Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis.

We show here that both SHIP1 (Inpp5d) and its paralog SHIP2 (Inppl1) are expressed at protein level in microglia. To examine whether targeting of SHIP paralogs might influence microglial physiology and function, we tested the capacity of SHIP1-selective, SHIP2-selective and pan-SHIP1/2 inhibitors for their ability to impact on microglia proliferation, lysosomal compartment size and phagocytic function. We find that highly potent pan-SHIP1/2 inhibitors can significantly increase lysosomal compartment size, and phagocytosis of dead neurons and amyloid beta (Aß)1-42 by microglia in vitro We show that one of the more-potent and water-soluble pan-SHIP1/2 inhibitors, K161, can penetrate the blood-brain barrier. Consistent with this, K161 increases the capacity of CNS-resident microglia to phagocytose Aß and apoptotic neurons following systemic administration. These findings provide the first demonstration that small molecule modulation of microglia function in vivo is feasible, and suggest that dual inhibition of the SHIP1 and 2 paralogs can provide a novel means to enhance basal microglial homeostatic functions for therapeutic purposes in Alzheimer's disease and, possibly, other types of dementia where increased microglial function could be beneficial.

Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score.

BACKGROUND: Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes. METHODS: A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores. RESULTS: Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m2, p < 0.0001), higher HOMA-IR score (2.4 vs. 1.4, p = 0.004), and more high-grade tumors (30% vs. 16%, p = 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p = 0.014). On subset analysis, this relationship was seen in White women (p = 0.005), but not in Black women (p = 0.55). CONCLUSION: In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.

Insulin resistance contributes to racial disparities in breast cancer prognosis in US women.

BACKGROUND: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (ß = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R >  1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001). CONCLUSIONS: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.

The ubiquitin-associated (UBA) domain of SCCRO/DCUN1D1 protein serves as a feedback regulator of biochemical and oncogenic activity.

Amplification of squamous cell carcinoma-related oncogene (SCCRO) activates its function as an oncogene in a wide range of human cancers. The oncogenic activity of SCCRO requires its potentiating neddylation domain, which regulates its E3 activity for neddylation. The contribution of the N-terminal ubiquitin-associated (UBA) domain to SCCRO function remains to be defined. We found that the UBA domain of SCCRO preferentially binds to polyubiquitin chains in a linkage-independent manner. Binding of polyubiquitin chains to the UBA domain inhibits the neddylation activity of SCCRO in vivo by inhibiting SCCRO-promoted nuclear translocation of neddylation components and results in a corresponding decrease in cullin-RING-ligase-promoted ubiquitination. The results of colony formation and xenograft assays showed a mutation in the UBA domain of SCCRO that reduces binding to polyubiquitin chains, significantly enhancing its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frameshift mutation in SCCRO that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of SCCRO, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. Combined, these data suggest that the UBA domain functions as a negative regulator of SCCRO function. Mutations in the UBA domain lead to loss of inhibitory control, which results in increased biochemical and oncogenic activity. The clustering of mutations in the UBA domain of SCCRO suggests that mutations may be a mechanism of oncogene activation in human cancers.

Safety and efficacy of the keystone and rhomboid flaps for immediate reconstruction after wide local excision of non-head and neck melanomas.

BACKGROUND: After wide local excision of cutaneous melanoma, large defects not amenable to simple primary closure are often covered with skin grafts. We report our experience using the rhomboid and keystone flaps to immediately close large axial and extremity wounds after potentially curative surgery for non-head and neck melanomas. METHODS: Between January 2011 and September 2016, demographic, operative, pathologic, and outcome data were prospectively collected on 60 patients who underwent wide local excision of melanoma followed by immediate flap reconstruction. Flaps were of either rhomboid or keystone type. Chi-square analysis was used to compare relationships between factors. RESULTS: All procedures were done by the senior author and as outpatient surgery. No patient required a surgical drain unless they were undergoing concomitant radical regional node dissection. Flap separation (arbitrarily defined as a >5-mm dehiscence of the suture line) occurred in 16/61 patients (26 %). No patient had flap loss. The risk of flap morbidity was significantly higher if the primary tumor was on the distal extremity-10 of 24 patients (42 %), all with keystone flaps-than if it was on the trunk or the proximal extremity (6/37 patients, 16 %), p = 0.04. There were no margins positive for either invasive or in situ melanoma in the entire cohort. CONCLUSIONS: Simple transposition flaps can successfully cover large defects after melanoma excision without the need for skin grafting. Keystone flaps in the distal extremity are more prone to separation, but this is minor and does not result in flap loss. There is minimal risk of a positive margin requiring flap takedown and a second re-excision.

