Fusion Challenges in Solid Tumors: Shaping the Landscape of Cancer Care in Precision Medicine.

Targeting actionable fusions has emerged as a promising approach to cancer treatment. Next-generation sequencing (NGS)-based techniques have unveiled the landscape of actionable fusions in cancer. However, these approaches remain insufficient to provide optimal treatment options for patients with cancer. This article provides a comprehensive overview of the actionability and clinical development of targeted agents aimed at driver fusions. It also highlights the challenges associated with fusion testing, including the evaluation of patients with cancer who could potentially benefit from testing and devising an effective strategy. The implementation of DNA NGS for all tumor types, combined with RNA sequencing, has the potential to maximize detection while considering cost effectiveness. Herein, we also present a fusion testing strategy aimed at improving outcomes in patients with cancer.

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer.

The cancer stem cell (SC) theory proposes that a population of SCs serves as the driving force behind fundamental tumor processes, including metastasis, recurrence, and resistance to therapy. The standard of care for patients with stage III and high-risk stage II colorectal cancer (CRC) includes surgery and adjuvant chemotherapy. Fluoropyrimidines and their combination with oxaliplatin increased the cure rates, being able to eradicate the occult metastatic SC in a fraction of patients. The treatment for unresectable metastatic CRC is based on chemotherapy, antibodies to VEGF and EGFR, and tyrosine-kinase inhibitors. Immunotherapy is used in MSI-H tumors. Currently used drugs target dividing cells and, while often effective at debulking tumor mass, these agents have largely failed to cure metastatic disease. SCs are generated either due to genetic and epigenetic alterations in stem/progenitor cells or to the dedifferentiation of somatic cells where diverse signaling pathways such as Wnt/ß-catenin, Hedgehog, Notch, TGF-ß/SMAD, PI3K/Akt/mTOR, NF-κB, JAK/STAT, DNA damage response, and Hippo-YAP play a key role. Anti-neoplastic treatments could be improved by elimination of SCs, becoming an attractive target for the design of novel agents. Here, we present a review of clinical trials assessing the efficacy of targeted treatment focusing on these pathways in CRC.

Poly(ADP-Ribose) Polymerase Inhibitor Development: Promising Strategies to Move Beyond Approved Indications.

Biomarker-based patient selection and rational combinations show promise in expanding the use of PARP inhibitors.

Case report: Fatal overwhelming post-splenectomy infection in a patient with metastatic angiosarcoma treated with immunotherapy.

A patient in his 40s with splenic angiosarcoma metastatic to the liver underwent splenectomy, chemotherapy, and partial hepatectomy before being treated on a clinical trial with CTLA4 and PD1 inhibitors. He had received pneumococcal and meningococcal vaccines post-splenectomy. On week 10, he developed grade 3 immune-related colitis, successfully treated with the anti-tumor necrosis factor-alpha inhibitor infliximab and steroids. After 4 cycles of treatment, scans showed partial response. He resumed anti-PD1 therapy, and 6 hours after the second dose of anti-PD1 he presented to the emergency room with hematemesis, hematochezia, hypotension, fever, and oxygen desaturation. Laboratory tests demonstrated acute renal failure and septicemia (Streptococcus pneumoniae). He died 12 hours after the anti-PD1 infusion from overwhelming post-splenectomy infection (OPSI). Autopsy demonstrated non-viable liver tumors among other findings. In conclusion, patients undergoing immunotherapy and with prior history of asplenia should be monitored closely for OPSI as they may be at increased risk.

Cabozantinib Response in a Patient With NSCLC Harboring Both MET Exon 14 Skipping Mutation and Secondary RET Fusion: A Case Report.

MET exon 14 skipping mutation has emerged as a new oncogenic driver in NSCLC with available targeted therapies, including Food and Drug Administration-approved inhibitors capmatinib and tepotinib. Potential resistance mechanisms are beginning to be described and include several on-target and off-target mutations. Here, we report an emergent secondary RET fusion in a patient with a primary MET exon 14 skipping mutation that progressed on capmatinib after the initial response. Subsequently, this patient received both a RET inhibitor (selpercatinib) followed by another MET-targeted treatment (tepotinib) without clinical benefit. Thereafter, cabozantinib, a multikinase inhibitor with activity against RET and MET was started with a rapid clinical and radiologic benefit.

