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– Selection criteria used in all three randomized trials are predictive of a complete cytoreduction and not the benefit of surgery– Post-hoc & prespecified subgroup analyses indicate that not all patients undergoing secondary cytoreduction benefit from it– Post-hoc and sub-group analysis should be performed separately for patients undergoing a complete gross resection– Impact of incomplete cytoreduction on quality of life and subsequent therapy needs further evaluation– Future randomized trials should use surgical prognostic factors like disease sites and extent as stratification factors

Objective:. The objective of this study is to analyze oncological outcomes of patients with peritoneal metastases (PM) of colorectal origin treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC). Background:. PIPAC has been demonstrated to be a feasible and safe novel treatment for patients with PM of various origins. Only small series reports on survival after PIPAC by disease entity. Methods:. International retrospective cohort study of consecutive patients with PM of colorectal origin. Outcome measures were overall survival (OS), radiological response according to Response Evaluation Criteria in Solid Tumors (RECIST), histological response (peritoneal regression grading score [PRGS]: complete response: 1–4: no response), change of peritoneal cancer index (PCI), and symptom control. Results:. Seventeen eligible centers compiled 256 non-selected patients (mean age 61 [50.6–69.2], 43% female) and 606 procedures. Sixty-three percent were treated after 2 lines of chemotherapy, median PCI at PIPAC1 was 18 (interquartile range [IQR] = 10–27). Median OS was 19.00 months (IQR = 12.9–29.8) from diagnosis and 9.4 months (IQR = 4.5–16.8) from PIPAC1. One hundred and four of 256 patients (40.6%) had ≥3 procedures (per protocol [pp]) with the following outcomes at PIPAC3: RECIST: 59.3% partial response/stable, 40.7% progression; mean PRGS: 2.1 ± 0.9. Median PCI was 21 (IQR = 15–29) at baseline and 20 (IQR = 12–27) at PIPAC3 (P = 0.02). Fifty-six (54%) and 48 (46%) patients were symptomatic at baseline and PIPAC3, respectively (P = 0.267). Median OS for the pp cohort was 11.9 months (IQR = 10.7–15.0) from PIPAC1. Independent predictors for survival were radiological response (HR = 3.0; 95% CI = 1.6–5.7) and no symptoms (HR = 4.5, 95% CI = 2.2–9.1) at PIPAC3. Conclusions:. Objective treatment response and encouraging survival were demonstrated after PIPAC for colorectal PM. Prospective registry data and comparative studies are now needed in to confirm these data.

Enhanced recovery after surgery (ERAS) protocols have been questioned in patients undergoing cytoreductive surgery (CRS) with/without hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies. This survey was performed to study clinicians’ practice about ERAS in patients undergoing CRS-HIPEC.

Early embryos often have unique chromatin states prior to zygotic genome activation (ZGA). In Drosophila , ZGA occurs after 13 reductive nuclear divisions during which the nuclear to cytoplasmic (N/C) ratio grows exponentially. Previous work found that histone H3 chromatin incorporation decreases while its variant H3.3 increases leading up to ZGA. In other cell types, H3.3 is associated with sites of active transcription and heterochromatin, suggesting a link between H3.3 and ZGA. Here, we test what factors regulate H3.3 incorporation at ZGA. We find that H3 nuclear availability falls more rapidly than H3.3 leading up to ZGA. We generate H3/H3.3 chimeric proteins at the endogenous H3.3A locus and observe that chaperone binding, but not gene structure, regulates H3.3 behavior. We identify the N/C ratio as a major determinant of H3.3 incorporation. To isolate how the N/C ratio regulates H3.3 incorporation we test the roles of genomic content, zygotic transcription, and cell cycle state. We determine that cell cycle regulation, but not H3 availability or transcription, controls H3.3 incorporation. Overall, we propose that local N/C ratios control histone variant usage via cell cycle state during ZGA., Competing Interests: Competing interest statement The authors declare no competing interests.

Biophysical stimulus quantifies the osteoinductivity of the scaffold concerning the mechanoregulatory mathematical models of scaffold-assisted cellular differentiation. Consider a set of independent structural variables ($) that comprises bulk porosity levels ([Formula: see text]) and a set of morphological features of the micro-structure ([Formula: see text]) associated with scaffolds, i.e., [Formula: see text]. The literature suggests that biophysical stimulus ([Formula: see text]) is a function of independent structural variables ($). Limited understanding of the functional correlation between biophysical stimulus and structural features results in the lack of the desired osteoinductivity in a scaffold. Consequently, it limits their broad applicability to assist bone tissue regeneration for treating critical-sized bone fractures. The literature indicates the existence of multi-dimensional independent design variable space as a probable reason for the general lack of osteoinductivity in scaffolds. For instance, known morphological features are the size, shape, orientation, continuity, and connectivity of the porous regions in the scaffold. It implies that the number of independent variables ([Formula: see text]) is more than two, i.e., [Formula: see text], which interact and influence the magnitude of [Formula: see text] in a unified manner. The efficiency of standard engineering design procedures to analyze the correlation between dependent variable ([Formula: see text]) and independent variables ($) in 3D mutually orthogonal Cartesian coordinate system diminishes proportionally with the increase in the number of independent variables ([Formula: see text]) (Deb in Optimization for engineering design-algorithms and examples, PHI Learning Private Limited, New Delhi, 2012). Therefore, there is an immediate need to devise a framework that has the potential to quantify the micro-structural's morphological features in a unified manner to increase the prospects of scaffold-assisted bone tissue regeneration., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Locally advanced tumors of the head and neck region often lie in close proximity to critical organs at risk (OARs). Providing effective treatment coverage to these malignancies while minimizing radiation dose to surrounding OARs is advantageous. Our aim is to compare dosimetric data of OARs from proton beam therapy (PBT) plans to volumetric modulated arc therapy (VMAT) treatment plans, and to evaluate clinical outcomes in patients treated with PBT., Methods: We identified patients with locally advanced head and neck tumors treated with PBT at our institution from 2016 to 2019. Study endpoints included mean and maximum doses for the OAR structures for each treatment plan, overall survival, time to local-regional or distant progression, and presence of acute and late toxicities. Mean and maximum doses to OAR structures were compared between treatment modalities using a paired Wilcoxon signed-rank test. P-values <0.05 were considered significant., Results: A total of 42 patients were identified. Clinical target volume coverage was >95% for both PBT and VMAT plans. PBT plans showed a significant reduction to the mean doses to all OARs, and max doses to most OARs (P<0.05). The largest reduction mean dose was seen in the contralateral cochlea and parotid glands at 71% and 75%, respectively. Median follow-up was 27 months. Overall survival at 4 years was 44.75%. Freedom from local-regional progression was 73.28% at 2 years. The majority of patients developed Common Terminology Criteria for Adverse Events (CTCAE) grade I dermatitis, mucositis, or both., Conclusions: PBT resulted in meaningful dose reductions to OARs while maintaining comparable target coverage when compared with VMAT plans. Further refinements to proton therapy may have the potential to further minimize dose to critical structures., Competing Interests: M.X.M. has received grant funding from Elekta and honoraria and additional support from Elekta and Varian. The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Muscular Dystrophies (MDs) are a group of inherited diseases and heterogeneous in nature. To date, 40 different genes have been reported for the occurrence and/or progression of MDs. This study was conducted to demonstrate the application of next-generation sequencing (NGS) in developing a time-saving and cost-effective diagnostic method to detect single nucleotide variants (SNVs) and copy number variants (CNVs) in a single test. A total of 123 cases clinically suspected of MD were enrolled in this study. Amplicon panel-based diagnosis was carried out for 102 (DMD/BMD) cases and the results were further screened using multiplex ligation-dependent probe amplification (MLPA). Whilst in the case of LGMD (N = 19) and UMD (N = 2), only NGS panel-based analysis was carried out. We identified the large deletions in 74.50% (76/102) of the cases screened with query DMD or BMD. Further, the large deletion in CAPN3 gene (N = 3) and known SNV mutations (N = 4) were identified in LGMD patients. Together, the total diagnosis rate for this amplicon panel was 70.73% (87/123) which demonstrated the utility of panel-based diagnosis for high throughput, affordable, and time-saving diagnostic strategy. Collectively, present study demonstrates that the panel based NGS sequencing could be superior over to MLPA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Patel, Bhatt, Shah, Waghela, Pandit, Sheth, Joshi and Joshi.)