Discovery and development of small molecule SHIP phosphatase modulators.

Inositol phospholipids play an important role in the transfer of signaling information across the cell membrane in eukaryotes. These signals are often governed by the phosphorylation patterns on the inositols, which are mediated by a number of inositol kinases and phosphatases. The src homology 2 (SH2) containing inositol 5-phosphatase (SHIP) plays a central role in these processes, influencing signals delivered through the PI3K/Akt/mTOR pathway. SHIP modulation by small molecules has been implicated as a treatment in a number of human disease states, including cancer, inflammatory diseases, diabetes, atherosclerosis, and Alzheimer's disease. In addition, alteration of SHIP phosphatase activity may provide a means to facilitate bone marrow transplantation and increase blood cell production. This review discusses the cellular signaling pathways and protein-protein interactions that provide the molecular basis for targeting the SHIP enzyme in these disease states. In addition, a comprehensive survey of small molecule modulators of SHIP1 and SHIP2 is provided, with a focus on the structure, potency, selectivity, and solubility properties of these compounds.

Impact of margin assessment method on positive margin rate and total volume excised.

BACKGROUND: For breast-conserving surgery, the method of margin assessment that most frequently achieves negative margins without increasing the volume of tissue excised is uncertain. We examined our institutional experience with three different margin assessment methods used by six experienced breast surgeons. METHODS: Patients undergoing breast-conserving surgery for invasive carcinoma during July to December of a representative year during which each method was performed (perpendicular, 2003; tangential, 2004; cavity shave, 2011) were included. The effect of margin method on the positive margin rate at first excision and the total volume excised to achieve negative margins were evaluated by multivariable analysis, by surgeon, and by tumor size and presence of extensive intraductal component (EIC). RESULTS: A total of 555 patients were identified, as follows: perpendicular, 140; tangential, 124; and cavity shave, 291. The tangential method had a higher rate of positive margins at first excision than the perpendicular and cavity-shave methods (49, 15, 11 %, respectively; p < 0.0001). Median volumes to achieve negative margins were similar (55 ml perpendicular; 64 ml tangential; 62 ml cavity shave; p = 0.24). Four of six surgeons had the lowest rate of positive margins with the cavity-shave method, which was significant when compared to the tangential method (p < 0.0001) but not the perpendicular method (p = 0.37). The volume excised by the three methods varied by surgeon (p < 0.0001). The perpendicular method was optimal for T1 tumors without EIC; the cavity-shave method tended to be superior for T2-T3 tumors and/or EIC. CONCLUSIONS: Although the cavity-shave method may decrease the rates of positive margins, its effect on volume is variable among surgeons and may result in an increase in the total volume excised for some surgeons and for small tumors without EIC.

Improved Rate of Negative Margins for Inflammatory Breast Cancer Using Intraoperative Frozen Section Analysis.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer with a poor survival rate. Modified radical mastectomy (MRM) with negative pathologic margins is critical for improved survival. We aim to study the potential benefit of intraoperative frozen section analysis (FSA) to improve disease-free margins. METHODS: This prospective, monocentric study included 19 patients who underwent MRM for IBC. For each patient, a 2 mm continuous skin edge was sent for FSA to guide further resection. The rate of tumor-free margins and the concurrence between the FSA and permanent pathological results were analyzed. RESULTS: Overall, 15 of the 19 patients achieved negative margins, including four patients who would have had positive margins without FSA. The odds ratio of achieving a negative final margin with FSA was infinity (p = 0.031), and there was a strong agreement between the FSA and permanent pathological results (Kappa-0.83; p < 0.0001). CONCLUSIONS: The FSA technique decreased the number of positive margins in IBC patients undergoing MRM, thereby potentially reducing the need for re-operation, allowing immediate wound closure, and preventing delays in the administration of adjuvant radiation therapy. More extensive trials are warranted to establish the use of intraoperative FSA in IBC treatment.

Axillary Needle Biopsy in the Era of American College of Surgeons Oncology Group (ACOSOG) Z0011: Institutional Experience With a Largely Urban Minority Population and Review of the Literature.

