CCRT (cisplatin + etoposide), CCRT (carboplatin + paclitaxel), CCRT (pemetrexed + cisplatin), CCRT (S-1 + cisplatin), and CCRT (cisplatin + vinorelbine) had relatively better efficacies compared with other regimens. As for toxicities of different CCRT regimens, the CCRT (carboplatin + paclitaxel), CCRT (pemetrexed + cisplatin), and CCRT (docetaxel + cisplatin) were relatively lower.ConclusionsOur study demonstrated that CCRT (pemetrexed + cisplatin) and CCRT (carboplatin + paclitaxel) might be the best options for the treatment of LA-NSCLC, and CCRT (pemetrexed + cisplatin) had the highest 3-year overall survival (OS) rate.

High-Dose Vitamin C for Cancer Therapy

In recent years, the idea that Vitamin C (Vit-C) could be utilized as a form of anti-cancer therapy has generated many contradictory arguments. Recent insights into the physiological characteristics of Vit-C, its pharmacokinetics, and results from preclinical reports, however, suggest that high-dose Vit-C could be effectively utilized in the management of various tumor types. Studies have shown that the pharmacological action of Vit-C can attack various processes that cancerous cells use for their growth and development. Here, we discuss the anti-cancer functions of Vit-C, but also the potential for the use of Vit-C as an epigenetic regulator and immunotherapy enhancer. We also provide a short overview of the current state of systems for scavenging reactive oxygen species (ROS), especially in the context of their influencing high-dose Vit-C toxicity for the inhibition of cancer growth. Even though the mechanisms of Vit-C action are promising, they need to be supported with robust randomized and controlled clinical trials. Moreover, upcoming studies should focus on how to define the most suitable cancer patient populations for high-dose Vit-C treatments and develop effective strategies that combine Vit-C with various concurrent cancer treatment regimens.

Does probiotic Kefir reduce dyslipidemia, hematological disorders and oxidative stress induced by zearalenone toxicity in wistar rats?

Zearalenone (ZEA) is a toxic metabolite of the genus Fusarium, which causes hepatotoxicity and induces oxidative stress. Kefir is an important probiotic dairy-product showing important in vitro antioxidant potential. In this study, the effect of Kefir supplementation to mitigate ZEA toxicity in rats was investigated. Animals were divided into four groups of five rats each, which received sterile milk (200 μL/day) during the first week. Then, they were switched to Kefir (200 μL/day), ZEA (40 mg/kg b. w./day) and Kefir + ZEA for the second week. Hematological and biochemical parameters, as well as liver histological analysis were determined. Kefir administration prevented the changes occurred in the count of all blood cells, and improved the antioxidant enzymes in the liver, such as catalase, glutathione peroxidase and superoxide dismutase activities that increased by 6, 4.5 and 1.3 folds, respectively, compared to ZEA group. Interestingly, the concurrent regimen Kefir + ZEA removed ZEA residues in the serum and liver. Furthermore, the Kefir + ZEA group showed a reduction in the levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and hepatic malonaldehyde by ∼82, 54, 66, 50 and 36%, respectively, compared to the ZEA group. The histopathological analysis showed a normal liver histological architecture in Kefir + ZEA group, while degenerative changes were observed in ZEA group. These results suggest that Kefir as probiotic consortium may have a hepatoprotective effect against ZEA poisoning.

Safety and efficacy of immunotherapy in combination with epigenetic therapy in an esophageal adenocarcinoma model.