Background: Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT., Methods: We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV., Results: Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p < 0.0001). In model II, average mean dose was reduced to 3154 cGy (p < 0.0001). For PTV low and PTV int, all had acceptable target coverage., Conclusion: In patients with oral-cavity and oropharyngeal cancers, mean dose could be significantly reduced using a thyroid-optimized or thyroid-sparing IMRT technique with adequate coverage., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Purpose: During the COVID-19 pandemic, telemedicine became an attractive alternative to in-person appointments. The role of telemedicine in patients who undergo frequent on-site treatment, such as radiation therapy, is unclear. The purpose of this study was to examine telemedicine use, physician satisfaction, and barriers to continued use in radiation oncology., Methods and Materials: An anonymous, electronic survey was distributed to radiation oncologists internationally between June and October 2020. Respondents described demographic and practice characteristics, and a 5-point Likert scale assessed provider satisfaction, ease of use, and overall utility of telemedicine. Analyses include descriptive statistics and subgroup comparisons using the χ 2 test and Fisher's exact test., Results: The response rate was 4.3%. Two hundred thirty-two respondents completed the survey, 63.8% of whom were male, 52.6% aged 50 or younger, and 78.0% from the United States. Only 14.2% used telemedicine previously, which increased to 93.1% during COVID-19. Among all telemedicine users, usage rates were 77.9% for initial consultations, 97.2% for follow-up visits, and 35.9% for on-treatment visits. Of the respondents, 69.8% reported that <25% of patients requiring treatment experienced delays due to COVID-19. Most conducted appointments from the workplace, with 40.1% also doing so from home. Satisfaction was high at 73.8%, perceived usefulness was 76.9%, and 81.5% hope to continue using telemedicine after the pandemic. However, 82.4% had concerns with the inability to examine patients and 63.0% had concerns about poor patient access to the required technology. In addition, 49.5% had concerns regarding continued billing/reimbursement, less commonly at government centers (18.8%) compared with academic/satellite facilities (52.7%) and free-standing centers/community hospitals (50.7%, P  = .039 for both comparisons). These concerns were also significantly higher among US physicians (53.2% vs 34.9%, P  = .048)., Conclusions: Widespread adoption of telemedicine by radiation oncologists occurred during COVID-19 with high rates of satisfaction and interest in continued use. Sustained reimbursement for telemedicine services is a significant concern, particularly in the United States and outside of government facilities., (© 2021 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.)

Porous scaffolds assisted bone tissue engineering is a viable alternative for reconstruction of large segmental bone defects caused by bone pathologies or trauma. In the current study, we intend to develop trabecular bone scaffolds using gyroid architecture. An interactive modeling framework is developed for the design of three-dimensional gyroid scaffolds using advanced generative tools including K3DSurf, MeshLab, and Netfabb. The suggested modeling approach resulted in uniform and interconnected pores. Subsequently, fused deposition modeling 3D-printing is employed to fabricate the scaffolds using poly lactic acid material. The pores interconnectivity, porosity, and surface finish of the fabricated scaffolds are characterized using micro-computer tomography and scanning electron microscopy. Additionally, to assess the performance of scaffolds as a bone substitute, compression, and in-vitro biocompatibility tests on sterilized scaffolds are conducted. Compression tests reveal mechanical strength in the range of native bone while human adipose-derived mesenchymal stem cells show high proliferation after 72 h of incubation. Based on these results, the fabricated gyroid scaffolds can be said to possess favorable properties for trabecular bone scaffold.

