A signal-seeking phase 2 study of Trastuzumab emtansine in tumours harbouring HER2 amplification or mutation.

This single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS). The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2). After 17 months median follow-up, ORs occurred in 19% of group 1 (1 salivary gland carcinoma (SGC), 2 lung cancers) and 25% of group 2 (3 SGCs, 1 uterine carcinoma). Fourteen of 29 TTP-evaluable patients achieved a TTP ratio ≥1.3, including 10 without an OR. Median PFS and OS were 4.5 (95% CI 2.1-7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers.

Temperature-dependent predation predicts a more reptilian future.

Diversity increases toward the tropics, but the strength of this pattern diverges with thermoregulatory strategy. Synthesizing over 30,000 species distributions, we quantified patterns of richness in terrestrial vertebrates, and present evidence for a latitudinal gradient of community composition. We observe a two orders of magnitude shift in comparative diversity with temperature, from endothermic mammal and avian dominance near the poles, toward ectothermic reptile and amphibian majority in the tropics. Next, we provide mechanistic support for a corresponding latitudinal gradient of predatory interactions. Using automated video tracking in >4500 trials, we show that differences in thermal sensitivity of locomotion in endothermic predators and ectothermic prey favors endotherms in colder environments and yields theoretically predicted foraging outcomes across thermal conditions, including the number of strikes, the distance traveled, and the time to capture prey. We also present evidence that endotherms use thermal cues to anticipate prey behavior, modulating the impact of temperature. Finally, we integrate theory and data to forecast future patterns of diversity, revealing that as the world get warmer, it will become increasingly reptilian. Overall, our results point toward a broad reorganization of vertebrate diversity with latitude, elevation, and temperature: from endotherm dominance in cold systems toward ectotherm dominance in warm.

Genomic insights into the population history and adaptive traits of Latin American Criollo cattle.

Criollo cattle, the descendants of animals brought by Iberian colonists to the Americas, have been the subject of natural and human-mediated selection in novel tropical agroecological zones for centuries. Consequently, these breeds have evolved distinct characteristics such as resistance to diseases and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.

A pan-sarcoma landscape of telomeric content shows that alterations in RAD51B and GID4 are associated with higher telomeric content.

Tumor cells need to activate a telomere maintenance mechanism, enabling limitless replication. The bulk of evidence supports that sarcomas predominantly use alternative lengthening of telomeres (ALT) mechanism, commonly associated with alterations in ATRX and DAXX. In our dataset, only 12.3% of sarcomas harbored alterations in these genes. Thus, we checked for the presence of other genomic determinants of high telomeric content in sarcomas. Our dataset consisted of 13555 sarcoma samples, sequenced as a part of routine clinical care on the FoundationOne®Heme platform. We observed a median telomeric content of 622.3 telomeric reads per GC-matched million reads (TRPM) across all samples. In agreement with previous studies, telomeric content was significantly higher in ATRX altered and POT1 altered sarcomas. We further observed that sarcomas with alterations in RAD51B or GID4 were enriched in samples with high telomeric content, specifically within uterus leiomyosarcoma for RAD51B and soft tissue sarcoma (not otherwise specified, nos) for GID4, Furthermore, RAD51B and POT1 alterations were mutually exclusive with ATRX and DAXX alterations, suggestive of functional redundancy. Our results propose a role played by RAD51B and GID4 in telomere elongation in sarcomas and open research opportunities for agents aimed at targeting this critical pathway in tumorigenesis.

Plantar Fasciitis or Flexor Digitorum Brevis Myositis.

BACKGROUND: As common as plantar fasciitis is, there's a lack of evidence regarding the true pathophysiologic process causing plantar fasciitis and plantar heel pain in general. This may partially explain the high variability and outcomes with current treatment of recalcitrant plantar fasciitis. Although Lemont reported myxoid degeneration of plantar fascia with histologic analysis of patients with fasciitis, muscle biopsy results were not reported. So far it appears we have not focused on the muscular component that may be present with plantar heel pain in general and in patients we diagnose with plantar fasciitis in particular. METHODS: In this article we performed a retrospective analysis of biopsy results from five patients with the diagnosis of recalcitrant plantar fasciitis to determine whether this diagnosis was correct or whether other component pathologies contribute to the chronicity of symptoms or to the failure of treatment. RESULTS: Three of the five pathology reports included specific mention of inflammation, degeneration and atrophy of the intrinsic musculature consistent with myositis. Two of these showed lymphocytic infiltration in the muscle consistent with inflammation, with no signs of inflammation in the fascia. One showed inflammation of the fascia without signs of inflammation of the muscle. CONCLUSIONS: This small study introduces the idea that intrinsic myositis may contribute to, or be responsible for some cases of plantar heel pain and plantar fasciitis. This may be important in changing the way we deal with plantar heel pain in the future.

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations.