335 Background: There is a critical need to develop effective therapeutic approaches for patients with esophageal cancer, a leading cause of cancer mortality. Recently, immune checkpoint blockade (ICB) has demonstrated modest survival benefit in gastroesophageal cancer patients. Epigenetic therapies, including DNA methyltransferases (DNMT) and histone deacetylases (HDACs), have shown to enhance tumor immune recognition by directly upregulating antigen presentation and by activation of type-1 interferon response triggered by cytoplasmic double-stranded RNA, a phenomenon known as viral mimicry. In other cancer models, epigenetic therapy has shown early promise by enhancing the effectiveness of ICB via addictive antiproliferative effects, enhanced immune activation and reversal of T cell exhaustion towards a memory-effector T-cell phenotypes. Methods: Esophagojejunostomy was performed to induce gastroduodenojejunal reflux in rats, leading to development of EAC. At 32 weeks postop, animals were randomized into eight treatment and control groups: placebo ± radiation, epigenetic treatment ± radiation, immunotherapy treatment ± radiation, and concurrent epigenetic and immunotherapy ± radiation. Animals underwent three 14 day cycles of epigenetic treatment or placebo. Each cycle consisted of one week of DNMT treatment or placebo at a dose of 0.5mg/kg, followed by one week of HDAC treatment or placebo at a dose of 2mg/kg. Animals received one 3mg/kg dose of PD1 inhibitor or placebo on day 12 of each cycle. Safety and efficacy were evaluated via objective health assessments, change in tumor volume, immunofluorescent labeling and RT-PCR. Results: Seventy of 74 randomized animals reached study end-point with no significant differences in mortality observed across groups (p = 0.556). There were no significant differences in observed health scores or weights between all groups (p = 0.431 and p = 0.882, respectively). Pre to posttreatment, mean MRI tumor volume increased by 263.1% and 90.9% in the placebo and the placebo plus radiation groups, respectively. The largest tumor reduction was observed in the concurrent treatment groups, 84.5% and 61.8% with and without radiation, respectively. Additionally, independent epigenetic and immunotherapy treatments with or without radiation also exhibited decrease in tumor volume, but to a lesser extent than the concurrent regimens (p = 0.005). Immunofluorescent labeling demonstrated a significant increase in CD3+ CD8+ T cells in all treatment groups compared to placebo (p = &lt; 0.001). Gene expression displayed upregulation of CD206 (p = 0.002), TNFα (p = &lt; 0.001), and Arg1 (p = &lt; 0.001) in treatment arms compared to placebo. Conclusions: This study establishes addictive antitumor efficacy and enhanced immune sensitization for a concurrently sequenced treatment, combining epigenetic therapy and radiation with immunotherapy, to treat EAC.

CLINICAL OUTCOME USING WEEKLY PACLITAXEL WITH RADIATION IN LOCALLY ADVANCED LUNG CANCER

Background: Non-small cell lung cancer is the second most common malignancy worldwide with very high mortality rate. The aim of this study is to evaluate the locoregional response and toxicity prole using weekly paclitaxel along with radiation in locally advanced inoperable non-small cell lung cancer in a tertiary care centre. A prospective analysis was Methods: carried out on non-metastatic locoregionally advanced non-small cell lung cancer patients who were treated in the Radiotherapy Department, Medical College, Kolkata from January 2014 to July 2015. The patients received concurrent chemoradiotherapy with weekly paclitaxel. Out of 54 patients Results: analysed, overall response rate was 81.48% and complete response rate was 12.96%. The progression free survival rate at 1 year was 41.30%. Median progression free survival was 10.00 ±0.40 months. The most common toxicities were acute pharyngeal and esophageal toxicity. The toxicity was acceptable and response was Conclusion: comparable with other platinum based concurrent chemoradiation regimens.

A PROSPECTIVE COMPARATIVE STUDY BETWEEN CONCURRENT CHEMO RADIOTHERAPY WITH CISPLATIN AND ETOPOSIDE VERSUS PACLITAXEL AND CARBOPLATIN IN LOCALLY ADVANCED NON SMALL CELL LUNG CARCINOMA

Background-The current standard of treatment for unresectable locally advanced Non-small cell lung carcinoma is radiation with concurrent platinum based doublet chemotherapy. But there remains considerable debate over the optimal concurrent regimen , with some advocating Cisplatin-Etoposide , others prefer carboplatin-paclitaxel as an equally effective and better tolerable concurrent regimen.. With this background, our study was aimed at comparing loco-regional control and toxicity prole between these two regimens. Material And Methods- Locally advanced non-metastatic Non-small cell lung carcinoma patients were randomized in two groups- study group received External beam radiotherapy(60Gy/30 fractions/6 weeks) in conventional fractionation along with concurrent weekly chemotherapy with Inj.paclitaxel (45 mg/m2 ) and Inj. Carboplatin (AUC2 ) and control group received same radiotherapy dose with concurrent Inj.cisplatin (50mg/m2) Day 1,8,29,36 and Inj.Etoposide (50 mg/m2) Day 1-5 and Day 29-33. After treatment completion , Locoregional Tumor response was assessed . Patients were evaluated weekly for acute toxicity during radiation therapy, then once at 6-8 weeks after completion of treatment and thereafter every three months for at least 6 months. Results- Overall treatment Response in Study Arm was higher than control arm (73% vs 70%). Complete response rate was also higher in study arm (40% vs 30%) though these differences were not statistically signicant [p value 0.701]. Although statistically not signicant ,Grade III haematological toxicity was less (3% vs 6%) in study arm .Other toxicity proles including acute lung, esophageal and skin toxicities are comparable in both the arms of the study. Conclusion- Concurrent chemo- radiotherapy with cisplatin -etoposide versus paclitaxel -carboplatin in locally advanced NSCLC are comparable in terms of loco-regional control and acute toxicity.

