Deep learning-aided decision support for diagnosis of skin disease across skin tones.

Although advances in deep learning systems for image-based medical diagnosis demonstrate their potential to augment clinical decision-making, the effectiveness of physician-machine partnerships remains an open question, in part because physicians and algorithms are both susceptible to systematic errors, especially for diagnosis of underrepresented populations. Here we present results from a large-scale digital experiment involving board-certified dermatologists (n = 389) and primary-care physicians (n = 459) from 39 countries to evaluate the accuracy of diagnoses submitted by physicians in a store-and-forward teledermatology simulation. In this experiment, physicians were presented with 364 images spanning 46 skin diseases and asked to submit up to four differential diagnoses. Specialists and generalists achieved diagnostic accuracies of 38% and 19%, respectively, but both specialists and generalists were four percentage points less accurate for the diagnosis of images of dark skin as compared to light skin. Fair deep learning system decision support improved the diagnostic accuracy of both specialists and generalists by more than 33%, but exacerbated the gap in the diagnostic accuracy of generalists across skin tones. These results demonstrate that well-designed physician-machine partnerships can enhance the diagnostic accuracy of physicians, illustrating that success in improving overall diagnostic accuracy does not necessarily address bias.

Pediatric Melanoma Arising in a Background of Melanocytic Nevi.

Malignant melanoma is an aggressive neoplasm primarily involving the skin. They may arise de novo or from a premalignant melanocytic lesion. Melanomas are primarily known to occur in adults. Pediatric melanomas (PM) are rare and predominantly occur de novo following ultraviolet deoxyribonucleic acid (DNA) damage. They may also be associated with the presence of congenital melanocytic nevi. We report a rare case of a 6-year-old child with multiple melanocytic nevi subsequently diagnosed with melanoma of the back and metastatic disease.

Catalytic C-H Trifluoromethylation of Arenes and Heteroarenes via Visible Light Photoexcitation of a Co(III)-CF3 Complex.

A cobalt photocatalyst for direct trifluoromethylation of (hetero)arene C(sp2)-H bonds is described and shown to operate via visible light activation of a Co-CF3 intermediate, which functions as a combined chromophore and organometallic reaction center. Chemical oxidations of previously reported (OCO)Co complexes containing a redox-active [OCO] pincer ligand afford a Co-CF3 complex two oxidation states above Co(II). Computational and spectroscopic studies are consistent with formulation of the product as [(OCO•)CoIII(CF3)(THF)(OTf)] (II) containing an open-shell [OCO•]1- radical ligand bound to a S = 0 Co(III) center. II is thermodynamically stable, but exposure to blue (440 nm) light induces Co-CF3 bond homolysis and release of •CF3, which is trapped by radical acceptors including TEMPO•, (hetero)arenes, or the radical [OCO•] ligand in II. The latter comprises a competitive degradation pathway, which is overcome under catalytic conditions by using excess substrate. Accordingly, generation of II from the reaction of [(OCO)CoIIL] (III) (L = THF, MeCN) with Umemoto's dibenzothiophenium trifluoromethylating reagent (1) followed by photolytic Co-CF3 bond activation completes a photoredox catalytic cycle for C-H (hetero)arene trifluoromethylation utilizing visible light. Electronic structure and photophysical studies, including time-dependent density functional theory (TDDFT) calculations, suggest that Co-CF3 bond homolysis at II occurs via an ligand-to-metal charge-transfer (LMCT) (OCO0)CoII(CF3) state, revealing ligand redox activity as a critical design feature and establishing design principles for the use of base metal chromophores for selectivity in photoredox bond activations occurring via free radical intermediates.

An assessment of childhood cancer care services in India - gaps, challenges and the way forward.

Background: Childhood cancers are emerging as an essential concern in India where there is lack of a specific programme component or policy to address childhood cancer control. There is limited information on the status and quality of childhood cancer care services in India. This paper describes the childhood cancer care services available at secondary and tertiary-level hospitals in India through a cross sectional study design. Methods: The survey was conducted in 137 tertiary-level and 92 secondary-level hospitals in 26 states and 4 Union Territories (UTs), ensuring a uniform representation of public and private care hospitals. The study tool collected data on the organisational infrastructure, type of oncology services, health workforce, equipment, treatment and referral protocols, and treatment guidelines. Descriptive statistics was used to primarily present the health service status and data on childhood cancer care services in proportions and mean. Findings: A dedicated pediatric oncology department was available in 41.6% of the public, 48.6% of private, and 64% Non Government Organization (NGO) managed tertiary-level hospitals. In 36 (39%) of the 92 hospitals providing secondary care, childhood cancer care was provided. The availability of bone (41.5%) and positron emission tomography (PET) scans (25.9%) was lower in public tertiary hospitals, whereas histopathology, computerised tomography (CT scan), and magnetic resonance imaging (MRI) were lower in public secondary hospitals than private and NGO managed hospitals for the corresponding level of care. Most tertiary hospitals had the required supportive care facilities except for play therapy and hospice care. Less than 50% of the public tertiary hospitals had stocks of the four categories of cancer-treating drugs and essential infrastructure for radiotherapy and chemotherapy. Most secondary-level hospitals not treating childhood cancer had referral linkages with tertiary hospitals. Interpretation: The situational analysis of childhood cancer care services in India showed the concentration of availability of childhood cancer care services at the tertiary level of health care. There were gaps in the availability of specialised pediatric oncology care in all the tertiary hospitals. The availability of childhood cancer care services was higher in private and NGO-managed hospitals than in public hospitals. Integration of childhood cancer as a part of the national cancer control response should be taken up as a matter of priority. The need of the hour is to formulate a childhood cancer policy that will enable timely access to care universally. Funding: World Health Organization, India provided funding and technical support.