BACKGROUND:  The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that sentinel lymph node biopsy (SLNB) alone is adequate for axillary control in patients with one to two positive axillary lymph nodes. However, axillary lymph node dissection (ALND) is required in patients with N1 disease diagnosed with a preoperative needle biopsy. In this report, we determined how many patients could potentially have had SNB alone based on finding only one to two positive nodes in the axilla. METHODS:  A retrospective review of patients with positive preoperative axillary needle biopsy undergoing ALND was used to identify rates of high volume axillary disease (>2 positive nodes). Wilcoxon's rank-sum and Fisher's exact test were used for statistical analysis. A review of the literature is included for comparison. RESULTS:  73% of 51 total patients with a positive needle biopsy had >2 positive nodes on axillary dissection. The high-volume axillary disease was significantly more likely with the presence of lymphovascular invasion and extranodal extension. CONCLUSIONS:  Patients with positive preoperative axillary needle biopsies have a significantly higher rate of high volume axillary disease. However, at least one-quarter of these patients will have <3 positive nodes and potentially could have been treated with SNB alone.

Insulin resistance and racial disparities in breast cancer prognosis: a multi-center cohort study.

The survival for breast cancer (BC) is improving but remains lower in Black women than White women. A number of factors potentially drive the racial differences in BC outcomes. The aim of our study was to determine if insulin resistance (defined as homeostatic model assessment for insulin resistance (HOMA-IR)), mediated part of the relationship between race and BC prognosis (defined by the improved Nottingham prognostic index (iNPI)). We performed a cross-sectional study, recruiting self-identified Black and White women with newly diagnosed primary invasive BC from 10 US hospitals between March 2013 and February 2020. Survey, anthropometric, laboratory, and tumor pathology data were gathered, and we compared the results between Black and White women. We calculated HOMA-IR as well as iNPI scores and examined the associations between HOMA-IR and iNPI. After exclusions, the final cohort was 1206: 911 (76%) White and 295 (24%) Black women. Metabolic syndrome and insulin resistance were more common in Black than White women. Black women had less lobular BC, three times more triple-negative BC, and BCs with higher stage and iNPI scores than White women (P < 0.001 for all comparisons). Fewer Black women had BC genetic testing performed. HOMA-IR mediated part of the association between race and iNPI, particularly in BCs that carried a good prognosis and were hormone receptor (HR)-positive. Higher HOMA-IR scores were associated with progesterone receptor-negative BC in White women but not Black women. Overall, our results suggest that HOMA-IR contributes to the racial disparities in BC outcomes, particularly for women with HR-positive BCs.

Rare case of primary leiomyosarcoma of the breast treated with wide local excision and planned cosmetic breast reduction surgery.

Primary leiomyosarcoma of the breast is an extremely rare neoplasm accounting for less than 0.0006% of all breast malignancies, with fewer than 80 cases reported in the literature to date. Here, we present a case of leiomyosarcoma of the breast in a 61-year-old woman without traditional risk factors. This case was treated with lumpectomy requiring wide margins due to the high rate of local recurrence. A planned breast reduction surgery was deemed adequate postlumpectomy therapy to prevent cancer recurrence, negating the need for chemotherapy or radiation therapy. To our knowledge, this is the first case in which cosmetic breast reduction surgery will be used as postlumpectomy cancer recurrence risk mitigation for primary leiomyosarcoma of the breast. Patients with this malignancy have a relatively poor prognosis compared with other breast cancer types, with a 5-year disease-free survival of 33%-52%. As such, frequent follow-up and monitoring for postresection recurrence is essential.

Radiation-induced undifferentiated pleomorphic sarcoma of the breast.

Breast sarcoma is a rare form of malignancy that arises from connective tissue within the breast, comprising less than 5% of all sarcomas. They develop as primary tumours or as secondary following radiation therapy. Diagnosis can be challenging as breast sarcomas are often asymptomatic and resemble benign breast tissue changes. Radiation-induced breast sarcomas present in various forms with an average latency period of 10-20 years following initial radiation therapy. Angiosarcomas are the most common form, while other types such as undifferentiated pleomorphic sarcomas remain rare. Here, we report a case of radiation-induced undifferentiated pleomorphic breast sarcoma in a 75-year-old woman that developed nearly 20 years following breast conserving surgery and radiation for invasive ductal carcinoma. The patient initially noticed a mass in 2017 on self-examination. The mammogram, ultrasound and biopsy at the time showed a benign 2.2 cm nodular fasciitis without malignancy. The mass grew rapidly in the next 6 months to 5.6 cm and repeat biopsy diagnosed undifferentiated pleomorphic sarcoma. The mass abutted the pectoralis muscle but staging workup ruled out distant metastasis and the patient underwent wide local resection of the mass with clear margins. The patient subsequently underwent further postoperative radiation due to insufficient posterior margin width on wide local excision, as chest wall resection would have been required for a wider posterior margin. Prognosis for postradiation sarcomas is generally poor with 27%-36% 5-year survival, with surgical resection as the main line of treatment. The patient currently remains disease-free after 15 months of surveillance.