PURPOSE: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. PATIENTS AND METHODS: In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on archival tumour tissue and serial bloods. RESULTS: The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival. CONCLUSIONS: O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers.

Recall patterns and risk of primary liver cancer for subcentimeter ultrasound liver observations: a multicenter study.

BACKGROUND: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC). AIMS: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound. METHODS: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively. RESULTS: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein >10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08). CONCLUSIONS: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels.

Transmetatarsal Amputations: Outcomes of Primary Healing versus Secondary Healing.

BACKGROUND: Transmetatarsal amputations are limb salvage surgical procedures that preserve limb length and functional ankle joints. Indications for transmetatarsal amputations include forefoot trauma, infection, and ischemia. Prior research demonstrates patients who undergo transmetatarsal amputations have a lower 2-year mortality rate compared to those who undergo more proximal amputations. The aim of this study was to determine whether primary closure of a transmetatarsal amputation is a superior treatment compared to secondary healing of a transmetatarsal amputation for forefoot abnormality of infection, gangrene, or chronic ulceration. METHODS: A retrospective chart review was performed on patients aged 18 years or older requiring a transmetatarsal amputation because of forefoot abnormality between September of 2011 and December of 2019. Foot and ankle surgeons performed transmetatarsal amputations. Outcome variables measured included healing time of transmetatarsal amputation site, recurrent infection, recurrent gangrene, and the need for revision surgery or higher level amputations. RESULTS: Of the original 112 patients, 76 met the inclusion criteria; 47 of these had primary closure of transmetatarsal amputation and 29 of these had an open transmetatarsal amputation performed. Primarily closed transmetatarsal amputations resulted in a significantly greater overall healing rate of 78.8% (37 of 47) compared to open transmetatarsal amputations, with a healing rate of 37.9% (11 of 29) (P < .01). Closed transmetatarsal amputations were statistically significantly less likely than open transmetatarsal amputations to have recurrent gangrene, require revision pedal operations, or progress to higher level amputations. CONCLUSIONS: Our research demonstrated that primary closure of transmetatarsal amputations is a superior treatment compared with secondary healing of transmetatarsal amputations in specific cases of infection, dry gangrene, or chronically nonhealing ulcerations.

Making computed tomography safer for patients with Crohn's disease.

Background and aims: Computed tomography (CT), often more accessible than magnetic resonance imaging (MRI), remains widely used though radiation exposure is an obvious disadvantage. We previously showed that modern CT technology can achieve over 70% reduction in radiation-dose without loss of accuracy. Here, we compare low- versus conventional-dose CT in patients with known Crohn's disease to assess clinical confidence and accuracy of the low-dose procedure in the semi-acute setting.Methods: A comparative study of low-dose CT with full iterative reconstruction (IR) versus conventional-dose CT was conducted in 50 consecutive outpatients with Crohn's disease. Clinicians were provided with the low-dose images and reports, whereas conventional-dose images were reviewed after 4 weeks.Results: The clinical question was adequately addressed with low-dose IR imaging in all cases. Complications of Crohn's were detected in 37/50 (74%) with no disagreement between low- and conventional-dose imaging. The effective radiation dose reduction was 76.5% (low-dose mean 2.15 mSv versus conventional-dose CT 6.99 mSv).Conclusion: Low-dose IR CT is safe and accurate for evaluating distribution and complications of known Crohn's disease in the outpatient setting. We propose that low-dose radiation imaging should be adopted as standard-of-care for the evaluation of Crohn's disease and an acceptable alternative to MR particularly in the acute setting. ClinicalTrials.gov: NCT03140306.

Liver transplantation for alcohol-related liver disease in the UK: revised UK Liver Advisory Group recommendations for referral.

Liver disease, of which liver cirrhosis is the most advanced stage, constitutes the fourth most common cause of life-years lost in men and women younger than 75 years in England, where mortality rates from liver disease have increased by 25% in the past decade. Alcohol consumption is the most common modifiable risk factor for disease progression in these individuals, but within the UK, there is substantial variation in the distribution, prevalence, and outcome of alcohol-related liver disease, and no equity of access to tertiary transplantation services. These revised recommendations were agreed by an expert panel convened by the UK Liver Advisory Group, with the purpose of providing consensus on referral for transplant assessment in patients with alcohol-related disease, and clarifying the terminology and definitions of alcohol use in liver injury. By standardising clinical management in these patients, it is hoped that there will be an improvement in the quality of care and better access to liver transplant assessment for patients with alcohol-related liver disease in the UK.

Criteria-based curation of a therapy-focused compendium to support treatment recommendations in precision oncology.