Importance: The health effects of restrictive immigration and refugee policies targeting individuals from Muslim-majority countries are largely unknown., Objective: To analyze whether President Trump's 2017 executive order 13769, "Protecting the Nation from Foreign Terrorist Entry into the United States" (known as the "Muslim ban" executive order) was associated with changes in health care utilization by people born in targeted nations living in the US., Design, Setting, and Participants: This retrospective cohort study included adult patients treated at Minneapolis-St. Paul HealthPartners primary care clinics or emergency departments (EDs) between January 1, 2016, and December 31, 2017. Patients were categorized as (1) born in Muslim ban-targeted nations, (2) born in Muslim-majority nations not listed in the executive order, or (3) non-Latinx and born in the US. Data were analyzed from October 1, 2019, to May 12, 2021., Exposures: Executive order 13769, "Protecting the Nation from Foreign Terrorist Entry into the United States.", Main Outcomes and Measures: Primary outcomes included the number of (1) primary care clinic visits, (2) missed primary care appointments, (3) primary care stress-responsive diagnoses, (4) ED visits, and (5) ED stress-responsive diagnoses. Visit trends were evaluated before and after the Muslim ban issuance using linear regression, and differences between the study groups after the executive order issuance were evaluated using difference-in-difference analyses., Results: A total of 252 594 patients were included in the analysis: 5667 in group 1 (3367 women [59.4%]; 5233 Black individuals [92.3%]), 1254 in group 2 (627 women [50%]; 391 White individuals [31.2%]), and 245 673 in group 3 (133 882 women [54.5%]; 203 342 White individuals [82.8%]). Group 1 was predominantly born in Somalia (5231 of 5667 [92.3%]) and insured by Medicare or Medicaid (4428 [78.1%]). Before the Muslim ban, primary care visits and stress-responsive diagnoses were increasing for individuals from Muslim-majority nations (groups 1 and 2). In the year after the ban, there were approximately 101 additional missed primary care appointments among people from Muslim-majority countries not named in the ban (point estimate [SE], 6.73 [2.90]; P = .02) and approximately 232 additional ED visits by individuals from Muslim ban-targeted nations (point estimate [SE], 3.41 [1.53]; P = .03)., Conclusions and Relevance: Results of this cohort study suggest that after issuance of the Muslim ban executive order, missed primary care appointments and ED visits increased among people from Muslim-majority countries living in Minneapolis-St. Paul.

Purpose: Periorbital tumor location presents a significant challenge with 3-dimensional conformal radiation therapy or intensity modulated radiation therapy due to high tumor dose needed in the setting of close proximity to orbital structures with lower tolerance. Proton beam therapy (PBT) is felt to be an effective modality in such cases due to its sharp dose gradient., Materials and Methods: We reviewed our institutional PBT registry and identified 17 patients with tumor epicenters within 2 cm of the eye and optic apparatus treated with passive scatter PBT with comparison volumetric arc therapy plans available. Maximum and mean doses to organs at risk of interest, including optic nerves, optic chiasm, lens, eye ball, pituitary, cochlea, lacrimal gland, and surrounding brain, were compared using the paired Wilcoxon signed rank test. Overall survival was determined using the Kaplan-Meier method., Results: Median age was 67. Median follow-up was 19.7 months. Fourteen patients underwent upfront resection and received postoperative radiation and 3 received definitive radiation. One patient received elective neck radiation, 2 underwent reirradiation, and 3 had concurrent chemotherapy. There was a statistically significant reduction in mean dose to the optic nerves and chiasm, brain, pituitary gland, lacrimal glands, and cochlea as well as in the maximum dose to the optic nerves and chiasm, pituitary gland, lacrimal glands, and cochlea with PBT. The 18-month cumulative incidence of local failure was 19.1% and 1-year overall survival was 80.9%., Conclusion: Proton beam therapy resulted in significant dose reductions to several periorbital and optic structures compared with volumetric arc therapy. Proton beam therapy appears to be the optimal radiation modality in such cases to minimize risk of toxicity to periorbital organs at risk., Competing Interests: Conflicts of Interest: Mitchell X. Machtay, MD reports travel funding from Mevion Inc. and Varian Inc., and grants and travel funding from Elekta Inc., outside the submitted work. The authors have no other relevant conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Background: Endometriosis is a pathological state in which the endometrial glands and stroma are originated at sites other than the uterine cavity. Endometriotic cystic lesions are principally positioned in ovaries but, infrequently, can also be encountered in the myometrium. It is a rare manifestation which poses a multitude of differential diagnoses and therapeutic options., Case Study: A 27-year-old female patient walked into hospital complaining of severe abdominal pain since 2 days with a medical history of dysmenorrhoea since one and a half years. On examination, the abdomen was found to be soft with the existence of lower abdominal tenderness. An Ultrasonography revealed a myometrial posterior wall cyst of size 4 x 4 cm with thick wall and spotted internal echoes favoring a differential diagnosis of either an endometriotic cyst or rudimentary horn. Both ovaries were found normal. The patient was taken for laparoscopy in which a bulge was seen on the posterior uterine wall. It was punctured to expose a myometrial cyst with dark chocolate colored fluid collection. The intact cyst was enucleated and sent for histopathology, which confirmed the diagnosis of the endometriotic cyst. Upon the literature survey, it was found that only two such cases were available in the literature on internet which described a similar pathology., Conclusion: Endometrioma should be considered as a probable pathology whenever myometrial cysts are encountered. A focused transvaginal examination can be very accommodating as a diagnostic modality to set up proper management. This case should not only make the health careproviders rethink the etiopathogenesis of endometriosis and debate the credibility of the retrograde menstruation hypothesis but also encourage to accurately investigate any lesion anywhere in the body, which looks like an endometriotic chocolate cyst. In this case, it is evident that a myometrial spot is rare but not impossible. These rare occurrences shall direct to diversify the perception of this pathology., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Reirradiation in the scalp area can be challenging given the proximity to organs at risk (OARs), such as the eye and brain. Our aim is to evaluate the dosimetric differences of volumetric modulated arc therapy (VMAT) and electron beam therapy (EBT) compared with 3-dimensional proton beam therapy (PBT)., Patients and Methods: We evaluated a patient with recurrent angiosarcoma of the left temporal scalp after prior surgical resections and radiation therapy to 60 Gy in 30 fractions who needed reirradiation. We generated VMAT, EBT, and PBT plans using the Pinnacle Treatment Planning System (TPS). Both VMAT and EBT plans used a skin bolus, whereas no bolus was used for the proton plan. Doses to the OARs, including cochlea, eyes, lens, lacrimal glands, optic nerves, optic chiasm, pituitary gland, and underlying brain, were compared., Results: The reirradiation treatment dose was 60 Gy(RBE). Target volume coverage was comparable in all plans. Compared with VMAT and EBT, the PBT plan showed reductions in mean and maximum doses to all OARs. Without the use of protons, several OARs would have exceeded dose tolerance utilizing VMAT or electrons. Dose reduction of up to 100% was achieved for central and contralateral OARs., Conclusion: Compared with VMAT and EBT, PBT resulted in dose reductions to all OARs, while maintaining excellent target coverage. PBT showed a significant advantage in treating superficially located skin cancers, such as angiosarcoma, without the need for a bolus. PBT can be considered in the upfront treatment and certainly in the reirradiation setting., Competing Interests: Conflicts of Interest: The authors have no relevant conflicts of interest to disclose., (© Copyright 2019 The Author(s).)