High glycemic index and glycemic load diets as risk factors for insomnia: analyses from the Women's Health Initiative.

BACKGROUND: Previous studies have shown mixed results on the association between carbohydrate intake and insomnia. However, any influence that refined carbohydrates have on risk of insomnia is likely commensurate with their relative contribution to the overall diet, so studies are needed that measure overall dietary glycemic index (GI), glycemic load, and intakes of specific types of carbohydrates. OBJECTIVE: We hypothesized that higher GI and glycemic load would be associated with greater odds of insomnia prevalence and incidence. METHODS: This was a prospective cohort study with postmenopausal women who participated in the Women's Health Initiative Observational Study, investigating the relations of GI, glycemic load, other carbohydrate measures (added sugars, starch, total carbohydrate), dietary fiber, and specific carbohydrate-containing foods (whole grains, nonwhole/refined grains, nonjuice fruits, vegetables, dairy products) with odds of insomnia at baseline (between 1994 and 1998; n = 77,860) and after 3 y of follow-up (between 1997 and 2001; n = 53,069). RESULTS: In cross-sectional and longitudinal analyses, higher dietary GI was associated with increasing odds of prevalent (fifth compared with first quintile OR: 1.11; CI: 1.05, 1.16; P-trend = 0.0014) and incident (fifth compared with first quintile OR: 1.16; CI: 1.08, 1.25; P-trend < 0.0001) insomnia in fully adjusted models. Higher intakes of dietary added sugars, starch, and nonwhole/refined grains were each associated with higher odds of incident insomnia. By contrast, higher nonjuice fruit and vegetable intakes were significantly associated with lower odds of incident insomnia. Also, higher intakes of dietary fiber, whole grains, nonjuice fruit, and vegetables were significantly associated with lower odds of prevalent insomnia. CONCLUSIONS: The results suggest that high-GI diets could be a risk factor for insomnia in postmenopausal women. Substitution of high-GI foods with minimally processed, whole, fiber-rich carbohydrates should be evaluated as potential treatments of, and primary preventive measures for, insomnia in postmenopausal women.

Tubular adenomas of the breast: a rare diagnosis.

Tubular adenomas of the breast are rare benign tumours and few cases have been reported. Most often, the tumours are described as palpable, well-circumscribed masses in women of childbearing age and are commonly diagnosed as fibroadenomas both clinically and radiographically. Surgical excision is required for diagnosis and to prevent continuing growth. Here, we present two cases of these rare tumours, both with unusual presentations. The first case describes a very large specimen (10 cm × 9.5 cm × 4 cm mass) with tubular adenoma pathology, which is one of the largest reported in medical literature. The second case illustrates another rare specimen, a mixture of both tubular adenoma and fibroadenoma pathology. We elected to document these cases to assist in the management of these rare lesions. Our hope is that this will allow future physicians to better identify and treat the pathology with improved outcomes for these patients.

Estrogen-alone therapy and invasive breast cancer incidence by dose, formulation, and route of delivery: findings from the WHI observational study.

OBJECTIVE: Research on the relationships between different hormone therapy doses, formulation and routes of delivery, and subsequent breast cancer incidence has been limited. This study directly compared different estrogen doses, formulations, and route of delivery of estrogen alone among women with a hysterectomy in relation to invasive breast cancer incidence. METHODS: The Women's Health Initiative Observational Study is a large multicenter prospective cohort study conducted at 40 US sites. Analyses included 26,525 postmenopausal women with a hysterectomy, aged 50 to 79 years, at study entry, recruited between September, 1993 and December, 1998, with annual follow-up through September 12, 2005. RESULTS: Average follow-up was 8.2 years. For conjugated equine estrogen (CEE) users, no difference was observed between low-dose CEE (<0.625 mg) compared with conventional-dose CEE (0.625 mg) for breast cancer (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.65, 1.48)]. Compared with conventional-dose CEE, transdermal estrogen was associated with a nonsignificant lower risk of invasive breast cancer (HR 0.75, 95% CI 0.47, 1.19). The low prevalence of transdermal use likely limited power for this comparison, and for a comparison of oral estradiol to conventional-dose CEE (HR 1.20, 95% CI 0.84, 1.39). CONCLUSION: Our results indicate that invasive breast cancer risk did not differ appreciably in women with a hysterectomy using estrogen-alone when directly comparing different doses, formulations, and routes of delivery to the conventional oral CEE. These findings suggest that the lower breast cancer risk found in the WHI estrogen-alone trial may extend to lower doses of CEE. Additional research is needed to confirm these hypotheses.

Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics.

Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.

Body fat and breast cancer risk in postmenopausal women: a longitudinal study.

Associations between anthropometric indices of obesity and breast cancer risk may fail to capture the true relationship between excess body fat and risk. We used dual-energy-X-ray-absorptiometry- (DXA-) derived measures of body fat obtained in the Women's Health Initiative to examine the association between body fat and breast cancer risk; we compared these risk estimates with those for conventional anthropometric measurements. The study included 10,960 postmenopausal women aged 50-79 years at recruitment, with baseline DXA measurements and no history of breast cancer. During followup (median: 12.9 years), 503 incident breast cancer cases were diagnosed. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. All baseline DXA-derived body fat measures showed strong positive associations with breast cancer risk. The multivariable-adjusted HR for the uppermost quintile level (versus lowest) ranged from 1.53 (95% CI 1.14-2.07) for fat mass of the right leg to 2.05 (1.50-2.79) for fat mass of the trunk. Anthropometric indices (categorized by quintiles) of obesity (BMI (1.97, 1.45-2.68), waist circumference (1.97, 1.46-2.65), and waist : hip ratio (1.91, 1.41-2.58)) were all strongly, positively associated with risk and did not differ from DXA-derived measures in prediction of risk.

Case report: a left upper quadrant complex cystic mass.

A 61-year-old woman presented with left upper quadrant/flank pain and increasing abdominal girth. CT scan showed a large complex, multi-cystic lesion in the left abdomen. Laparotomy revealed a large retroperitoneal mass attached to the left kidney. Left nephrectomy was performed and pathology demonstrated a benign cystic nephroma. Surgical oncologists should be aware of this rare renal lesion as the clinical and radiographic presentation may mimic other intra-abdominal cystic lesions.

Prevention of postpneumonectomy syndrome in children with prophylactic tissue expander insertion.

INTRODUCTION: Postpneumonectomy syndrome (PPS) is an often life-threatening complication of pneumonectomy that occurs in up to 15% of children. This occurrence is higher than in adults, presumably because of more elastic tissues in younger patients. METHODS: We present a case series of 4 pediatric patients at Memorial Sloan Kettering Cancer Center, in whom prophylactic tissue expanders were inserted immediately after pneumonectomy. RESULTS: Insertion of the tissue expander and prevention of PPS was successful in all patients. The presence of the tissue expander did not result in infection in any patient. Our only complication was rupture of the tissue expander in 1 patient, but by the time of removal, a capsule had already formed within the lung and replacement was unnecessary. CONCLUSION: This case series, although limited in number and follow-up, presents evidence that prophylactic tissue expander insertion appears to be a safe option for children requiring pneumonectomy. Its insertion at the time of pneumonectomy may prevent the devastating complications of PPS. Because it may result in a higher total number of procedures, the benefits must be weighed against the risks of insertion and decisions made for individual patients on a case-by-case basis.

SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation.

Covalent modification of cullins by the ubiquitin-like protein NEDD8 (neddylation) regulates protein ubiquitination by promoting the assembly of cullin-RING ligase E3 complexes. Like ubiquitination, neddylation results from an enzymatic cascade involving the sequential activity of a dedicated E1 (APPBP1/Uba3), E2 (Ubc12), and an ill-defined E3. We show that SCCRO (also known as DCUN1D1) binds to the components of the neddylation pathway (Cullin-ROC1, Ubc12, and CAND1) and augments but is not required for cullin neddylation in reactions using purified recombinant proteins. We also show that SCCRO recruits Ubc12 approximately NEDD8 to the CAND1-Cul1-ROC1 complex but that this is not sufficient to dissociate or overcome the inhibitory effects of CAND1 on cullin neddylation in purified protein assays. In contrast to findings in cellular systems where no binding is seen, we show that SCCRO and CAND1 can bind to the neddylated Cul1-ROC1 complex in assays using purified recombinant proteins. Although neddylated (not unneddylated) Cul1-ROC1 is released from CAND1 upon incubation with testis lysate from SCCRO+/+ mice, the addition of recombinant SCCRO is required to achieve the same results in lysate from SCCRO(-/-) mice. Combined, these results suggest that SCCRO is an important component of the neddylation E3 complex that functions to recruit charged E2 and is involved in the release of inhibitory effects of CAND1 on cullin-RING ligase E3 complex assembly and activity.