Antiangiogenics in Malignant Granular Cell Tumors: Review of the Literature.

Granular cell tumors (GCT) represent 0.5% of all soft tissue sarcomas (STS), and when metastatic, they exhibit aggressive behavior and determine limited survival. Metastatic GCTs are relatively chemo-resistant; however, there is growing evidence of the benefit of using pazopanib and other targeted therapies in this histology. This is a review of the role of pazopanib and other targeted therapies in the treatment of GCTs, along with some insights on pathology and molecular biology described in GCTs. From 256 articles found in our search, 10 case-report articles met the inclusion criteria. Pazopanib was the most employed systemic therapy. The median reported time on therapy with pazopanib was seven months. Eight out of ten patients (80%) experienced disease control with pazopanib, while four out of ten (40%) patients achieved an objective RECIST response. Molecular studies suggested that antitumoral effects of pazopanib in GCT might be due to a loss-of-function of ATP6AP1/2 genes which consequently enhance signaling through several molecular pathways, such as SFKs, STAT5a/b, and PDGFR-ß. Other reported targeted therapies for malignant GCTs included pazopanib in combination with crizotinib, which showed disease control for four months in one patient, and a PI3K inhibitor which achieved disease control for nine months in another patient. Dasatinib and megestrol were ineffective in two other different patients. Pazopanib has been demonstrated to be active in advanced GCTs and may be considered as a preferable treatment option.

Semantic Deep Learning: Prior Knowledge and a Type of Four-Term Embedding Analogy to Acquire Treatments for Well-Known Diseases.

BACKGROUND: How to treat a disease remains to be the most common type of clinical question. Obtaining evidence-based answers from biomedical literature is difficult. Analogical reasoning with embeddings from deep learning (embedding analogies) may extract such biomedical facts, although the state-of-the-art focuses on pair-based proportional (pairwise) analogies such as man:woman::king:queen ("queen = -man +king +woman"). OBJECTIVE: This study aimed to systematically extract disease treatment statements with a Semantic Deep Learning (SemDeep) approach underpinned by prior knowledge and another type of 4-term analogy (other than pairwise). METHODS: As preliminaries, we investigated Continuous Bag-of-Words (CBOW) embedding analogies in a common-English corpus with five lines of text and observed a type of 4-term analogy (not pairwise) applying the 3CosAdd formula and relating the semantic fields person and death: "dagger = -Romeo +die +died" (search query: -Romeo +die +died). Our SemDeep approach worked with pre-existing items of knowledge (what is known) to make inferences sanctioned by a 4-term analogy (search query -x +z1 +z2) from CBOW and Skip-gram embeddings created with a PubMed systematic reviews subset (PMSB dataset). Stage1: Knowledge acquisition. Obtaining a set of terms, candidate y, from embeddings using vector arithmetic. Some n-gram pairs from the cosine and validated with evidence (prior knowledge) are the input for the 3cosAdd, seeking a type of 4-term analogy relating the semantic fields disease and treatment. Stage 2: Knowledge organization. Identification of candidates sanctioned by the analogy belonging to the semantic field treatment and mapping these candidates to unified medical language system Metathesaurus concepts with MetaMap. A concept pair is a brief disease treatment statement (biomedical fact). Stage 3: Knowledge validation. An evidence-based evaluation followed by human validation of biomedical facts potentially useful for clinicians. RESULTS: We obtained 5352 n-gram pairs from 446 search queries by applying the 3CosAdd. The microaveraging performance of MetaMap for candidate y belonging to the semantic field treatment was F-measure=80.00% (precision=77.00%, recall=83.25%). We developed an empirical heuristic with some predictive power for clinical winners, that is, search queries bringing candidate y with evidence of a therapeutic intent for target disease x. The search queries -asthma +inhaled_corticosteroids +inhaled_corticosteroid and -epilepsy +valproate +antiepileptic_drug were clinical winners, finding eight evidence-based beneficial treatments. CONCLUSIONS: Extracting treatments with therapeutic intent by analogical reasoning from embeddings (423K n-grams from the PMSB dataset) is an ambitious goal. Our SemDeep approach is knowledge-based, underpinned by embedding analogies that exploit prior knowledge. Biomedical facts from embedding analogies (4-term type, not pairwise) are potentially useful for clinicians. The heuristic offers a practical way to discover beneficial treatments for well-known diseases. Learning from deep learning models does not require a massive amount of data. Embedding analogies are not limited to pairwise analogies; hence, analogical reasoning with embeddings is underexploited.