Bazex syndrome is a rare paraneoplastic dermatosis that precedes diagnosis of cancer. Awareness of this syndrome is important, as it allows early detection of underlying malignancy and may prevent misdiagnosis and delays in cancer treatment., Competing Interests: None declared., (© 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

For patients ineligible for cisplatin with definitive radiotherapy (CP-CRT) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), concurrent cetuximab (C225-RT) is a popular substitute. Carboplatin-based chemoradiation (CB-CRT) is another option; however, relative efficacies of CP-CRT, CB-CRT and C225-RT are unclear, particularly in the human papillomavirus (HPV)-unrelated population. We identified 316 patients with stage III-IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225-RT (N = 61), CB-CRT (N = 74) or CP-CRT (N = 181). Kaplan-Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3-year cumulative incidences for CP-CRT, CB-CRT and C225-RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan-Meier estimates for 3 year OS were: CP-CRT: 71%; CB-CRT: 59% and C225-RT: 54%; p = 0.0094. CP-CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203-0.557, p < 0.01) and CB-CRT (HR 0.279; 95% CI 0.141-0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP-CRT (HR 0.548; 95% CI 0.355-0.845, p < 0.01) and CB-CRT (HR 0.549; 95% CI 0.334-0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB-CRT group compared to C225-RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB-CRT group compared to C225-RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB-CRT is an effective alternative to CP-CRT in HPV-unrelated LA-HNSCC with superior locoregional control and OS compared to C225-RT., (© 2019 UICC.)

Lichens have been widely studied for their symbiotic properties and for the secondary metabolites production by its fungal symbiont. Recent molecular studies have confirmed coexistence of bacteria along with the fungal and algal symbionts. Direct nucleic acid study by -omics approaches is providing better insights into their structural and functional dynamics. However, genomic analysis of individual members of lichen is difficult by the conventional approach. Hence, genome assembly from metagenome data needs standardization in the eukaryotic system like lichens. The present study aimed at metagenomic characterization of rock associated lichen Dirinaria collected from Kutch and Dang regions of Gujarat, followed by genome reconstruction and annotation of the mycobiont Dirinaria. The regions considered in the study are eco-geographically highly variant. The results revealed higher alpha diversity in the dry region Kutch as compared to the tropical forest associated lichen from Dang. Ascomycota was the most abundant eukaryote while Proteobacteria dominated the bacterial population. There were 23 genera observed only in the Kutch lichen (KL) and one genus viz., Candidatus Vecturithrix unique to the Dang lichen (DL). The exclusive bacterial genera in the Kutch mostly belonged to groups reported for stress tolerance and earlier isolated from lithobionts of extreme niches. The assembled data of KL & DL were further used for genome reconstruction of Dirinaria sp. using GC and tetra-pentamer parameters and reassembly that resulted into a final draft genome of 31.7 Mb and 9556 predicted genes. Twenty-eight biosynthesis gene clusters were predicted that included genes for polyketide, indole and terpene synthesis. Association analysis of bacteria and mycobiont revealed 8 pathways specific to bacteria with implications in lichen symbiosis and environment interaction. The study provides the first draft genome of the entire fungal Dirinaria genus and provides insights into the Dirinaria lichen metagenome from Gujarat region., (Copyright © 2019. Published by Elsevier GmbH.)

Lung cancer, one of the most frequently diagnosed cancers worldwide has long relied on testing for the molecular biomarkers EGFR / ALK . However, achieving superior clinical outcomes for patients with lung cancer requires developing comprehensive techniques beyond contemporary EGFR / ALK testing. Current technologies are on par with molecular testing for EGFR / ALK in terms of efficacy, most of them failing to offer improvements perhaps primarily due to skepticism among clinicians, despite being recommended in the NCCN guidelines. The present study endeavored to minimize chemotherapy-dependence in EGFR / ALK -negative patient cohorts, and use evidence-based methods to identify ways to improve clinical outcomes. In total, 137 lung cancer cases obtained from 'PositiveSelect NGS data', comprising 91 males and 46 females, were investigated. EGFR - and ALK -positivity was used for data dichotomization to understand the therapeutic utility of rare gene alterations beyond just EGFR / ALK . Statistics obtained from PositiveSelect were collated with data from international studies to construct a meta-analysis intended to achieve better clinical outcomes. Upon dichotomization, 23% of cases harbored EGFR variants indicating that treating with EGFR TKIs would be beneficial; the remaining 77% exhibited no EGFR variants that would indicate favorable results using specific currently available chemotherapy practices. Similarly, 28% of cases had EGFR + ALK variants favoring EGFR / ALK -based targeted therapeutics; the remaining 72% harbored no EGFR / ALK variants with known beneficial chemotherapy routes. The present study aimed to overcome current inadequacies of targeted therapies in patients with a conventional EGFR / ALK -positive diagnosis and those in EGFR + ALK -negative cohorts. Upon analysis of the negative cohorts, significant and clinically relevant single nucleotide variants were identified in KRAS, ERBB2, MET and RET , with frequencies of 7, 1, 2 and 3% in patients who were EGFR -negative and 6, 1, 1, and 3% in patients who were EGFR and ALK -negative, respectively, enabling the use of targeted therapeutics aside from EGFR / ALK TKIs. From the results of the current study only 35% of the two negative arms ( EGFR negative and EGFR + ALK negative) would be recommended NCCN or off-label chemotherapy; prior to the current study, the entire cohorts would have been recommended this treatment. The present study emphasizes the potential of comprehensive genomics in identifying hallmarks of lung cancer beyond EGFR / ALK , using broad-spectrum genetic testing and data-sharing among medical professionals to circumvent ineffective chemotherapy.

