Long-term Musculoskeletal Consequences of Chemotherapy in Pediatric Mice.

Thanks to recent progress in cancer research, most children treated for cancer survive into adulthood. Nevertheless, the long-term consequences of anticancer agents are understudied, especially in the pediatric population. We and others have shown that routinely administered chemotherapeutics drive musculoskeletal alterations, which contribute to increased treatment-related toxicity and long-term morbidity. Yet, the nature and scope of these enduring musculoskeletal defects following anticancer treatments and whether they can potentially impact growth and quality of life in young individuals remain to be elucidated. Here, we aimed at investigating the persistent musculoskeletal consequences of chemotherapy in young (pediatric) mice. Four-week-old male mice were administered a combination of 5-FU, leucovorin, irinotecan (a.k.a., Folfiri) or the vehicle for up to 5 wk. At time of sacrifice, skeletal muscle, bones, and other tissues were collected, processed, and stored for further analyses. In another set of experiments, chemotherapy-treated mice were monitored for up to 4 wk after cessation of treatment. Overall, the growth rate was significantly slower in the chemotherapy-treated animals, resulting in diminished lean and fat mass, as well as significantly smaller skeletal muscles. Interestingly, 4 wk after cessation of the treatment, the animals exposed to chemotherapy showed persistent musculoskeletal defects, including muscle innervation deficits and abnormal mitochondrial homeostasis. Altogether, our data support that anticancer treatments may lead to long-lasting musculoskeletal complications in actively growing pediatric mice and support the need for further studies to determine the mechanisms responsible for these complications, so that new therapies to prevent or diminish chemotherapy-related toxicities can be identified.

Risk Factors for Skin Flap and Nipple-Areolar Necrosis in Patients Undergoing Nipple-Sparing Mastectomy With Deep Inferior Epigastric Perforator Flap Reconstruction.

INTRODUCTION: Nipple-sparing mastectomy (NSM) with deep inferior epigastric perforator (DIEP) flap reconstruction is a surgical option for select patients with or at risk of breast cancer. However, post-operative skin flap and nipple-areolar complex (NAC) necrosis remain common complications. This study aimed to identify factors associated with necrosis in patients undergoing NSM with DIEP reconstruction. METHODS: A retrospective cohort study was performed from 2015 to 2023. 74 variables were analyzed in patients undergoing NSM with DIEP. Patients were stratified into 3 groups based on post-operative skin/NAC necrosis: none, partial thickness, and full thickness. Comparative and descriptive statistics were performed via t-tests, ANOVA, and chi-squared tests. RESULTS: 34 women with 31 breast cancers met inclusion. 44% experienced necrosis: 15% partial thickness and 29% full thickness. The majority were white (85.3%) with mean age of 50 years (SD = 9.11). In patients with immediate DIEP reconstruction, hypoperfused areas identified by SPY angiography increased risk of necrosis (P = .012). Approximately 50% of both partial thickness and full thickness necrosis patients had concerns on SPY angiography. Former smokers in the full thickness necrosis group had more pack years than those without necrosis (9 vs .65 pack years, P = .035). CONCLUSION: In patients receiving NSM with DIEP flap reconstruction, those with hypoperfusion on SPY angiography and longer smoking history had higher necrosis rates. This supports the continued used of SPY angiography and the role of pre-operative counseling in former smokers with increased pack years on their risk of necrosis and the role of preventative measures in the perioperative setting.

The stuck haemodialysis catheter-a case report of a rare but dreaded complication following kidney transplantation.

BACKGROUND: Tunnelled cuffed haemodialysis catheters are at increased risk of incarceration or becoming 'stuck' via fibrotic adhesion to the central veins when left in situ for prolonged periods of time. Stuck catheters cannot be removed using standard techniques such as bedside dissection of the cuff. Whilst there are several strategies published for the removal of these incarcerated lines, there is no consensus on the best approach. Here we present a challenging case of a stuck haemodialysis catheter in the acute post transplantation period. CASE PRESENTATION: A 66-year-old female on haemodialysis presented for kidney transplantation with a tunnelled-cuffed haemodialysis catheter in situ for five years. Following transplantation, removal of the line was unsuccessful despite dissection of the cuff, with traction causing a choking sensation with tracheal movement. Eventually, the line was removed without complications utilising sequential balloon dilatation by interventional radiology and the patient was discharged without complications. CONCLUSIONS: This case serves as a timely reminder of the risks of long-term tunnelled haemodialysis catheters and as a caution towards proceeding with kidney transplantation in those with long-term haemodialysis catheters in situ. Greater nephrologist awareness of interventional radiology techniques for this challenging situation will help to avoid more invasive strategies. The risks of a stuck catheter should be included in the discussions about the optimal vascular access and transplantation suitability for a given patient.

