Systematic Literature Review of Pediatric Male and Female Genital Hair Thread Tourniquet Syndrome.

OBJECTIVE: The aim of this study was to describe genital hair thread tourniquet syndrome (HTTS) and its treatment by pediatric and adolescent health care providers through a systematic literature review. METHODS: We performed a systematic literature review on pediatric male and female genital HTTS. Studies were included if they involved genital HTTS in males or females 21 years and younger and were published in English. The main outcomes were body parts involved, symptoms, treatment, anesthetic type, providers involved in diagnosis and management, and implications of delayed or missed diagnosis. RESULTS: There were 38 female cases from 33 publications (1973-2020) and 147 male cases from 47 publications (1951-2019). The average age among females and males was 9.1 and 5.1 years, respectively. Among cases involving female patients, 93% of them were premenarchal; patients were circumcised in 90% of reviewed cases of male HTTS. The most commonly involved body parts were clitoris and labia minora in females, and penis and urethra in males. Males most commonly presented with edema and urinary symptoms, whereas females most commonly presented with edema and pain. General anesthesia was used for tourniquet excision in most cases. Male and female genital HTTS were mostly managed by urologists and emergency medicine physicians, respectively. CONCLUSION: This systematic literature review of more than 150 cases of male and female genital HTTS describes evaluation and management of genital HTTS spanning 7 decades. The main treatment of genital HTTS remains prompt diagnosis and removal of the tourniquet, as well as education on prevention strategies. Delayed diagnosis due to lack of recognition of the HTTS can lead to serious sequelae. Development of national guidelines regarding best practices in management of genital HTTS disseminated to all providers taking care of pediatric and adolescent patients will lead to improved patient care.

PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers.

OBJECTIVE: Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu. METHODS: We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting. RESULTS: We found PI3K wild-type cell-lines to be significantly more sensitive (lower IC50) than PI3K-mutated cell-lines p = 0.004). In vivo, xenografts of primary cell-line USC-ARK2, transfected with the PIK3CA-H1047R or E545K hotspot-mutations, exhibited significantly more rapid tumor growth when treated with afatinib, compared to mice harboring ARK2-tumors transfected with wild-type-PIK3CA (p = 0.041 and 0.001, respectively). By western-blot, afatinib effectively reduced total and phospho-HER2 proteins in all cell-lines. However, H1047R/E545K-PIK3CA-transfected-ARK2-cells demonstrated a greater compensatory increase in phosphorylated-AKT proteins after afatinib exposure when compared to controls ARK2. CONCLUSIONS: Oncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.

Natural Orifice-Assisted Laparoscopic Meckel Diverticulectomy Incidentally Found During Para-Aortic Mass Resection.

STUDY OBJECTIVE: To show a surgical video in which an incidentally found Meckel diverticulum was resected with a natural orifice-assisted laparoscopic approach during para-aortic resection of a retroperitoneal schwannoma. DESIGN: Case report (Canadian Task Force classification III). SETTING: Tertiary referral center in New Haven, Connecticut. INTERVENTIONS: This is a step-by-step illustration for resection of a retroperitoneal para-aortic schwannoma and of an incidentally found Meckel diverticulum. The patient was a 39-year-old white woman diagnosed with stage IV choriocarcinoma with metastasis to the lungs and left para-aortic area. She received chemotherapy in the form of etoposide, methotrexate, actinomycin-D, cyclophosphamide, oncovine (EMA-CO) and had an excellent clinical response with resolution of all metastatic disease except for the para-aortic mass. Therefore, she was taken to the operating room for laparoscopic resection of the persistent left para-aortic mass. After placement of four 5-mm abdominal ports, the pelvis and abdomen were explored and revealed an incidental Meckel diverticulum as well as the 5 cm left para-aortic mass. The peritoneum overlying the para-aortic mass was incised and the retroperitoneum explored. Given the proximity to the mass, left ureterolysis was performed. The retroperitoneal attachments were resected, and the left para-aortic mass was removed without any complications. At this point attention was turned to the Meckel diverticulum. In order not to extend the abdominal incisions, a posterior colpotomy was performed in the cul-de-sac equidistant from the uterosacral ligaments. Endo-GIA (Covidien, New Haven CT) was introduced through the 10-mm port site at the posterior colpotomy. Meckel diverticulum was resected without narrowing the lumen of the distal ileum. The specimen was removed in a contained manner through posterior colpotomy. MEASUREMENTS AND MAIN RESULTS: The procedure was performed without any complications. The patient had an uneventful postoperative course and was discharged home on postoperative day 0. Pathology revealed a retroperitoneal schwannoma with negative margins and benign Meckel diverticulum without ectopic gastric or pancreatic tissue. The patient has been disease-free since the completion of surgery. CONCLUSION: Laparoscopic resection of the retroperitoneal schwannoma and Meckel diverticulum were successfully performed in this patient with history of stage IV choriocarcinoma. To our knowledge, this is the first report describing a natural orifice-assisted laparoscopic approach for resection of Meckel diverticulum. Natural orifice-assisted laparoscopy should be considered when the surgeon needs to remove a large specimen and/or to introduce >5-mm diameter instruments into the peritoneal cavity without having to extend the abdominal incisions.

Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression.

BACKGROUND: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression. METHODS: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression. RESULTS: High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04). CONCLUSION: In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.

Pharmacist consult to prevent hypoglycemia in adult inpatients with renal dysfunction.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The objective of this study was to evaluate the impact of a pharmacist consult service on rates of hypoglycemia in adult inpatients with renal dysfunction receiving antidiabetic medications. METHODS: This was a single-center, institutional review board-approved, quasi-experimental, 2-phase prospective study. Adult inpatients admitted within 48 to 96 hours of hospitalization with a creatine clearance of less than 30 mL/min or estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 and an active antidiabetic medication order were included. Patients located in a critical care unit or with a previous or planned transplantation were excluded. Each phase was conducted over 4 months. The primary endpoint was the change in the incidence of hypoglycemic episodes (blood glucose [BG] of <70 mg/dL) per 100 patient days when comparing the cohorts. Secondary endpoints included the incidence of recurrent and severe (BG of <40 mg/dL) episodes of hypoglycemia per 100 patient days, occurrence of a BG concentration of higher than 300 mg/dL, and length of stay. RESULTS: Overall, 150 patients were included in the retrospective preimplementation phase and 172 were included in the prospective postimplementation phase. In the postimplementation group, there was a significant decrease in the rate of hypoglycemia per 100 patient days when compared to the retrospective group (5.8 vs 9.0; incidence rate ratio, 1.55; 95% confidence interval, 1.2-2.0; P < 0.05). There was no difference in secondary endpoints between the groups. CONCLUSION: The implementation of a pharmacy consult service resulted in lower rates of hypoglycemic events, which supports pharmacist involvement to prevent hypoglycemia in this at-risk population. Additional studies involving pharmacists working under collaborative practice agreements may reinforce the results.

Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis.

To determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state.

The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis.

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.

Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation.

The metabolic demands and synthetic capacity of the lactating mammary gland exceed that of any other tissue, thereby providing a useful paradigm for understanding the developmental regulation of cellular metabolism. By evaluating mice bearing targeted deletions in Akt1 or Akt2, we demonstrate that Akt1 is specifically required for lactating mice to synthesize sufficient quantities of milk to support their offspring. Whereas cellular proliferation, differentiation, and apoptosis are unaffected, loss of Akt1 disrupts the coordinate regulation of metabolic pathways that normally occurs at the onset of lactation. This results in a failure to upregulate glucose uptake, Glut1 surface localization, lipid synthesis, and multiple lipogenic enzymes, as well as a failure to downregulate lipid catabolic enzymes. These findings demonstrate that Akt1 is required in an isoform-specific manner for orchestrating many of the developmental changes in cellular metabolism that occur at the onset of lactation and establish a role for Akt1 in glucose metabolism.

Analysis of cell migration using whole-genome expression profiling of migratory cells in the Drosophila ovary.

Cell migration contributes to normal development and homeostasis as well as to pathological processes such as inflammation and tumor metastasis. Previous genetic screens have revealed signaling pathways that govern follicle cell migrations in the Drosophila ovary, but few downstream targets of the critical transcriptional regulators have been identified. To characterize the gene expression profile of two migratory cell populations and identify Slbo targets, we purified border cells and centripetal cells expressing the mouse CD8 antigen and carried out whole-genome microarray analysis. Genes predicted to control actin dynamics and the endocytic and secretory pathways were overrepresented in the migratory cell transcriptome. Mutations in five genes, including ttk, failed to complement previously isolated mutations that cause cell migration defects in mosaic clones. Functional analysis revealed a role for the Notch-activating protease Kuzbanian in border cell migration and identified Tie as a guidance receptor for the border cells.

Medically Indicated Labiaplasty in a Case of Recurrent Labial Hair Thread Tourniquet Syndrome in a Premenarchal Girl.

BACKGROUND: Despite controversy surrounding labiaplasty in adolescent girls, labiaplasty might be indicated in the case of recurrent labial hair thread tourniquet syndrome (HTTS). CASE: We describe a case of an 11-year-old girl with recurrent labial HTTS who underwent labiaplasty. SUMMARY AND CONCLUSION: Recurrent labial HTTS can lead to disfigurement and partial loss of labium. Labiaplasty can restore normal anatomy of the labia and prevent further recurrence in select cases.

Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy.

Women who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-beta signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer.

In Vitro and In Vivo Activity of IMGN853, an Antibody-Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers.

Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRα) expression in these biologically aggressive (type II) endometrial cancers and evaluate FRα as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRα was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRα. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (i.e., 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRα showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRα = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRα, IMGN853 treatment showed complete resolution of tumors (P < 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2+ FRα, induced twofold increase in median survival (P < 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FRα 2+ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRα may benefit from this treatment. Mol Cancer Ther; 17(5); 1003-11. ©2018 AACR.

Genomic analysis of early murine mammary gland development using novel probe-level algorithms.

We describe a novel algorithm (ChipStat) for detecting gene-expression changes utilizing probe-level comparisons of replicate Affymetrix oligonucleotide microarray data. A combined detection approach is shown to yield greater sensitivity than a number of widely used methodologies including SAM, dChip and logit-T. Using this approach, we identify alterations in functional pathways during murine neonatal-pubertal mammary development that include the coordinate upregulation of major urinary proteins and the downregulation of loci exhibiting reciprocal imprinting.

Developmental stage determines the effects of MYC in the mammary epithelium.

Epidemiological findings suggest that the consequences of a given oncogenic stimulus vary depending upon the developmental state of the target tissue at the time of exposure. This is particularly evident in the mammary gland, where both age at exposure to a carcinogenic stimulus and the timing of a first full-term pregnancy can markedly alter the risk of developing breast cancer. Analogous to this, the biological consequences of activating oncogenes, such as MYC, can be influenced by cellular context both in terms of cell lineage and cellular environment. In light of this, we hypothesized that the consequences of aberrant MYC activation in the mammary gland might be determined by the developmental state of the gland at the time of MYC exposure. To test this hypothesis directly, we have used a doxycycline-inducible transgenic mouse model to overexpress MYC during different stages of mammary gland development. Using this model, we find that the ability of MYC to inhibit postpartum lactation is due entirely to its activation within a specific 72-hour window during mid-pregnancy; by contrast, MYC activation either prior to or following this 72-hour window has little or no effect on postpartum lactation. Surprisingly, we find that MYC does not block postpartum lactation by inhibiting mammary epithelial differentiation, but rather by promoting differentiation and precocious lactation during pregnancy, which in turn leads to premature involution of the gland. We further show that this developmental stage-specific ability of MYC to promote mammary epithelial differentiation is tightly linked to its ability to downregulate caveolin 1 and activate Stat5 in a developmental stage-specific manner. Our findings provide unique in vivo molecular evidence for developmental stage-specific effects of oncogene activation, as well as the first evidence linking MYC with activation of the Jak2-Stat5 signaling pathway.

Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis.

Aberrant activation of Wnt signaling is oncogenic and has been implicated in a variety of human cancers. We have developed a doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt signaling. Using this model we show that targeted down-regulation of the Wnt pathway results in the rapid disappearance of essentially all Wnt-initiated invasive primary tumors as well as pulmonary metastases. Tumor regression does not require p53 and occurs even in highly aneuploid tumors. However, despite the dependence of primary mammary tumors and metastases on continued Wnt signaling and the dispensability of p53 for tumor regression, we find that a substantial fraction of tumors progress to a Wnt-independent state and that p53 suppresses this process. Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor regression, it nevertheless plays a critical role in the suppression of tumor recurrence. Our findings demonstrate that although even advanced stages of epithelial malignancy remain dependent upon continued Wnt signaling for maintenance and growth, loss of p53 facilitates tumor escape and the acquisition of oncogene independence.

A lysosomal tetraspanin associated with retinal degeneration identified via a genome-wide screen.

The Drosophila visual system has provided a model to study phototransduction and retinal degeneration. To identify new candidate proteins that contribute to these processes, we conducted a genome-wide screen for genes expressed predominately in the eye, using DNA microarrays. This screen appeared to be comprehensive as it led to the identification of all 22 eye-enriched genes previously shown to function in phototransduction or implicated in retinal degeneration. In addition, we identified 93 eye-enriched genes whose roles have not been previously defined. One of the eye-enriched genes encoded a member of a large family of transmembrane proteins, referred to as tetraspanins. We created a null mutation in the eye-enriched tetraspanin, Sunglasses (Sun), which resulted in light-induced retinal degeneration. We found that the Sun protein was distributed primarily in lysosomes, and functioned in a long-known but poorly understood phenomenon of light-induced degradation of rhodopsin. We propose that lysosomal tetraspanins in mammalian cells may also function in the downregulation of rhodopsin and other G-protein-coupled receptors, in response to intense or prolonged agonist stimulation.