The purpose of this article is to present the recent imaging advancements enabled by digital photon counting positron emission tomography detector technology and discuss its potential applications in the clinical management of head and neck cancer (HNC) and nodal metastases. 18 F-fluorodeoxyglucose positron-emission tomography is a clinically useful biomarker for the detection, targeted biopsy, treatment planning, and therapeutic response assessment of HNC. This article highlights the current state of 18 F-fluorodeoxyglucose positron-emission tomography imaging in HNC management as well as the emerging capabilities of the recently introduced digital photon counting positron emission tomography/computed tomography platform for more effective molecular and functional HNC imaging., (Copyright © 2018. Published by Elsevier Inc.)

Cutaneous wounds caused by an exposure to high doses of ionizing radiation remain a therapeutic challenge. While new experimental strategies for treatment are being developed, there are currently no off-the-shelf therapies for the treatment of cutaneous radiation injury that have been proven to promote repair of the damaged tissues. Plasma-based biomaterials are biologically active biomaterials made from platelet enriched plasma, which can be made into both solid and semi-solid forms, are inexpensive, and are available as off-the-shelf, nonrefrigerated products. In this study, the use of plasma-based biomaterials for the mitigation of acute and late toxicity for cutaneous radiation injury was investigated using a mouse model. A 2-cm diameter circle of the dorsal skin was irradiated with a single dose of 35 Gy followed by topical treatment with plasma-based biomaterial or vehicle once daily for 5 weeks postirradiation. Weekly imaging demonstrated more complete wound resolution in the plasma-based biomaterial vs. vehicle group which became statistically significant (p < 0.05) at weeks 12, 13, and 14 postmaximum wound area. Despite more complete wound healing, at 9 and 17 weeks postirradiation, there was no statistically significant difference in collagen deposition or skin thickness between the plasma-based biomaterial and vehicle groups based on Masson trichrome staining nor was there a statistically significant difference in inflammatory or fibrosis-related gene expression between the groups. Although significant improvement was not observed for late toxicity, plasma-based biomaterials were effective at promoting wound closure, thus helping to mitigate acute toxicity., (© 2018 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound Healing Society.)

Objectives: Randomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response., Materials and Methods: Cases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups., Results: We identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings., Conclusion: When treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Radiation therapy (RT) improves local tumor control in axial chondrosarcomas (CS). It is, however, often difficult to safely deliver the high doses (range, 70.2-77.4 Gy) required for achieving a high likelihood of local control, especially in the spine, using photons. This, however, can be achieved with proton beam therapy (PBT) due to its unique physical characteristics. The main goal of our study is to evaluate the outcomes of CS patients treated with passive scattered PBT., Materials and Methods: Forty-four patients (N = 44) were identified who received PBT as part of their treatment from 1990 to 2012. A retrospective review of their medical and RT treatment records was conducted. Multivariate analyses were performed to identify patient- and tumor-related factors predicting for improved local control and overall survival., Results: Median age was 45.5 years and 55% were female. Median tumor size was 13 cm. Most common anatomical location was the spine (80%). Median follow-up was 29.1 months. Median external beam RT dose was 70.2 Gy relative biological effectiveness (RBE) at 1.8 Gy (RBE) per fraction typically administered using a combination of photon RT + PBT (77%) or PBT alone (23%). Local control was 76% and 57%, and overall survival was 90% and 68% at 2 and 5 years, respectively. Toxicity was acceptable, with the most frequent being wound complications (16%). On multivariate analyses, grade III tumors were significantly associated with decreased local control ( P  = 0.019), while female sex ( P  = 0.037) and grade III tumors ( P  = 0.005) were associated with a poorer overall survival., Conclusions: High-dose proton-based RT in combination with surgery resulted in local tumor control in most of these high-risk CS patients. Female sex was predictive for decreased survival, while higher tumor grade (grade III) was predictive of decreased local control and survival. Proton beam therapy is an attractive treatment modality for these challenging tumors., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose., (© Copyright 2016 International Journal of Particle Therapy.)

Background: The purpose of this study was to review long-term outcomes of sinonasal adenoid cystic carcinoma (ACC) and to clarify its association with human papillomavirus (HPV)., Methods: The medical records of 23 patients with sinonasal ACC treated with primary surgical resection between 1998 and 2013 were reviewed. Tissue specimens were available for 17 patients. The p16 testing was performed using immunohistochemistry (IHC), and HPV infection was determined using quantitative polymerase chain reaction (PCR) with primers targeting the E6/E7 region., Results: Two of the 17 samples showed strong and diffuse p16 staining, whereas the remaining 15 cases showed p16-positivity isolated to the luminal cells. Only one of the p16-positive cases was positive for HPV. The 5-year local failure, disease-free survival (DFS), and overall survival (OS) were 51%, 52%, and 62%, respectively., Conclusion: Local failures are common with advanced sinonasal ACC, and the association of HPV with true sinonasal ACC is low., (© 2017 Wiley Periodicals, Inc.)

Background: Thyroid dysfunction is common after radiotherapy (RT) for patients with head and neck cancers. We attempted to discover RT dose parameters that correspond with RT-induced thyroid dysfunction., Methods: Records of 102 patients who received RT from 2008 to 2010 were reviewed with respect to thyroid function. Abnormalities were grouped in 2 ways: (1) none, transient, or permanent; and (2) overt or subclinical., Results: At median follow-up of 33.5 months, incidence of any thyroid abnormality was 39.2% (women vs men - 50% vs 35%). Permanent dysfunction was seen in 24.5% with higher incidence in women versus men (42.9% vs 17.6%; p = .0081). Permanent abnormalities most strongly correlated with D 50% (p = .0275). V 50Gy also correlated with thyroid dysfunction post-RT (p = .0316). Concurrent chemotherapy increased permanent dysfunction (p = .0008)., Conclusion: Achieving D 50% <50 Gy, V 50 <50%, and mean dose <54.58 Gy during RT planning may decrease the incidence; whereas female sex and concurrent chemotherapy seem to increase the risk of RT-induced hypothyroidism. © 2016 Wiley Periodicals, Inc. Head Neck 39: 548-554, 2017., (© 2016 Wiley Periodicals, Inc.)

