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Background: Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients, and a phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors., Methods: Vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly) was investigated in a phase 1 trial of advanced melanoma, with a modified Ji dose-escalation design., Results: Twenty-five patients were enrolled. After two dose-limiting toxicities (DLTs) (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses. Three DLTs (rash) were observed in 12 patients in the XL888 60-mg cohort, and this was determined as the maximum tolerated dose. Objective responses were observed in 19 patients (76%), and the median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. Single-cell RNA sequencing was performed on baseline and on-treatment biopsies; treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells., Conclusions: Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors., (© 2023 American Cancer Society.)

Introduction: Global HIV infections due to HIV-1 recombinants are increasing and impede prevention and treatment efforts. Key populations suffer most new HIV infections, but their role in the spread of HIV-1 recombinants is unknown. We conducted a global analysis of the associations between key populations and HIV-1 recombinants., Methods: We searched PubMed, EMBASE, CINAHL, and Global Health for HIV-1 subtyping studies published from 1/1/1990 to 31/12/2015. Unpublished data was collected through a global survey. We included studies with HIV-1 subtyping data of key populations collected during 1990-2015. Key populations assessed were heterosexual people (HET), men who have sex with men (MSM), people who inject drugs (PWID), vertical transmissions (VERT), commercial sex workers (CSW), and transfusion-associated infections (BLOOD). Logistic regression was used to determine associations of key populations with HIV-1 recombinants. Subgroup analyses were performed for circulating recombinant forms (CRFs), unique recombinant forms (URFs), regions, and time periods., Results: Eight hundred and eighty five datasets including 77,284 participants from 83 countries were included. Globally, PWID were associated with the greatest odds of recombinants and CRFs (OR 2.6 [95% CI 2.46-2.74] and 2.99 [2.83-3.16]), compared to HET. CSW were associated with increased odds of recombinants and URFs (1.59 [1.44-1.75] and 3.61 [3.15-4.13]). VERT and BLOOD were associated with decreased odds of recombinants (0.58 [0.54-0.63] and 0.43 [0.33-0.56]). MSM were associated with increased odds of recombinants in 2010-2015 (1.43 [1.35-1.51]). Subgroup analyses supported our main findings., Discussion: As PWID, CSW, and MSM are associated with HIV-1 recombinants, increased preventative measures and HIV-1 molecular surveillance are crucial within these key populations., Systematic Review Registration: PROSPERO [CRD42017067164]., 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 © 2023 Nchinda, Elangovan, Yun, Dickson-Tetteh, Kirtley, Hemelaar and WHO-UNAIDS Network for HIV Isolation and Characterisation.)

Background: While potentially timesaving, there is no program to automatically transform diagnosis codes of the ICD-10 German modification (ICD-10-GM) into the injury severity score (ISS)., Objective: To develop a mapping method from ICD-10-GM into ICD-10 clinical modification (ICD-10-CM) to calculate the abbreviated injury scale (AIS) and ISS of each patient using the ICDPIC-R and to compare the manually and automatically calculated scores., Methods: Between January 2019 and June 2021, the most severe AIS of each body region and the ISS were manually calculated using medical documentation and radiology reports of all major trauma patients of a German level I trauma centre. The ICD-10-GM codes of these patients were exported from the electronic medical data system SAP, and a Java program was written to transform these into ICD-10-CM codes. Afterwards, the ICDPIC-R was used to automatically generate the most severe AIS of each body region and the ISS. The automatically and manually determined ISS and AIS scores were then tested for equivalence., Results: Statistical analysis revealed that the manually and automatically calculated ISS were significantly equivalent over the entire patient cohort. Further sub-group analysis, however, showed that equivalence could only be demonstrated for patients with an ISS between 16 and 24. Likewise, the highest AIS scores of each body region were not equal in the manually and automatically calculated group., Conclusion: Though achieving mapping results highly comparable to previous mapping methods of ICD-10-CM diagnosis codes, it is not unrestrictedly possible to automatically calculate the AIS and ISS using ICD-10-GM codes., Competing Interests: The authors have declared that no competing interests exist.