Molecular Markers to Predict Prognosis and Treatment Response in Uterine Cervical Cancer.

Simple SummaryDespite the implementation of efficient screening and vaccination programs, uterine cervical cancer remains a leading cause of cancer-related mortality in women worldwide. New therapeutic approaches have so far failed to improve treatment response and prognosis significantly, especially in patients with recurrent disease or metastases. Further, robust molecular markers to predict therapy response and survival are scarce and their routine use is limited in clinical practice. Accordingly, there is an urgent need to identify and establish molecular markers to predict therapy response and clinical outcome to improve treatment and survival in cervical cancer.Uterine cervical cancer is one of the leading causes of cancer-related mortality in women worldwide. Each year, over half a million new cases are estimated, resulting in more than 300,000 deaths. While less-invasive, fertility-preserving surgical procedures can be offered to women in early stages, treatment for locally advanced disease may include radical hysterectomy, primary chemoradiotherapy (CRT) or a combination of these modalities. Concurrent platinum-based chemoradiotherapy regimens remain the first-line treatments for locally advanced cervical cancer. Despite achievements such as the introduction of angiogenesis inhibitors, and more recently immunotherapies, the overall survival of women with persistent, recurrent or metastatic disease has not been extended significantly in the last decades. Furthermore, a broad spectrum of molecular markers to predict therapy response and survival and to identify patients with high- and low-risk constellations is missing. Implementation of these markers, however, may help to further improve treatment and to develop new targeted therapies. This review aims to provide comprehensive insights into the complex mechanisms of cervical cancer pathogenesis within the context of molecular markers for predicting treatment response and prognosis.

Mesoporous Silica Nanoparticle-Based Combination of Niclosamide and Doxorubicin: Effect of Treatment Regimens on Breast Cancer Subtypes.

Overexpressed Wnt/β-catenin signaling acts as a major cancer driver and plays an important role in the development of resistance against cancer chemotherapy. Therefore, the combinatorial approach of downregulating Wnt/β-catenin signaling along with using a chemotherapeutic agent may improve cancer therapy. However, systemic administration of free anticancer agents is nonspecific and poses serious side effects. Hence, the present study aimed at developing mesoporous silica nanoparticle (MSN)-based targeted combination therapy of a Wnt signaling inhibitor, niclosamide (Nic), and a conventional anticancer agent, doxorubicin (Dox). The results demonstrated the reproducible synthesis of highly stable and monodispersed sub-100 nm spherical shaped NPs. In vitro cytotoxicity studies demonstrated that the individual drug formulations caused concentration-dependent cytotoxicity to all of the three breast cancer subtypes, with higher concentrations being more cytotoxic. Further, sequential and concurrent combination of Nic-loaded MSNs with Dox-loaded MSNs was synergistic and caused significantly enhanced death in all breast cancer subtypes. Quantification of the combinatorial efficacy suggested that multiple combinatorial pairs were synergistic in all of the breast cancer types for both (sequential and concurrent) treatment regimens. However, the extent of synergism varied between the two treatment regimens in different clinical subtypes of breast cancer. Overall, the combination of Nic-loaded MSNs with Dox-loaded MSNs holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of the clinical subtype in both sequential and concurrent treatment regimens.