Background: The purpose of this study was to investigate the role of transcutaneous neuromuscular electrical stimulation (TNMES) therapy in maintaining swallowing function during chemoradiation for locally advanced head and neck cancer., Methods: We retrospectively compared 43 consecutive patients with locally advanced head and neck cancer treated with TNMES (treatment group) to 55 control patients. Validated swallowing scale scores were assigned., Results: All patients' swallowing scores declined post-chemoradiotherapy. A difference in mean decline in scores for the control group versus the treatment group using the Functional Oral Intake Scale (FOIS) was seen, favoring TNMES intervention (23% vs 7%; p = .015). Age, race, >10 pack-years smoking, diabetes, stage, nodal disease, accelerated fractionation, weight loss, dietary modification, no TNMES, and radiotherapy dose were all significant for poorer scores on the swallowing scales., Conclusion: TNMES should be considered an adjunct to dysphagia reduction and possible prevention in patients with locally advanced head and neck cancer. Further studies should be conducted to define the benefit of TNMES intervention., (© 2015 Wiley Periodicals, Inc.)

Objectives: To quantify gross tumor volume (GTV) change during stereotactic body radiotherapy (SBRT) and on first follow-up, as well as to evaluate for any predictive prognostic risk factors related to GTV decrease. An attempt was also made to identify the potential timing for adaptive SBRT., Methods: Twenty-five tumors in 24 consecutive patients were treated with SBRT to total dose of 50 Gy in 5 fractions. Median age was 72.5 years. Tumor stage was T1, 68%; T2, 20%; and other, 12%. The GTVs of on the 5 cone-beam computed tomographies (CBCT1-5) obtained before each fraction and the first follow-up CT (CTPOST) were analyzed., Results: Median time from diagnosis to initiation of radiotherapy was 64 days. GTV on CBCT1 was the baseline for comparison. GTV decreased by a mean of 7% on CBCT2 (P=0.148), 11% on CBCT3 (P=0.364), 19% on CBCT4 (P=0.0021), and 32% on CBCT5 (P=0.0004). Univariate analyses of GTV shrinkage was significantly associated with "time from CBCT5 to CTPOST" (P=0.027) and "T-stage" (P=0.002). In multivariate analyses, "T-stage" remained significant with T1 tumors showing greater GTV shrinkage than T2 tumors., Conclusions: Significant decrease in GTV volume based on daily CBCT was demonstrated during SBRT treatment. Adaptive SBRT has the potential to minimize integral dose to the surrounding normal tissues without compromising GTV coverage.

Purpose: Balloon brachytherapy is commonly used to deliver Accelerated Partial Breast Irradiation (APBI). Seroma interference is a relatively common phenomenon during APBI. The negative effect of seroma accumulation on the planning target volume evaluation (PTV&#95;Eval) coverage is not well understood., Methods and Materials: This is a dosimetric replanning study on 10 patients with evidence of seroma collection at time of initial computed tomographic simulation around the catheter. Total dose was 34 Gy given at 3.4 Gy twice a day over 5 treatment days. A total of 20 plans were generated, 10 plans without accounting for and 10 after subtracting the seroma. We then compared the changes seen in PTV&#95;Eval between plans as a factor of the seroma volume., Results: Median age was 62 years (51-83). Histology was invasive in 7/10 cases and in situ in 3/10. Median balloon to skin distance was 8.5 mm (3-14). Median balloon volume was 39 cc (30-104). Median seroma volume was 3.34 cc (1.13-13.71). For every 1 cc of accumulated seroma the percentage of PTV&#95;Eval coverage by the 90% isodose line (V90) was found to decrease by 2.45% (P < .0001; confidence interval [CI], 1.87-3.03) and coverage by the 100% isodose line (V100) was decreased by 1.11% (P < .0001; CI, 0.81-1.41). Fifty percent (5/10) of previously acceptable plans with seroma not accounted for failed to meet the V90 ≥90% requirement after subtracting the seroma., Conclusions: Accumulation of seroma was associated with a considerable negative impact on PTV&#95;Eval dosimetry with a greater impact on V90 compared with the V100. Clinicians must be careful in detecting and accounting for such accumulation in treatment plans to prevent underdosing of the at risk target breast tissue., (Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

The skin is an unusual site of metastases from solid organ malignancies. We report the case of a patient with a malignant mixed non-seminomatous germ cell tumor of the testis, presenting with cutaneous metastasis, which was treated with salvage chemotherapy.

Objective: The objective of this study was to conduct feasibility study of phase III breast and lung cancer clinical trials in India., Materials and Methods: Study synopsis and feasibility questionnaire were mailed to 300 oncologists for each indication. Criteria of selection were enrolment of ≥2 patients per month, frequency of Ethics Committee (EC) meeting ≤4 weeks, dropout rate <20%, adequacy of infrastructure and training of site in good clinical practice (GCP). Descriptive analyses of the data were performed., Results: For both indications, 50/300 (16.7%) sites responded. The median number of patients seen by a site per month for breast and lung cancer was 20 (range 0-300) and 10 (range 0-75), respectively. Median number of eligible patients was 4 (range 0-20) and 3 (range 0-15) per month, for breast and lung cancer respectively. The frequency of EC meeting was ≤4 weeks at 36-56% of sites. All sites were trained in GCP and had adequate infrastructure to conduct the clinical trial. For breast cancer 22 (44%) sites (public 14 [28%]; private 8 [16%)]), and for lung cancer 18 (36%) sites (public 15 [30%], private: 3 [6%]) met the criteria of selection., Conclusion: Preliminary feasibility study would require for confirmation of the important feasibility criteria by in depth discussion during the personal visit to the potential sites.