Background: Nursing is an embodiment of knowledge, clinical work, and interpersonal communication. Effective nursing care has a distinct influence on the overall satisfaction and experience of the patient. Communication is said to be indispensable in the delivery of quality healthcare. Effective communication between nurses and patients has proven to yield better results with pain control and improved psychological status of patients., Objectives: The aim of the study is to explore nurses' perceptions on the role of communication in the management of burns pain., Methods: A qualitative design with purposive sampling was carried out to recruit 11 registered nurses from a Reconstructive Plastic Surgery and Burns Center in Ghana. To identify the participants' perception on the role of nurse-patient communication in the management of burns pain, a face to face semi-structured interviews were conducted using an interview guide to collect data., Results: Thematic analysis was done with various themes emerging. Helping patients manage pain, early detection of patient's distress, improved patient participation in their care were some of the positive effects of nurse-patient communication whiles reduced level of cooperation during caregiving, and endurance of pain by the patient were the results of poor nurse-patient communication. Language and time factor were the barriers that were identified to hinder effective communication between nurses and patients., Conclusions: Due to the subjective nature of pain, the current study highlights the need for increased communication for an effective assessment and management of pain among patients with burns. It is, therefore, imperative that nurses be well trained in communication with an emphasis on patient-centered communication., (Copyright © 2020 Elsevier Ltd and ISBI. All rights reserved.)

Global HIV-1 genetic diversity forms a major obstacle to the development of an HIV vaccine. It may be necessary to employ subtype-specific HIV-1 vaccines in individual countries according to their HIV-1 subtype distribution. We estimated the global and regional need for subtype-specific HIV-1 vaccines. We took into account the proportions of different HIV-1 variants circulating in each country, the genetic composition of HIV-1 recombinants, and the different genome segments ( gag , pol , env ) that may be incorporated into vaccines. We modeled different scenarios according to whether countries would employ subtype-specific HIV-1 vaccines against (1) the most common subtype; (2) subtypes contributing more than 5% of HIV infections; or (3) all circulating subtypes. For therapeutic vaccines targeting the most common HIV-1 subtype in each country, 16.5 million doses of subtype C vaccine were estimated globally, followed by subtypes A (14.3 million) and B (4.2 million). A vaccine based on env required 2.6 million subtype E doses, and a vaccine based on pol required 4.8 million subtype G doses. For prophylactic vaccines targeting the most common HIV-1 subtype in each country, 1.9 billion doses of subtype A vaccine were estimated globally, followed by subtype C (1.1 billion) and subtype B (1.0 billion). A vaccine based on env required 1.2 billion subtype E doses, and a vaccine based on pol required 0.3 billion subtype G doses. If subtype-specific HIV-1 vaccines are also directed against less common subtypes in each country, vaccines targeting subtypes D, F, H, and K are also needed and would require up to five times more vaccine doses in total. We conclude that to provide global coverage, subtype-specific HIV-1 vaccines need to be directed against subtypes A, B, and C. Vaccines targeting env also need to include subtype E and those targeting pol need to include subtype G., 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 Elangovan, Jenks, Yun, Dickson-Tetteh, Kirtley, Hemelaar and WHO-UNAIDS Network for HIV Isolation and Characterisation.)