Predictors of Ability to Complete Prescribed Concurrent Cisplatin Chemotherapy Regimen and Effect on Outcomes in Oropharyngeal Head and Neck Cancer Patients Treated With Radiotherapy

The addition of cisplatin to radiation therapy (RT) results in improved outcomes in oropharyngeal head and neck cancer (OHNC) patients. This comes at the cost of increased toxicities over RT alone and often results in the inability to complete the initially prescribed chemotherapy regimen. In this study, potential predictors of chemotherapy completion and their effect on outcomes were investigated in OHNC patients treated at two different institutions.We conducted a retrospective chart review of patients with OHNC at two different institutions. Patients were staged according to AJCC 8th Ed and separated into two groups: Completers (able to complete initially prescribed concurrent cisplatin regimen) and Non-Completers (unable to complete all prescribed cycles and/or required change to a different systemic therapy agent). Age, sex, race, ECOG, smoking status, HPV status, and stage were analyzed for ability to predict completion of chemotherapy regimen and for prognostic implication on outcomes. Overall survival (OS) and local control (LC) were calculated from start of RT. Chi-squared was used for associations, Kaplan-Meier estimates were compared using log-rank test, odds ratios (OR) and hazard ratios (HR) were generated from logistic and Cox regression analyses, respectively.Between 2007 and 2019, 271 patients with OHNC were reviewed and included in the study. Most patients were Stage II (60%) and HPV positive (83%). More patients were Completers (61%) than Non-Completers (39%). Mean age was 56.6 years in Completers and 58.0 years in Non-Completers. Comparing Stage I to IV was the only significant predictor of chemotherapy completion (OR 6.139, 95% CI 1.43-26.35). HPV negative status trended towards significance for non-completion (OR 0.520 P = 0.061). Predictors of inferior OS were race (Non-White vs White) HR 2.520 P = 0.001; ECOG (2-3 vs 0-1) HR 2.324 P = 0.018; ever smoker (Yes vs No) HR 2.582 P = 0.001; HPV status (Negative vs Positive) HR 3.584 P < 0.001; and Stage (IV vs I) HR 5.983, 95% CI 1.38, 25.97. Inability to complete chemotherapy was not found to be a predictor of inferior survival (HR 0.737 P = 0.173). OS at 3 years was not statistically different between Completers (81%) and Non-Completers (77%), P = 0.404. LC at 3 years was not statistically different between Completers (93%) and Non-Completers (92%), P = 0.755.In our study of OHNC patients who were mostly HPV positive and early stage, cancer stage was found to be the only significant predictor of chemotherapy completion. Chemotherapy completion was not found to be a predictor of outcome. Provided the Non-Completer group included those who had a change in systemic agent but may have completed the same total number of planned chemotherapy cycles, this study suggests the need for further multivariate analysis and potentially more upfront individualized chemotherapy regimens.

The effect of combined TPF and intensity modulated radiotherapy after TPF induction chemotherapy on locally advanced nasopharyngeal carcinoma: a retrospective analysis.

To evaluate the efficacy and toxicity of docetaxel, cisplatin, and fluorouracil (TPF) regimen followed by intensity modulated radiotherapy (IMRT) on locally advanced nasopharyngeal carcinoma (NPC). A total of 150 patients with locally advanced NPC [American Joint Committee on Cancer (AJCC) 2009 stage IIIa-IVb] received 2 or 3 cycles of a TPF regimen as induction chemotherapy. A group of 67 participants (TPF group) continued to receive TPF chemotherapy and radiotherapy, and the remaining 83 participants (P group) received cisplatin chemotherapy and radiotherapy. A median follow-up of 35 months (4-66 months) showed that there was no significant difference between P group and TPF group in progression-free survival (PFS) and overall survival (OS). The incidence rate of myelosuppression at 3-4 degrees was 16.9% and 34.3% in the P group and TPF group (P=0.029), respectively, and the oral mucosa reaction at 3-4 degrees was 18.1% and 37.3% in the P group and TPF group, respectively (P=0.007). The 3-4-degree skin reaction in the P group and TPF group was 15.7% and 29.9% (P=0.030), respectively. The rate of liver function injury in the P group was significantly lower than that in TPF group (P<0.05). Compared with concurrent cisplatin chemotherapy and radiotherapy, the concurrent TPF regimen and IMRT showed no significant improvement in OS and PFS in patients with advanced NPC, but exhibited more severe hematologic toxicity, oral mucosal responses, skin reactions, and liver functional impairment.