Context: Alterations in the human chromosomal complement are expressed phenotypically ranging from (i) normal, via (ii) frequent fetal loss in otherwise normal person, to (iii) sub-clinical to severe mental retardation and dysmorphism in live births. A subtle and microscopically undetectable chromosomal alteration is uniparental disomy (UPD), which is known to be associated with distinct birth defects as per the chromosome involved and parental origin. UPD can be evident due to imprinted genes and/or activation of recessive mutations., Aims: The present study comprises of data mining of published UPD cases with a focus on associated phenotypes. The goal was to identify non-random and recurrent associations between UPD and various genetic conditions, which can possibly indicate the presence of new imprinted genes., Settings and Design: Data mining was carried out using the homepage "http://www.fish.uniklinikum-jena.de/UPD.html.", an online catalog of published cases with UPD., Materials and Methods: The UPD cases having normal karyotype and with or without clinical findings were selected to analyze the associated phenotypes for each chromosome, maternal or paternal involved in UPD., Results: Our results revealed many genetic conditions (other than the known UPD syndromes) to be associated with UPD. Even in cases of bad obstetric history as well as normal individuals chance detection of UPD has been reported., Conclusions: The role of UPD in human genetic disorders needs to be studied by involving larger cohorts of individuals with birth defects as well as normal population. The genetic conditions were scrutinized in terms of inheritance patterns; majority of these were autosomal recessive indicating the role of UPD as an underlying mechanism.

Introduction: We performed retrospective analysis of 106 patients with lung cancer for which formalin-fixed paraffin-embedded tissues was available. Their epidermal growth factor receptor (EGFR) mutation status and treatment outcomes are described., Materials and Methods: All patients with confirmed non-small cell lung cancer (NSCLC) during Jan 2008 to Dec 2010 were included. EGFR sequencing was performed with ABI PRISM 310 genetic analyzer., Results: Forty-two (39.6%) patients had mutation in one of the four exons characterized. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy, n = 46 (43.39%). If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront tyrosine kinase inhibitor (TKI), n = 15 (14.15%) or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, n = 26 (24.52%). The median progression free survival for patients with and without mutations was 11 months (95% CI,7-14) and 9 months (95% CI,7-10) respectively. A median PFS of 14 months (95%CI, 12-16) was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 8 months (95%CI, 7-8 months) in the group that received only TKI., Conclusion: The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question, can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study.

To provide a comprehensive review on the presentation, work-up and the management of spine metastasis with or without epidural spinal cord compression with focus on the roles of surgery and radiotherapy. Emphasis has been laid on the technological advances with recent development of stereotactic body radiotherapy (SBRT) or radiosurgery (SRS) and minimally invasive surgical approaches like kyphoplasty and vertebroplasty., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The incidence of osteonecrosis of the jaw (ONJ) among patients with cancer and metastatic bone disease being treated with bisphosphonates is as high as 10%, which dictates that an understanding of the risk factors, preventative measures, means of early diagnosis, and treatment is critical. Despite ONJ occurring in the clinical setting of intravenous bisphosphonates, there are other causes associated with higher risk of ONJ, such as multiple dental extractions. Overall, it is important for imaging health care professionals to recognize, describe, and understand ONJ to help minimize biopsies and allow proper treatment to begin as soon as possible.

Purpose: To quantify and characterize the process of seroma accumulation during accelerated partial breast irradiation using multicatheter balloon brachytherapy., Materials and Methods: Twenty-two patients were treated using the Contura Multilumen brachytherapy catheter to a dose of 34Gy in 10 fractions over 5 treatment days. Serial aspirations of the vacuum port of the catheter were performed at the time of CT simulation and before each treatment. Volume and characteristics of fluid drawn were recorded. Univariate analysis was performed to evaluate various factors predictive of seroma formation., Results: Median patient age was 59.5 years, body mass index was 31, and volume of surgical specimen was 62.4cm(3). Median time from breast conservation surgery to placement of Contura catheter was 18.5 days. Pericatheter seroma, typically scant with a median volume of 0.75mL, was noted in 91% of patients at CT simulation. A total of 203 aspirations were performed with a median-aspirated seroma volume of 4.05mL. There was no significant correlation between the volume of seroma and histology (invasive vs. in situ), quadrant of location, body mass index, reexcision or reoperation, days from breast conservation surgery to balloon placement, or the volume of specimen removed. Radiation treatment factors, including balloon volume, balloon to skin distance, and planning target volume evaluation, also did not correlate with aspirated seroma., Conclusions: Interfraction seroma accumulation has a variable pattern of development with no discernible predictors of occurrence. Routine pretreatment aspirations via vacuum port may potentially improve dosimetric reproducibility for a minority of patients., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Bone is a complex biological tissue and natural heterogeneous object. The main objective of this study is to simulate quasi-static loading of bio-objects like human femur with B-spline based modeling and its 3D finite element analysis with graded element. B-spline surface representation method is extended to represent material composition to develop heterogeneous solid model of proximal femur. Lagrangian graded element is used to assign inhomogeneous isotropic elastic properties in finite element model to improve the performance. Convergence study is carried out with finite element model in single leg stance load condition. To test the feasibility of the model, sensitivity of simulation is investigated. To validate the model, numerical results are compared with those of an experimental work for the same specimen in simple stance load condition obtained from one of the reference paper. Good agreement is achieved for vertical displacement and strains in most of the locations.

Globally there is an increasing interest in alternative routes to health such as ayurveda. There is a need to conduct globally acceptable clinical research in ayurvedic therapeutics (AT). Some of the issues in investigating AT in randomised clinical trials (CT) are: selection of appropriate AT, non-drug and/or drug AT, identification of objective outcomes, devising adequate placebo/positive controls, difficulties of blinding, guarding against bias, duration of trials, number of patients, dose optimisation, etc. There is also a need to establish reasonable safety of this therapy in CT. If AT has to complete with new chemical entities and biotechnology products, clinical research and development of AT should be focussed on unmet medical needs utilising principles and practices of modern CT approaches.