The global diversity of HIV forms a major challenge to the development of an HIV vaccine, as well as diagnostic, drug resistance, and viral load assays, which are essential to reaching the UNAIDS 90:90:90 targets. We sought to determine country level HIV-1 diversity globally between 1990 and 2015. We assembled a global HIV-1 molecular epidemiology database through a systematic literature search and a global survey. We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published from 1 January 1990 to 31 December 2015. We collected additional unpublished data through a global survey of experts. Prevalence studies with original HIV-1 subtyping data collected between 1990 and 2015 were included. This resulted in a database with 383,519 subtyped HIV-1 samples from 116 countries over four time periods (1990 to 1999, 2000 to 2004, 2005 to 2009, and 2010 to 2015). We analyzed country-specific numbers of distinct HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in each time period. We also analyzed country-specific proportions of infections due to HIV-1 recombinants, CRFs, and URFs and calculated the Shannon diversity index for each country. Finally, we analyzed global temporal trends in each of these measures of HIV-1 diversity. We found extremely wide variation in complexity of country level HIV diversity around the world. Central African countries such as Chad, Democratic Republic of the Congo, Angola, and Republic of the Congo have the most diverse HIV epidemics. The number of distinct HIV-1 subtypes and recombinants was greatest in Western Europe (Spain and France) and North America (United States) (up to 39 distinct HIV-1 variants in Spain). The proportion of HIV-1 infections due to recombinants was highest in Southeast Asia (>95% of infections in Viet Nam, Cambodia, and Thailand), China, and West and Central Africa, mainly due to high proportions of CRF01_AE and CRF02_AG. Other CRFs played major roles (>75% of HIV-1 infections) in Estonia (CRF06_cpx), Iran (CRF35_AD), and Algeria (CRF06_cpx). The highest proportions of URFs (>30%) were found in Myanmar, Republic of the Congo, and Argentina. Global temporal analysis showed consistent increases over time in country level numbers of distinct HIV-1 variants and proportions of CRFs and URFs, leading to increases in country level HIV-1 diversity. Our study provides epidemiological evidence that the HIV pandemic is diversifying at country level and highlights the increasing challenge to prevention and treatment efforts. HIV-1 molecular epidemiological surveillance needs to be continued and improved. IMPORTANCE This is the first study to analyze global country level HIV-1 diversity from 1990 to 2015. We found extremely wide variation in complexity of country level HIV diversity around the world. Central African countries have the most diverse HIV epidemics. The number of distinct HIV-1 subtypes and recombinants was greatest in Western Europe and North America. The proportion of HIV-1 infections due to recombinants was highest in South-East Asia, China, and West and Central Africa. The highest proportions of URFs were found in Myanmar, Republic of the Congo, and Argentina. Our study provides epidemiological evidence that the HIV pandemic is diversifying at country level and highlights the increasing challenge to HIV vaccine development and diagnostic, drug resistance, and viral load assays., (Copyright © 2020 American Society for Microbiology.)

Background: Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015., Methods: We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164., Findings: Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02&#95;AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01&#95;AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (<1% each), they were prominent in regional epidemics, including in east and southeast Asia, west and central Africa, Middle East and north Africa, and eastern Europe and central Asia. In addition, in 2010-15, central Africa (21·3% [243 041 of 1 143 531]), west Africa (15·5% [838 476 of 5 419 010]), east Africa (12·6% [591 140 of 4 704 986]), and Latin America (9·6% [153 069 of 1 586 605]) had high proportions of URFs., Interpretation: HIV-1 recombinants are increasingly prominent in global and regional HIV epidemics, which has important implications for the development of an HIV vaccine and the design of diagnostic, resistance, and viral load assays. Continued and improved surveillance of the global molecular epidemiology of HIV is crucial., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Global genetic diversity of HIV-1 is a major challenge to the development of HIV vaccines. We aimed to estimate the regional and global distribution of HIV-1 subtypes and recombinants during 1990-2015., Methods: We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published between Jan 1, 1990, and Dec 31, 2015. We collected additional unpublished HIV-1 subtyping data through a global survey. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. We grouped countries into 14 regions and analysed data for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV (PLHIV) in each country to generate regional and global estimates of HIV-1 diversity in each time period. The primary outcome was the number of samples designated as HIV-1 subtypes A, B, C, D, F, G, H, J, K, CRFs, and URFs. The systematic review is registered with PROSPERO, number CRD42017067164., Findings: This systematic review and global survey yielded 2203 datasets with 383 519 samples from 116 countries in 1990-2015. Globally, subtype C accounted for 46·6% (16 280 897/34 921 639 of PLHIV) of all HIV-1 infections in 2010-15. Subtype B was responsible for 12·1% (4 235 299/34 921 639) of infections, followed by subtype A (10·3%; 3 587 003/34 921 639), CRF02&#95;AG (7·7%; 2 705 110/34 921 639), CRF01&#95;AE (5·3%; 1 840 982/34 921 639), subtype G (4·6%; 1 591 276/34 921 639), and subtype D (2·7%; 926 255/34 921 639). Subtypes F, H, J, and K combined accounted for 0·9% (311 332/34 921 639) of infections. Other CRFs accounted for 3·7% (1 309 082/34 921 639), bringing the proportion of all CRFs to 16·7% (5 844 113/34 921 639). URFs constituted 6·1% (2 134 405/34 921 639), resulting in recombinants accounting for 22·8% (7 978 517/34 921 639) of all global HIV-1 infections. The distribution of HIV-1 subtypes and recombinants changed over time in countries, regions, and globally. At a global level during 2005-15, subtype B increased, subtypes A and D were stable, and subtypes C and G and CRF02&#95;AG decreased. CRF01&#95;AE, other CRFs, and URFs increased, leading to a consistent increase in the global proportion of recombinants over time., Interpretation: Global and regional HIV diversity is complex and evolving, and is a major challenge to HIV vaccine development. Surveillance of the global molecular epidemiology of HIV-1 remains crucial for the design, testing, and implementation of HIV vaccines., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients., Experimental Design: HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies., Results: Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS., Conclusions: Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study., (©2014 American Association for Cancer Research.)