Rhegmatogenous Retinal Detachment and Solar Radiation in Northwestern Spain.

OBJECTIVE: The aim of this study was to investigate the association between rhegmatogenous retinal detachment (RRD) and solar radiation in northwestern Spain. METHODS: All RRD cases in Pontevedra from 2008 and 2014 were retrospectively analyzed. Climatological data from 4 weather stations in the area were collected. The association between RRD incidence and solar radiation was investigated. RESULTS: A total of 256 RRD cases were identified. There was a seasonal variation in the incidence of RRD with a maximum number of incident cases observed in June and July and a minimum number of cases observed in January and December. An association was found between RRD incidence and solar radiation both monthly (p = 0.004) and bimonthly (p = 0.057). The right eye was more frequently affected than the left eye (p = 0.035). RD cases other than rhegmatogenous showed neither seasonality nor association with radiation. CONCLUSIONS: Solar radiation may play a role in RRD genesis in our area. Laterality could be related to the amount of radiation reaching each eye.

Practical Approaches to Integrate the Topic of Drug Shortages Within Doctor of Pharmacy Curricula.

Drug shortages have a significant impact on the health care system. As concerns grow over this topic, the health care community continues to explore strategies for reducing its impact on patient care. Exposure during the pharmacy curriculum will prepare students to engage and be at the forefront of this issue. Pharmacy educators should evaluate if opportunities exist to incorporate discussions or activities related to drug shortages. Integration of this content can occur throughout the curriculum as introductory or reinforcement topics in courses related to social/administrative/behavioral sciences, informatics, drug information, case studies, pharmacotherapy, law, and ethics. Applying this topic can be done during pharmacy practice experiences and interprofessional activities. Addressing this topic intentionally and developing strategies to promote optimal care in patients amid drug shortages begins with educating pharmacy students about this issue and developing their problem-solving skills.

Palliative care in Africa: a scoping review from 2005-16.

Since the last comprehensive review on the development of national palliative care in Africa was undertaken 12 years ago, in 2005, we did a scoping review of peer-reviewed, published articles on palliative care development between 2005-16 for each African country. The scoping review was conducted by assessing the medical literature and including local expert recommendations of suggested articles. We did a basic quality assessment of the articles using the journals' impact factor, journal quartile, and the number of citations as suitable metrics for quality consideration. Articles published in English, Spanish, Portuguese, and French that mentioned at least one dimension of WHO's palliative care public health strategy (implementation of services, education, policies, or medicine availability) and vitality (activity by professionals or advocates) were included. Of the 518 articles found, 49 met the inclusion criteria. Information on 26 (48%) of 54 African countries was found. Most services were concentrated in Kenya, South Africa, and Uganda, and 14 (26%) countries showed an increase in services during this timeframe. Stand-alone palliative care policies exist in Malawi, Mozambique, Rwanda, Swaziland, Tanzania, and Zimbabwe. Postgraduate diplomas in palliative care are available in Kenya, South Africa, Uganda, and Tanzania. Restricted access to opioids, prescriber restriction laws, and a low prevalence of morphine use remain common barriers to adequate palliative care provision. Although information on palliative care is unevenly distributed, the available information showed an increased development of palliative care services in a subset of African countries. Despite this growth, however, there is still minimal to no identified palliative care development in most African countries.

