Citations

A previously healthy 67-year-old farmer presented to an outside hospital after a 2-week history of non-specific respiratory symptoms. A certain diagnosis was not initially apparent, and the patient was discharged home on a regimen for presumed chronic obstructive pulmonary disease exacerbation. He re-presented to the emergency department with shock and hypoxaemic respiratory failure requiring prompt intubation and fluid resuscitation. He was then transferred to our institution due to multiorgan failure. On arrival, the patient demonstrated refractory shock and worsening acute kidney injury, severe anaemia and thrombocytopaenia. The peripheral smear revealed absence of microangiopathic haemolytic anaemia. A closer review of the smear displayed red blood cell inclusion bodies consistent with babesiosis. The patient was started on clindamycin and loaded with intravenous quinidine, and subsequently transitioned to oral quinine. A red cell exchange transfusion was pursued with improvement of the parasite load. The patient was discharged home on clindamycin/quinine and scheduled for outpatient intermittent haemodialysis.

Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely “undruggable”. Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH). SIAH E3 ligase controls the signal output of oncogenic K-RAS hyperactivation that drives unchecked cell proliferation, uncontrolled tumor growth, and rapid cancer cell dissemination in human pancreatic cancer. Therefore, SIAH is an ideal therapeutic target as it is an extraordinarily conserved downstream signaling gatekeeper indispensable for proper RAS signaling. Guided by molecular insights and core principles obtained from developmental and evolutionary biology, we propose an anti-SIAH-centered anti-K-RAS strategy as a logical and alternative anticancer strategy to dampen uncontrolled K-RAS hyperactivation and halt tumor growth and metastasis in pancreatic cancer. The clinical utility of developing SIAH as both a tumor-specific and therapy-responsive biomarker, as well as a viable anti-K-RAS drug target, is logically simple and conceptually innovative. SIAH clearly constitutes a major tumor vulnerability and K-RAS signaling bottleneck in pancreatic ductal adenocarcinoma (PDAC). Given the high degree of evolutionary conservation in the K-RAS/SIAH signaling pathway, an anti-SIAH-based anti-PDAC therapy will synergize with covalent K-RAS inhibitors and direct K-RAS targeted initiatives to control and eradicate pancreatic cancer in the future.

AimsRhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harbouring a FUS–TFCP2 fusion and involving both soft tissue and bone locations has been reported very recently. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma.Material and resultsA previously well 72‐year‐old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA‐seq, RT–PCR and FISH confirmed the presence of the FUS–TFCP2 fusion.ConclusionsSpindle cell rhabdomyosarcomas carrying the FUS–TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/sclerosing rhabdomyosarcoma are discussed.

AbstractBackgroundTreatment options of Ewing sarcoma of the head and neck include surgery, radiotherapy (RT), and chemoradiotherapy. However, local control can be challenging.MethodsWe conducted a retrospective review of all patients with head and neck Ewing sarcoma treated from 1972 to 2015 at a single tertiary care hospital.ResultsSeventeen patients met criteria (median 21 years, range 5‐58 years; 5 women). Mean follow‐up was 10.4 years (range 2.2‐39 years). Tumors occurred commonly in the cervical spine (5/17), the skull (3/17), and the paranasal sinuses (3/17). A total of 14 of 17 patients underwent surgical resection, 9 with gross total resection. After multimodality therapy, the 5‐year overall survival (OS) and recurrence‐free survival (RFS) was 87% and 75%, respectively.ConclusionCombined multimodal treatment resulted in a 5‐year OS and RFS of 87% and 75%, respectively. Aggressive surgical resection with adjuvant chemoradiotherapy should be considered. Although negative margin surgery is the goal, subtotal resection may be acceptable in the setting of adjuvant treatment.

Abstract Introduction The interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood. Methods In the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45–64 years. In 2011–2013, 20–25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM. Results In 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late‐life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late‐life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model. Discussion Later life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition.

Background: Emergency departments (EDs) have recognized an increasing number of patients presenting with mental health (MH) concerns. This trend imposes greater demands upon EDs already operating at capacity. Many ED providers do not feel they are optimally prepared to provide the necessary MH care. One consideration in response to this dilemma is to use advanced telemedicine technology for psychiatric consultation. Introduction: We examined a rural- and community-based health system operating 21 EDs, none of which has direct access to psychiatric consultation. Dedicated beds to MH range from zero (in EDs with only 3 beds) to 6 (in an ED with 38 beds). Materials and Methods: We conducted a needs assessment of this health system. This included a survey of emergency room providers with a 67% response rate and site visits to directly observe patient flow and communication with ED staff. A visioning workshop provided input from ED staff. Data were also obtained, which reflected ED admissions for the year 2015. Results: The data provide a summary of provider concerns, a summary of MH presentations and diagnosis, and age groupings. The data also provide a time when most MH concerns present to the ED. Discussion: Based upon these results, a proposed model for delivering comprehensive regional emergency telepsychiatry and behavioral health services is proposed. Conclusions: Emergency telepsychiatry services may be a tenable solution for addressing the shortage of psychiatric consultation to EDs in light of increasing demand for MH treatment in the ED.

Early soft‐tissue coverage is critical for treating traumatic open lower‐extremity wounds. As free‐flap reconstruction evolves, injuries once thought to be nonreconstructable are being salvaged. Free‐tissue transfer is imperative when there is extensive dead space or exposure of vital structures such as bone, tendon, nerves, or blood vessels. We describe 2 cases of lower‐extremity crush injuries salvaged with the quad flap. This novel flap consists of parascapular, scapular, serratus, and latissimus dorsi free flaps in combination on one pedicle. This flap provides the large amount of soft‐tissue coverage necessary to cover substantial defects from skin degloving, tibia and fibula fractures, and soft‐tissue loss. In case 1, a 51‐year‐old woman was struck by an automobile and sustained bilateral tibia and fibula fractures, a crush degloving injury of the left leg, and a right forefoot traumatic amputation. She underwent reconstruction with a contralateral quad free flap. In case 2, a 53‐year‐old man sustained a right tibia plateau fracture with large soft‐tissue defects from a motorcycle accident. He had a crush degloving injury of the entire anterolateral compartment over the distal and lower third of the right leg. The large soft‐tissue defect was reconstructed with a contralateral quad flap. In both cases, the donor site was closed primarily and without early flap failures. There was one surgical complication, an abscess in case 2; the patient was taken back to the operating room for débridement of necrotic tissue. There have been no long‐term complications in either case. Both patients achieved adequate soft‐tissue coverage, avoided amputation, and had satisfactory aesthetic and functional outcomes. With appropriate surgical technique and patient selection, the quad‐flap technique is promising for reconstructing the lower extremity.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.