Does Neoadjuvant Chemotherapy in Clinical T1-T2 N0 Triple-Negative Breast Cancer Increase the Extent of Axillary Surgery?

BACKGROUND: Current management strategies for early-stage triple-negative breast cancer (TNBC) include upfront surgery to determine pathologic stage to guide chemotherapy recommendations, or neoadjuvant chemotherapy (NAC) to de-escalate surgery, elucidate tumor response, and determine the role of adjuvant chemotherapy. However, patients who receive NAC with residual pathological nodal (pN) involvement require axillary lymph node dissection (ALND) as they are Z11/AMAROS ineligible. We aimed to evaluate the impact of NAC compared with upfront surgery on pN status and ALND rates in cT1-2N0 TNBC. METHODS: The National Cancer Database (NCDB) was queried for women with operable cT1-2N0 TNBC from 2014 to 2019. Demographic, clinicopathologic, and treatment data were collected. Multivariable linear regression analysis was performed to assess the odds of pN+ disease and undergoing ALND. RESULTS: Overall, 55,624 women were included: 26.9% (n = 14,942) underwent NAC and 73.1% (n = 40,682) underwent upfront surgery. The NAC cohort was younger (mean age 52.9 vs. 61.3 years; p < 0.001) with more cT2 tumors (71.6% vs. 31.0%; p < 0.001), and had lower ALND rates (4.3% vs. 5.5%; p < 0.001). The upfront surgery cohort was more likely to have one to three pathologically positive nodes (12.1% vs. 6.5%; odds ratio [OR] 2.37, 95% confidence interval (CI) 2.17-2.58; p < 0.001) but there was no difference in the likelihood of ALND (OR 1.1, 95% CI 0.99-1.24; p = 0.08). CONCLUSION: Patients who underwent upfront surgery were more likely to be pN+; however, ALND rates were similar between the two cohorts. Thus, the use of NAC does not result in a higher odds of ALND and the decision for NAC should be individualized and based on modern guidelines and systemic therapy benefits.

National trends in neoadjuvant chemotherapy utilization in patients with early-stage node-negative triple-negative breast cancer: the impact of the CREATE-X trial.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) allows for assessment of tumor pathological response and has survival implications. In 2017, the CREATE-X trial demonstrated survival benefit with adjuvant capecitabine in patients TNBC and residual disease after NAC. We aimed to assess national rates of NAC for cT1-2N0M0 TNBC before and after CREATE-X and examine factors associated with receiving NAC vs adjuvant chemotherapy (AC). METHODS: A retrospective cohort study of women with cT1-2N0M0 TNBC diagnosed from 2014 to 2019 in the National Cancer Database (NCDB) was performed. Variables were analyzed via ANOVA, Chi-squared, Fisher Exact tests, and a multivariate linear regression model was created. RESULTS: 55,633 women were included: 26.9% received NAC, 52.4% AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71 years, p < 0.01). NAC utilization significantly increased over time: 19.5% in 2014-15 (n = 3,465 of 17,777), 27.1% in 2016-17 (n = 5,140 of 18,985), and 33.6% in 2018-19 (n = 6,337 of 18,871, p < 0.001). On multivariate analysis, increased NAC was associated with younger age (< 50), non-Hispanic white race/ethnicity, lack of comorbidities, cT2 tumors, care at an academic or integrated-network cancer program, and diagnosis post-2017 (p < 0.05 for all). Patients with government-provided insurance were less likely to receive NAC (p < 0.01). Women who traveled > 60 miles for treatment were more likely to receive NAC (p < 0.01). CONCLUSION: From 2014 to 2019, NAC utilization increased for patients with cT1-2N0M0 TNBC. Racial, socioeconomic, and access disparities were observed in who received NAC vs AC and warrants interventions to ensure equitable care.

The State of Pharmacoeconomics Education in the Doctor of Pharmacy Curriculum amid the Changing Face of Pharmacy Practice.