Objective: To assess the bioavailability of clonazepam from two brands of 2 mg tablet formulations--Epitril and reference brand., Methods: A two-way randomised cross-over bioavailability study was carried out in 12 healthy male volunteers. Coded plasma samples were analysed for levels of clonazepam by high performance liquid chromatography (HPLC) method., Results: The mean Cmax, Tmax t1/2 beta and AUC (0-48) for Epitril were: 16.31 +/- 3.07 ng/mL, 1.63 +/- 0.48 h, 46.97 +/- 12.26 h and 207.70 +/- 57.07 ng/ml.h; for reference brand were 19.75 +/- 5.95 ng/mL, 1.42 +/- 0.29 h, 46.88 +/- 11.29 h and 215.70 +/- 50.89 ng/ml.h respectively. These were comparable and the differences were not statistically significant., Conclusion: Based on above pharmacokinetic parameters, Epitril was bioequivalent to reference brand.

Skin adverse drug reactions (ADRs) generally present as transient erythematous macular/papular rashes. However these can many a times be the initial presentation of serious muco-cutaneous ADRs such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). The incidence of SJS varies from 1.2 to 6 per million patient-years and that of TEN to be 0.4 to 1.2 per million patient-years. The pathophysiological mechanism of SJS and TEN have not been fully elucidated. The aetiological factors of SJS and TEN are diverse; drugs being the cause in more than 80% cases of TEN and about 40-50% cases of SJS. Mucous membranes are affected in nearly all cases. The extent of epidermal sloughing may vary and forms a basis for the classification of an individual case as SJS or TEN. Prognosis of SJS is better than that of TEN; mortality rates being about 5% and 30%-40% respectively. Specific therapy for these conditions is yet not available. The use of systemic corticosteroids has been controversial. Early diagnoses can prevent/reduce the morbidity of such serious ADRs. This article provides a brief review of the clinical presentation and management of SJS and TEN.

In India, treatment of acute, uncomplicated Plasmodium falciparum malaria is becoming increasingly difficult due to resistance to chloroquine, thus there is a need for new antimalarial drugs. CGP 56697 (co-artemether), a new drug, is a combination of artemether and lumefantrine in a single oral formulation (one tablet = 20 mg of artemether plus 120 mg of lumefantrine). In a double-blind study, 179 patients with acute uncomplicated P. falciparum malaria were randomly assigned to receive either CGP (n = 89) given as a short course of 4 x 4 tablets over a 48-hr period or chloroquine (n = 90) given as four tablets (one tablet = 150 mg of chloroquine base) initially, followed by two tablets each at 6-8, 24, and 48 hr. Due to a death in the chloroquine group and a decrease in the chloroquine cure rate to < 50% (based on the blinded overall cure rate at that time), recruitment was terminated prematurely. CGP 56697 showed a superior 28-day cure rate (95.4% versus 19.7%; P < 0.001), time to parasite clearance (median = 36 versus 60 hr; P < 0.001), and resolution of fever (median = 18 versus 27 hr; P = 0.0456). This drug provides a safe, effective, and rapid therapy for the treatment of acute uncomplicated P. falciparum malaria.

Objectives: To assess the bioquivalence of carbamazepine (CBZ) controlled release formulation A (Tegretol CR, local) vs formulation B (Tegretol CR, Basel) and confirm their controlled release characteristics by comparing with conventional formulation (Tegretol)., Methods: A three-way randomized cross-over bioavailability study was carried out using CBZ 200 mg tablets of conventional and two controlled release formulations in twelve healthy volunteers. Coded plasma samples were analysed for levels of CBZ by HPLC method., Results: The mean Cmax, Tmax, t1/2 and AUC for formulation A were: 1.67 +/- 0.26 mcg/mL, 24 +/- 0 hr, 47.8 +/- 9.7 hr and 136.7 +/- 25.4 mcg/ml. h; for formulation B were 1.41 +/- 0.31 mcg/mL, 25 +/- 8 hr, 46.9 +/- 7.9 and 119 +/- 32.3 mcg/ml.h and for conventional formulation were 2.43 +/- 3.6 mcg/mL, 9.5 +/- 7.4 hr, 44.6 +/- 9.8 hr and 178.8 +/- 41.9 mcg/ml.h respectively. The fluctuation in plasma concentration within 24 h (peak:trough) were 11.7 +/- 8.14% with conventional formulation as compared to 0% and 1.2 +/- 3.98% with formulation A and B respectively. The mean Tmax for both the controlled release formulations was not statistically significant. On the basis of 90% confidence interval, mean AUC and Cmax values obtained after controlled release formulation A, though statistically significant (P < 0.05) lie well within the prescribed limits of 80-120% as compared to formulation B. Thus both the controlled release formulations were bioequivalent. In comparison to conventional formulation, both controlled release formulations gave lower Cmax, lower AUCs, higher Tmax values, less fluctuation in CBZ plasma concentrations, reduction in ratio of Cmax/AUC values, thus demonstrating controlled release characteristics of the formulation., Conclusions: Based on the above mentioned parameters both controlled release formulations are bioequivalent and demonstrate controlled release characteristics.

Objective: To assess the bioavailability of carbamazepine from two brands of carbamazepine--Tegretol 200 and Zen-200., Methods: A two-way randomised cross-over bioavailability of carbamazepine was carried out in twelve healthy male volunteers. Coded plasma samples were analysed for levels of carbamazepine by high performance liquid chromatography (HPLC) method. Tegretol 200 and Zen-200 were tested for in-vitro dissolution profiles., Results: The mean Cmax, Tmax and t1/2a for Tegretol 200 were: 2.17 +/- 0.42 mcg/mL, 11.67 +/- 6.37 h and 2.72 +/- 1.87 h; for Zen-200 were 3.10 +/- 0.05 mcg/mL, 3.50 +/- 2.11 h and 0.76 +/- 0.76 h respectively. These values were statistically significant. However AUC (0-96 h) value of 150.16 +/- 27.13 mcg/ml.h after Zen-200 was not statistically significant as compared to 128.68 +/- 20.22 mcg/ml.h after Tegretol 200. The in-vitro dissolution profiles of the two formulations were dissimilar. The fluctuations in CBZ levels after Tegretol 200 was significantly less as compared to Zen-200. The absorption profile as judged by parameter 'A' was 50.44 +/- 10.95 for Tegretol 200 and 42.49 +/- 18.89 for Zen-200., Conclusion: Based on parameter 'A' and other pharmacokinetic parameters, the marketed generic carbamazepine product, Zen-200 is not bioequivalent to Tegretol 200.