Is a single dose of prophylactic antibiotics sufficient in patients with acute noncomplicated appendicitis

Background Antibiotics prescription before surgery is considered to be effective in reducing the infectious complications of appendectomy. As a result, most surgeons prescribe antibiotics before surgery for patients diagnosed with appendicitis. Objective The aim of study was to evaluate the effect of a single antibiotic dose compared with the concurrent regimen on the outcome of appendectomy, especially infective complications. Patients and methods A total of 60 cases diagnosed with appendicitis were included, and they were divided into two groups: group A (single dose of cefotaxime 1 g and metronidazole 500 mg before surgery) and group B (the same regimen was received, and it was repeated twice daily for 4 days). All cases were subjected to history taking, physical examination, and routine investigations. At follow-up, all cases were clinically assessed. Results There were no significant statistical differences between groups in age, sex, and BMI variables. No significant statistical differences were observed during the surgery and hospitalization period between two groups. Wound infection occurred in 10 and 6.67% of cases in both groups, respectively (P > 0.05). However, the cost was significantly higher in group B. Conclusion A single dose preoperative antibiotics appears to be as efficacious as concurrent regimen in preventing wound infections after appendectomy. Continuing antibiotic prophylaxis in the postoperative period was not necessary, and it added additional unnecessary financial costs.

A Synergistic Combination of Niclosamide and Doxorubicin as an Efficacious Therapy for All Clinical Subtypes of Breast Cancer.

Simple SummaryChemotherapy is the gold standard treatment option for metastatic cancers. However, the efficacy of chemotherapy is limited due to the development of resistance. The aberrantly expressed Wnt/β-catenin signaling pathway acts as one of the major cancer drivers that also causes the development of resistance. Therefore, in this study, we explored the combinatorial approach of downregulating the Wnt/β-catenin pathway along with using a chemotherapeutic agent as a strategy to overcome drug resistance and improve cancer therapy. We evaluated the combinatorial efficacy of Niclosamide (an antihelminthic repurposed as a Wnt signaling inhibitor) and Doxorubicin (first-line treatment for multiple cancers in the clinic) against breast cancer. The combination showed synergistically enhanced death of all three clinical subtypes of breast cancer cells in both the sequential and concurrent treatment regimens and holds the potential to be developed as an efficient therapeutic option for breast cancer irrespective of its clinical subtype.Drug resistance is one of the major hurdles in the success of cancer chemotherapy. Notably, aberrantly expressed Wnt/β-catenin signaling plays a major role in the initiation and maintenance of oncogenesis along with development of chemoresistance. Therefore, the combinatorial approach of targeting Wnt/β-catenin pathway along with using a chemotherapeutic agent seems to be a promising strategy to improve cancer therapy. In the present study, we evaluated the combination of niclosamide (Nic), an FDA-approved antihelminthic drug repurposed as a Wnt signaling inhibitor, and doxorubicin (Dox), a conventional anticancer agent, in all clinical subtypes of breast cancer viz. triple negative breast cancer, HER2 positive breast cancer, and hormone receptor positive breast cancer. The results demonstrated that the combination induced apoptosis and caused synergistically enhanced death of all breast cancer cell types at multiple combinatorial concentrations using both the sequential and concurrent treatment regimens. Mechanistically, downregulation of Wnt/β-catenin signaling and cell cycle arrest at G0/G1 phase by Nic and increase in reactive oxygen species by both Nic and Dox along with the inherent cytotoxicity of Dox mediated the synergism between the two drugs in both the treatment regimens. Overall, the combination of Nic and Dox holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of its clinical subtype.

Similar Survival but Increased Toxicity with a Sequential Versus Concurrent FluBu4 Regimen