(1) Background: Continuous growth in pharmaceutical expenditure indicates the need for more advanced pharmacoeconomics evaluations to optimize healthcare outcomes and resource allocation. This study assesses the extent to which accredited pharmacy colleges in the United States cover pharmacoeconomics content within the didactic curriculum of their Doctor of Pharmacy (PharmD) programs. (2) Methods: We conducted a systematic search of the websites of accredited professional-degree programs in pharmacy schools located in the United States to identify pertinent content related to pharmacoeconomics. (3) Results: Out of 141 pharmacy programs, a total of 111 programs of varying sizes were found to have publicly accessible information regarding the content of their pharmacoeconomic curricula on their websites. All these programs required the inclusion of pharmacoeconomics content in their curricula. An examination of course syllabi revealed that the goals and descriptions were broad, aiming to provide students with an introductory understanding of the principles of pharmacoeconomics. The number of credit hours allocated to pharmacoeconomics education ranged from one to seven across the programs. The approach to delivering pharmacoeconomics content varied among the programs. (4) Conclusions: Advanced knowledge of the principles of pharmacoeconomics must be an integral component of all PharmD curricula to prepare pharmacists to assess the rational use of pharmacy products and services, improve clinical outcomes, and mitigate healthcare expenditures.

Mechanisms of Ovarian Cancer-Associated Cachexia.

Cancer-associated cachexia occurs in 50% to 80% of cancer patients and is responsible for 20% to 30% of cancer-related deaths. Cachexia limits survival and treatment outcomes, and is a major contributor to morbidity and mortality during cancer. Ovarian cancer is one of the leading causes of cancer-related deaths in women, and recent studies have begun to highlight the prevalence and clinical impact of cachexia in this population. Here, we review the existing understanding of cachexia pathophysiology and summarize relevant studies assessing ovarian cancer-associated cachexia in clinical and preclinical studies. In clinical studies, there is increased evidence that reduced skeletal muscle mass and quality associate with worse outcomes in subjects with ovarian cancer. Mouse models of ovarian cancer display cachexia, often characterized by muscle and fat wasting alongside inflammation, although they remain underexplored relative to other cachexia-associated cancer types. Certain soluble factors have been identified and successfully targeted in these models, providing novel therapeutic targets for mitigating cachexia during ovarian cancer. However, given the relatively low number of studies, the translational relevance of these findings is yet to be determined and requires more research. Overall, our current understanding of ovarian cancer-associated cachexia is insufficient and this review highlights the need for future research specifically aimed at exploring mechanisms of ovarian cancer-associated cachexia by using unbiased approaches and animal models representative of the clinical landscape of ovarian cancer.

Management of Lipedema Beyond Liposuction: A Case Study.

Lipedema is a pathologic accumulation of adipose tissue in the subcutaneous layer of the extremities. This connective tissue disorder, which predominately affects females, is often misdiagnosed despite an incidence of ∼11%. Misdiagnosis often leads to delays in appropriate treatment, further increasing the morbidity of the condition. The authors report their facilities' experience in treating a patient with lipedema, requiring multiple surgical interventions involving liposuction and skin debulking to achieve desired aesthetic outcomes. The patient presented to the plastic surgery clinic with severe lipedema of the bilateral lower extremities. She previously underwent a panniculectomy and bilateral lower extremity liposuction without achieving the desired aesthetic results. Prior conservative management and liposuction alone were both unsuccessful treatment options and she required debulking procedures, along with further liposuction, as definitive management. The patient underwent 2 procedures at the clinic, both consisting of liposuction and panniculectomy of the lower extremities and buttocks. The procedures were conducted 1 year apart but were able to achieve the patient's desired aesthetics goals. Management of lipedema can be challenging, but not impossible. This case report shows that local excision is a viable option for treatment if minimally invasive options yield limited results.

Functional analysis of cyclic diguanylate-modulating proteins in Vibrio fischeri.