Improvement of the surface hydrophilic properties of naproxen particles with addition of hydroxypropylmethyl cellulose and sodium dodecyl sulphate: In vitro and in vivo studies.

In this study, a new surface-modified naproxen was developed to enhance brain concentration in acute migraine treatment. Fast-dissolving naproxen granules were made by mixing hydroxypropylmethylcellulose (HPMC) sodium dodecyl sulphate (SDS) and sodium croscarmellose with micronized naproxen particles. The aim of this study was to evaluate the effect of adding proportions of SDS to the HPMC film caused changes in the polymer chains of the HPMC, producing a new hydrophilic HPMC-SDS structure. These formulations with different HPMC/SDS ratios were characterised using electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). SDS 10% (w/w) produced a highly hydrophilic HPMC-SDS structure on the surface of the naproxen microparticles. The fast dissolution granules (SF-10%) showed a significant improvement in the dissolution rate of naproxen. Pharmacokinetic studies were conducted with mice, showing an improvement of Cmax (1.38 and 1.41-fold) and AUC0-2h (30% and 10% higher) for plasma and brain samples compared to the reference naproxen suspension. The faster Tmax ratio for SF-10% may be related to increased hydration in the gastrointestinal environment, enabling the drug to permeate the gastrointestinal hydration layer more easily due to the presence of the hydrophilic HPMC-SDS structure in the formulation.

Publications on Palliative Care Development Can Be Used as an Indicator of Palliative Care Development in Africa.

BACKGROUND: Palliative care (PC) research in Africa has been proposed as a fifth dimension of the World Health Organization PC Public Health Strategy. We conducted a scoping review of published articles (2005-2016) on palliative care development (PCD) in African countries. Forty-seven articles were found across 26 countries. OBJECTIVE: To study whether the number of published articles on PCD in countries in Africa can be used as an indicator of PCD. DESIGN: This is a secondary analysis of a completed scoping review. MEASUREMENTS: Spearman correlations were applied to the number of published articles ("published articles") and the number of published articles with a coauthor from a high-income country (HIC) ("HIC published articles") with level of PCD using Lynch et al's updated world map (PC World Map) as a proxy. A subanalysis was undertaken for Anglophone versus non-Anglophone countries. RESULTS: There were positive Spearman correlations (r) between the PC World Map's levels and published articles (r = 0.73; p < 0.001), and with HIC published articles (r = 0.68; p < 0.001). For Anglophone countries, the r was statistically significant (p < 0.001) at 0.69 and 0.70, versus 0.58 and 0.45 for non-Anglophone countries for published articles and HIC published articles, respectively. Kruskal-Wallis test showed a statistically significant difference between Anglophone and non-Anglophone countries for both published articles and HIC published articles (p < 0.01). CONCLUSION: Published articles and HIC published articles on PCD in Africa had strong positive r's with the PC World Map. These measures may be considered as two indicators of PCD for countries in Africa, particularly for Anglophone countries.

Spiradenocarcinoma of the eyelid: a case report.

A 84-year-old-woman presented a painless eyelid mass in her right eyelid. A biopsy was made and the anatomopathologic study showed a spiradenoma with malignant changes. The patient rejected any kind of treatment in spite of the prognosis of the lesion. Radiological and pathological features of this infrequent eyelid tumour are discussed.

Primary orbital liposarcoma.

A 45-year-old-man presented a slightly painful proptosis and diplopia for 7 months. He had been kept elsewhere on oral steroids without evidence of any clinical response over an 8-week period with suspected diagnosis of an inflammatory pseudotumor upon referral to our clinic. An intraoperative biopsy positive for primary liposarcoma was followed by debulking surgery. Exenteration and radiotherapy were performed after pathologic confirmation of this diagnosis. No recurrence has been observed after 2 years of follow-up. We underline the importance of an accurate an early diagnosis in the management of this tumor, delayed in this case because of therapy with steroids.