Combined in vitro treatment with fludarabine and busulfan has been shown to lead to synergistic cytotoxicity. Maximal synergy is achieved when fludarabine is administered immediately prior to busulfan. However, fludarabine and myeloablative busulfan (FluBu4) has been administered in both a concurrent and a sequential, non-overlapping fashion. Because timed sequential regimens are becoming increasingly popular, we sought to compare survival and relapse outcomes as well as toxicity between patients receiving allogeneic stem cell transplant (SCT) with a concurrent 5-day versus a sequential 9-day FluBu4 regimen.We analyzed 102 consecutive patients who received FluBu4 prior to allogeneic SCT between 2003 and 2016. Thirty-seven (36%) patients received the 5-day regimen, which consisted of fludarabine 40 mg/m2 and intravenous busulfan (target AUC 4800 mmol-min per dose) administered daily from Day -5 to Day -2. In 65 (64%) patients, the 9-day regimen was administered, utilizing equivalent doses of fludarabine on day -9 to day -6 and busulfan on day -5 to day -2. All patients received graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate. Patients undergoing a matched unrelated donor transplant received anti-thymocyte globulin.Baseline characteristics including gender, race, median time to transplant, median lines of prior treatment, disease risk index, hematopoietic cell transplantation-comorbidity index (HCT-CI), donor type, stem cell source, and mean CD34 count were similar between the two groups. Patients in the 9-day group were younger compared to the 5-day group (median age 45 versus 51 years, p=0.003). The majority of patients in both groups were diagnosed with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.The median time to neutrophil and platelet engraftment was not different between the two groups. More patients receiving the 9-day regimen experienced Grade 4 mucositis (53 versus 6 patients, p<0.0001). Thus, 23 (35.4%) patients in the 9-day group versus 5 (13.5%) patients in the 5-day group required a day +11 methotrexate dose reduction or omission (p=0.02). This resulted in a higher cumulative incidence of both Grade 2-4 (27% versus 38%, p=0.01) and Grade 3-4 (11% versus 34%, p=0.006) acute GVHD (aGVHD) in the 9-day group compared to the 5-day group. In a multivariate analysis, receiving the 9-day regimen predicted for a greater risk of grade 3-4 aGVHD (p=0.025). Additonally, extensive chronic GVHD was found to be higher in the 9-day FluBu4 cohort (19% vs. 40% p=0.047).Median one-year GVHD-free, relapse-free survival (GRFS) was significantly worse for patients receiving a 9-day FluBu4 regimen (68.4 versus 144 days, p=0.032). In a multivariate analysis adjusted for HCT-CI, a trend towards significance was observed with the 5-day regimen predicting for longer GRFS compared to the 9-day regimen (p=0.07). Notably, we observed no differences in overall survival, progression-free survival, or relapse rates between the 5- and 9-day regimen.This is the first study to compare outcomes between a concurrent 5-day and sequential 9-day FluBu4 regimen. We demonstrate similar survival and relapse rates, suggesting that concurrent administration of fludarabine and busulfan may not be necessary for synergistic cytotoxicity. At the same time, we observed increased early toxicity, less MTX administration, and higher aGVHD rates in patients receiving sequential 9-day FluBu4. Contrary to what has been observed with timed sequential regimens, our data suggests that a prolonged administration schedule of conditioning chemotherapy leads to greater toxicity resulting in higher GVHD rates. DisclosuresPatel:Celgene: Consultancy, Honoraria.

Audit on clozapine dose and plasma level correlation for patients with chronic treatment-resistant psychosis

AimsClozapine is associated with a risk of severe adverse events for which there are current monitoring systems are in place; however, there are no established regimens for monitoring of clozapine plasma levels. Recent Medicines and Healthcare products Regulatory Agency (MHRA) guidance advises clozapine levels should be monitored in certain clinical situations where toxicity may be suspected. This audit aimed to evaluate current practice of clozapine level monitoring within one Local Mental Health Team (LMHT).MethodElectronic (RiO) records of 41 patients (33 male, 8 female; aged from 27 to 76 years; mean age 45 years) registered to the ZTAS system within the Nottingham City Central LMHT were reviewed. 46% had been on clozapine for over 16 years. 73.3% of patients were within clusters 12 and 13; 25.4% of patients were in cluster 11, with one patient in cluster 8. Dates of clozapine plasma level tests for each patient between 2006 and 2020 were found on the electronic NoTIS system, along with clozapine, norclozapine and total clozapine levels. Concurrent clozapine dose and regimens were obtained from pharmacy records from 2018 onwards.Result273 clozapine plasma levels were conducted between 2006 and 2020. The average interval between levels taken was 10 months, 2 weeks but had a wide range, the shortest interval being 2 days, the longest being 13 years. 88 levels taken were &gt;600 ug/L, suggesting increased toxicity risk. 108 levels were &lt;350 ug/L, suggesting possible sub-optimal dosing or non-compliance. Statistical tests on correlation coefficient, although statistically non-significant (R = 0.37), showed a positive trend between total clozapine dose and the plasma level between all 3 parameters (i.e. clozapine, norclozapine and total clozapine).ConclusionThere does not appear to be any routine plasma clozapine level monitoring throughout the LMHT with an average interval between tests of 10 months. There was a non-significant but positive trend between total daily dose of clozapine and clozapine level. 32% of clozapine levels returned were higher than the recommended level. We would recommend as suggested in the guidelines from MHRA, clozapine plasma levels should be monitored in certain clinical situations with increased toxicity risk. Trough levels should be taken with records of time of previous dose taken. Limitations of this study included a small sample size (41 patients) with data collection reliant on electronic systems. It was unclear if these results represent trough levels, making values difficult to interpret. Multifactorial impact on clozapine metabolism causes wide patient variability in plasma levels.