As bacterial symbionts transition from a motile free-living state to a sessile biofilm state, they must coordinate behavior changes suitable to each lifestyle. Cyclic diguanylate (c-di-GMP) is an intracellular signaling molecule that can regulate this transition, and it is synthesized by diguanylate cyclase (DGC) enzymes and degraded by phosphodiesterase (PDE) enzymes. Generally, c-di-GMP inhibits motility and promotes biofilm formation. While c-di-GMP and the enzymes that contribute to its metabolism have been well-studied in pathogens, considerably less focus has been placed on c-di-GMP regulation in beneficial symbionts. Vibrio fischeri is the sole beneficial symbiont of the Hawaiian bobtail squid (Euprymna scolopes) light organ, and the bacterium requires both motility and biofilm formation to efficiently colonize. C-di-GMP regulates swimming motility and cellulose exopolysaccharide production in V. fischeri. The genome encodes 50 DGCs and PDEs, and while a few of these proteins have been characterized, the majority have not undergone comprehensive characterization. In this study, we use protein overexpression to systematically characterize the functional potential of all 50 V. fischeri proteins. All 28 predicted DGCs and 14 predicted PDEs displayed at least one phenotype consistent with their predicted function, and a majority of each displayed multiple phenotypes. Finally, active site mutant analysis of proteins with the potential for both DGC and PDE activities revealed potential activities for these proteins. This work presents a systems-level functional analysis of a family of signaling proteins in a tractable animal symbiont and will inform future efforts to characterize the roles of individual proteins during lifestyle transitions.

National Trends in "Going Flat" After Mastectomy.

INTRODUCTION: The "Going Flat" movement became widely publicized in 2016 and provides information and support to women who choose to forego post-mastectomy breast reconstruction (PMBR). The objectives of this study were to evaluate temporal trends in PMBR to ascertain the potential impact of this movement and assess which factors are associated with going flat. METHODS: A retrospective cohort analysis was performed using the NCDB of women with non-metastatic breast cancer who underwent mastectomy between 2004 and 2019. Trends in going flat after mastectomy were examined and stratified by age (< 50, 50-69, ≥ 70). A multivariate logistic regression model was used to identify factors associated with going flat. RESULTS: 650,983 patients met the inclusion criteria: 244,201 (37.5%) underwent PMBR and 406,782 (62.5%) went flat. Among women < 70, rates of going flat steadily decreased from 2004 to 2015 and then stabilized after 2015, coinciding with the rise of the "Going Flat" movement. In multivariate analysis, non-White race, older age, increasing comorbidities, government provided insurance, treatment at a community program, radiotherapy, and adjuvant chemotherapy were associated with a higher likelihood of going flat (p < 0.001). CONCLUSION: In the first 2 years after the "Going Flat" movement, the number of women going flat after mastectomy has stabilized in women < 70 for the first time in over a decade. These trends suggest that the social and cultural impact of this movement may have contributed to the stabilization of PMBR rates.

Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy.

BACKGROUND: Endocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. METHODS: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. RESULTS: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. CONCLUSION: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03219476.

Associations Between Hospital Volume and Overall Survival After Surgery in Older Patients with Breast Cancer.

BACKGROUND: High-volume hospitals (HVHs) are associated with improved overall survival (OS) following surgery for breast cancer compared with low-volume hospitals (LVHs). We examined this association in patients age ≥ 80 years and described patient and treatment characteristics associated with HVHs. PATIENTS AND METHODS: The National Cancer Database was queried for women age ≥ 80 years who underwent surgery for stage I-III breast cancer between 2005 and 2014. Hospital volume was defined as the average number of cases during the year of the patient's index operation and the year prior. Hospitals were categorized into HVHs and LVHs using penalized cubic spline analysis of OS. A cutoff of ≥ 270 cases/year defined HVHs. RESULTS: Among 59,043 patients, 9110 (15%) were treated at HVHs and 49,933 (85%) at LVHs. HVHs were associated with more non-Hispanic Black and Hispanic patients, earlier stage disease (stage I 54.9% vs. 52.6%, p < 0.001), higher rates of breast-conserving surgery (BCS) (68.3% vs. 61.4%, p < 0.001), and adjuvant radiation (37.5% vs. 36.1%, p = 0.004). Improved OS was associated with surgery at a HVH (HR 0.85, CI 0.81-0.88), along with receipt of adjuvant chemotherapy (HR 0.73, CI 0.69-0.77), endocrine therapy (HR 0.70, CI 0.68-0.72), and radiation (HR 0.66, CI 0.64-0.68). CONCLUSIONS: Among patients with breast cancer age ≥ 80 years, undergoing surgery at a HVH was associated with improved OS. Patients who completed surgery at HVHs had earlier stage disease and more commonly received adjuvant radiation when appropriate. Processes of care at HVHs should be identified to improve outcomes in all settings.