While several resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. To this end, we have structured a compendium of approved and experimental therapies with associated biomarkers following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was categorised using a tiering system reflective of key therapeutic considerations: approved and reimbursed therapies with respect to a jurisdiction (Tier 1), evidence of efficacy or approval in another jurisdiction (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of efficacy (Tier R1) or antitumor activity (Tier R2). Based on this framework, we curated a digital resource focused on drugs relevant in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 biomarkers, and 106 cancer types. In the 345 therapies catalogued, 84 (24%) and 65 (19%) were designated Tiers 1 and 2, respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A companion algorithm was also developed to support rational, context-appropriate treatment selection informed by molecular biomarkers. This framework can be readily adapted to build similar resources in other jurisdictions to support therapeutic decision-making.

Management of Midfoot Cavus.

There is a deficiency in publications on the topic of midfoot cavus. The limited research available does not have a standard definition for the diagnosis of this deformity and lacks a reliable algorithm for its surgical management. The authors performed an extensive review of the literature that found a majority of patients are satisfied with the Cole osteotomy and the dorsiflexory first metatarsal osteotomy for treatment of this condition. High patient satisfaction has been observed with lateralizing calcaneal osteotomies in the setting of midfoot cavus with a secondary rigid rearfoot deformity. Further research on this topic is encouraged.

The allometry of locomotion.

Organismal locomotion mediates ecological interactions and shapes community dynamics. Locomotion is constrained by intrinsic and environmental factors and integrating these factors should clarify how locomotion affects ecology across scales. We extended general theory based on metabolic scaling and biomechanics to predict the scaling of five locomotor performance traits: routine speed, maximum speed, maximum acceleration, minimum powered turn radius, and angular speed. To test these predictions, we used phylogenetically informed analyses of a new database with 884 species and found support for our quantitative predictions. Larger organisms were faster but less maneuverable than smaller organisms. Routine and maximum speeds scaled with body mass to 0.20 and 0.17 powers, respectively, and plateaued at higher body masses, especially for maximum speed. Acceleration was unaffected by body mass. Minimum turn radius scaled to a 0.19 power, and the 95% CI included our theoretical prediction, as we predicted. Maximum angular speed scaled higher than predicted but in the same direction. We observed universal scaling among locomotor modes for routine and maximum speeds but the intercepts varied; flying organisms were faster than those that swam or ran. Acceleration was independent of size in flying and aquatic taxa but decreased with body mass in land animals, possibly due to the risk of injury large, terrestrial organisms face at high speeds and accelerations. Terrestrial mammals inhabiting structurally simple habitats tended to be faster than those in complex habitats. Despite effects of body size, locomotor mode, and habitat complexity, universal scaling of locomotory performance reveals the general ways organisms move across Earth's complex environments.

Macronutrients, microbiome and precision nutrition.

PURPOSE OF REVIEW: Precision nutrition and personalized diets are gaining popularity in nutritional science and medicine. To fully appreciate their potential benefits, a deep understanding of both macronutrients and nutrient-microbe interactions is required. RECENT FINDINGS: Microbiome science has reaffirmed the importance of dietary fiber in microbial and host health. Additional macronutrients, digestible carbohydrate, protein and fat also influence the composition and diversity of the microbiome and, therefore, microbial response to dietary intervention. Attention to macronutrient source, dose, microbial effect and metabolite production allows the development of more established links between diet and health. SUMMARY: The degree to which human diets need to be personalized for optimal health is still uncertain but a one-size-fits-all diet seems unlikely. However, for personal or precision nutrition to fulfill its promise, greater attention to the details of nutrient-microbe interactions will be required.

Mortality after Transplantation for Hepatocellular Carcinoma: A Study from the European Liver Transplant Registry.

Background and Aims: Prognosis after liver transplantation differs between hepatocellular carcinoma (HCC) arising in cirrhotic and non-cirrhotic livers and aetiology is poorly understood. The aim was to investigate differences in mortality after liver transplantation between these patients. Methods: We included patients from the European Liver Transplant Registry transplanted due to HCC from 1990 to November 2016 and compared cirrhotic and non-cirrhotic patients using propensity score (PS) calibration of Cox regression estimates to adjust for unmeasured confounding. Results: We included 22,787 patients, of whom 96.5% had cirrhosis. In the unadjusted analysis, non-cirrhotic patients had an increased risk of overall mortality with a hazard ratio (HR) of 1.37 (95% confidence interval [CI] 1.23-1.52). However, the HR approached unity with increasing adjustment and was 1.11 (95% CI 0.99-1.25) when adjusted for unmeasured confounding. Unadjusted, non-cirrhotic patients had an increased risk of HCC-specific mortality (HR 2.62, 95% CI 2.21-3.12). After adjustment for unmeasured confounding, the risk remained significantly increased (HR 1.62, 95% CI 1.31-2.00). Conclusions: Using PS calibration, we showed that HCC in non-cirrhotic liver has similar overall mortality, but higher HCC-specific mortality. This may be a result of a more aggressive cancer form in the non-cirrhotic liver as higher mortality could not be explained by tumour characteristics or other prognostic variables.