Early glottic cancer treatment with concurrent chemoradiotherapy with once-daily orally administered S-1.

ABSTRACTGlottic carcinoma is the most common laryngeal cancer. The outcomes for T1 bulky Glottic carcinoma and T2N0 Glottic carcinoma after radiation therapy alone are unsatisfactory. This study was conducted to evaluate the efficacy and safety of unique concurrent chemoradiotherapy regimen using S-1 for early glottic cancer. Concurrent chemoradiotherapy consisted of 60 Gy in 30 fractions with once-daily, orally administered S-1 exclusively within three to six hours prior to each irradiation. Twenty-one consecutive patients treated with this regimen were retrospectively reviewed. Initial complete remission was achieved in all patients without any subsequent local and/or regional recurrences to the last follow-up. The 4-year local control, overall survival, and disease-free survival rates were all 100%. No significant toxicities were observed, except for three cases with Grade 3 acute dermatitis.This regimen is highly effective and well-tolerated, and these results encourage further research to long-term efficacy and functional preservation.

Real World Clinical Experience of Biosimilar G-CSF (Grastofil) for Autologous Peripheral Blood Stem Cell Mobilization: Single Center Experience in Canada Following Early Adoption.

Introduction: Granulocyte colony-stimulating factor (G-CSF) is the first line treatment for mobilization, most commonly using a regimen of daily filgrastim. The use of biosimilars can provide substantial cost savings to the health care system while delivering comparable efficacy outcomes. In 2016, the Saskatchewan Cancer Agency was a leader in Canada, instituting formulary changed from a G-CSF originator product to a cost savings alternative biosimilar for stem cell mobilization prior to autologous stem cell transplant (ASCT) and for engraftment. The purpose of this study was to investigate the clinical comparability of biosimilar G-CSF to its reference product in a real-world clinical setting and to validate use of the biosimilar in mobilization and engraftment—an indication which had been granted by extrapolation. Methods: A retrospective chart review was completed including all patients diagnosed with a hematological malignancy between 2012 and 2018 who underwent ASCT. To assess real-world outcomes across a diverse population, successful CD34+ stem cell collection was compared between patients mobilized with originator filgrastim, Neupogen, and biosimilar filgrastim, Grastofil. Additional comparisons included the number of apheresis required, time to absolute neutrophil count (ANC) engraftment, platelet engraftment, length of hospital stay, and Plerixafor use. Results: 217 patients were mobilized and transplanted during the study period. There was no statistically significant difference in success rate between patients mobilized with biosimilar filgrastim and those who had received originator G-CSF (100% vs. 92.4%, p = 0.075). Neither disease type, nor concurrent chemomobilization regimen resulted in a detectable difference between the two G-CSF products in successful stem cell harvest. Engraftment was highly similar between groups, as demonstrated by ANC recovery (11.6 days Neupogen vs. 11.6 days Grastofil), platelet recovery (14.0 days Neupogen vs. 14.2 days Grastofil), and total length of hospital stay (22.4 days Neupogen vs. 22.3 days Grastofil). No statistically significant difference in adjunctive use of Plerixafor® was observed between Neupogen and Grastofil patients (25.9% vs. 23.4%, p = 0.72). Conclusion: Extrapolation of indications for biosimilars is justified. This real-world evidence builds upon registrational studies to confirm that no clinically meaningful differences were detected between originator Neupogen and biosimilar Grastofil in the setting of PBSC mobilization and engraftment post ASCT. Biosimilars are as safe and effective as originator products. Implementation across all approved indications without hesitation maximizes cost savings to the provincial system, allowing for more optimal allocation of health care resources.