Purpose: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer., Experimental Design: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed., Results: Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02)., Conclusions: We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role., (©2014 AACR.)

Purpose: Resistance to topoisomerase (topo) I inhibitors has been related to down-regulation of nuclear target enzyme, whereas sensitization to topo II inhibitors may result from induction of topo II by topo I inhibitors. Here, we evaluated a sequence-specific administration of a topo I inhibitor followed by a topo II inhibitor., Experimental Design: Twenty-five patients with advanced or metastatic malignancies were treated with increasing doses (0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mg/m(2)) of 9-nitrocamptothecin (9-NC) on days 1 to 3, followed by etoposide (100 or 150 mg/d) on days 4 and 5. At the maximally tolerated dose, 20 additional patients were enrolled. The median age was 60 years (range, 40-84 years). Endpoints included pharmacokinetic analyses of 9-NC and etoposide, and treatment-induced modulations of topo I and II expression in peripheral blood mononuclear cells., Results: Neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and fatigue were dose-limiting toxicities and occurred in six patients. Despite a median number of four prior regimens (range 1-12), 2 (4%) patients had an objective response and 13 (29%) patients had stable disease. In contrast to the expected modulation in topo I and IIalpha levels, we observed a decrease in topo IIalpha levels, whereas topo I levels were not significantly altered by 9-NC treatment., Conclusions: Sequence-specific administration of 9-NC and etoposide is tolerable and active. However, peripheral blood mononuclear cells may not be a predictive biological surrogate for drug-induced modulation of topo levels in tumor tissues and should be further explored in larger studies.

Unlabelled: Due to advances in the methods used to quantitate vinorelbine, this study was conducted to characterize fully the bioavailability of an oral dosage form of vinorelbine. Twenty-seven eligible patients with solid tumors were enrolled onto this study and were treated in a randomized crossover design to receive either 70 mg/m2 orally or 30 mg/m2 intravenously followed by the alternative treatment one week later. Vinorelbine was administered orally as a soft-gelatin capsule. Pharmacokinetic sampling was carried out for 7 days following each dose. Whole blood vinorelbine concentrations were measured using a sensitive LC/MS/MS method. The data from patients were excluded if they vomited within 3 h after the oral dose., Results: Three subjects were removed from study following the first dose due to safety reasons. Of the remaining 24 subjects, five experienced vomiting within 3 h of oral dosing. Total body clearance calculated from the intravenous dose was 43.65 L/h (+/-10.9) and the terminal half-life was estimated to be 49 h. Using complete data from the remaining 19 subjects, the mean absolute bioavailability of the oral dosage formulation of vinorelbine was calculated to be 33% (+/-18%). In conclusion we have characterized the pharmacokinetics of both orally administered and intravenous vinorelbine over 7 days after administration and have determined the mean oral bioavailability of this oral formulation to be 33%.