Role of Mismatch Repair Deficiency Status and Microsatellite Instability in Relation to the Expression of Immune Checkpoint Proteins in Colorectal Cancer.

Introduction Colorectal cancer (CRC) is the third most common cancer in the world among men and second among women worldwide. One of the major molecular pathways responsible for the development of colorectal cancer (CRC) is the microsatellite instability (MSI) pathway. During carcinogenesis, the tumor cells express programmed death ligand-1 (PD-L1), which reduces the immunogenicity leading to the escape of immune attack. Anti-PD-L1 interaction is an upcoming line of research for the treatment of colorectal carcinoma patients. Materials and methods The present study was an ambispective study where the mismatch repair deficiency status (MMR) and programmed death ligand-1 (PD-L1) expression were studied using immunohistochemistry and then later analyzed and compared with the clinicopathological parameters and MSI status in relation to the expression of programmed death ligand-1 (PD-L1) in neoplastic and immune cells in a total of 55 biopsy specimen. MMR expression was reported as retained or loss of nuclear staining, and PD-L1 expression was taken as positive with a cut-off of more than or equal to 5% membranous positivity in both tumor cells and immune cells. Results The analysis showed a significant correlation of microsatellite instability (MSI) status with two of the clinicopathological parameters, which were the site of the tumor (p-value<0.001) and M stage (p-value<0.001). PD-L1 expression in neoplastic cells showed no significant correlation with the clinicopathological parameters, whereas PD-L1 expression in immune cells showed a significant association with gender (p-value=0.043). Also, MSI status showed a significant association with PD-L1 expression in tumor cells (p-value <0.001).

Diruthenium Tetracarboxylate-Catalyzed Enantioselective Cyclopropanation with Aryldiazoacetates.

A series of chiral bowl-shaped diruthenium(II,III) tetracarboxylate catalysts were prepared and evaluated in asymmetric cyclopropanations with donor/acceptor carbenes derived from aryldiazoacetates. The diruthenium catalysts self-assembled to generate C4-symmetric bowl-shaped structures in an analogous manner to their dirhodium counterparts. The optimum catalyst was found to be Ru2(S-TPPTTL)4·BArF [S-TPPTTL = (S)-2-(1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate, BArF = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate], which resulted in the cyclopropanation of a range of substrates in up to 94% ee. Synthesis and evaluation of first-row transition-metal congeners [Cu(II/II) and Co(II/II)] invariably resulted in catalysts that afforded little to no asymmetric induction. Computational studies indicate that the carbene complexes of these dicopper and dicobalt complexes, unlike the dirhodium and diruthenium systems, are prone to the loss of carboxylate ligands, which would destroy the bowl-shaped structure critical for asymmetric induction.

Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.

PURPOSE: Preventing metastases by using perioperative interventions has not been adequately explored. Local anesthesia blocks voltage-gated sodium channels and thereby prevents activation of prometastatic pathways. We conducted an open-label, multicenter randomized trial to test the impact of presurgical, peritumoral infiltration of local anesthesia on disease-free survival (DFS). METHODS: Women with early breast cancer planned for upfront surgery without prior neoadjuvant treatment were randomly assigned to receive peritumoral injection of 0.5% lidocaine, 7-10 minutes before surgery (local anesthetics [LA] arm) or surgery without lidocaine (no LA arm). Random assignment was stratified by menopausal status, tumor size, and center. Participants received standard postoperative adjuvant treatment. Primary and secondary end points were DFS and overall survival (OS), respectively. RESULTS: Excluding eligibility violations, 1,583 of 1,600 randomly assigned patients were included in this analysis (LA, 796; no LA, 804). At a median follow-up of 68 months, there were 255 DFS events (LA, 109; no LA, 146) and 189 deaths (LA, 79; no LA, 110). In LA and no LA arms, 5-year DFS rates were 86.6% and 82.6% (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95; P = .017) and 5-year OS rates were 90.1% and 86.4%, respectively (HR, 0.71; 95% CI, 0.53 to 0.94; P = .019). The impact of LA was similar in subgroups defined by menopausal status, tumor size, nodal metastases, and hormone receptor and human epidermal growth factor receptor 2 status. Using competing risk analyses, in LA and no LA arms, 5-year cumulative incidence rates of locoregional recurrence were 3.4% and 4.5% (HR, 0.68; 95% CI, 0.41 to 1.11), and distant recurrence rates were 8.5% and 11.6%, respectively (HR, 0.73; 95% CI, 0.53 to 0.99). There were no adverse events because of lidocaine injection. CONCLUSION: Peritumoral injection of lidocaine before breast cancer surgery significantly increases DFS and OS. Altering events at the time of surgery can prevent metastases in early breast cancer (CTRI/2014/11/005228).[Media: see text].

High-grade transformation of adenoid cystic carcinoma of parotid gland with isolated intratemporal facial nerve involvement: a case report and literature review.

BACKGROUND: High-grade transformation Adenoid cystic carcinoma (HGT-AdCC) of the parotid gland is a rare transformation noted in slow growing low grade AdCC. Perineural invasion and spread is an important feature of this tumor. Temporal bone involvement is rare. A total of only 10 cases of HGT-AdCC in parotid gland has been reported in literature so far predominantly in the elderly with peak incidence in 5th-6th decade. CASE PRESENTATION: We present a young lady of HGT-AdCC of right parotid gland with temporal bone involvement in the form of isolated perineural invasion (PNI) of facial nerve till the tympanic segment. She underwent right radical parotidectomy with modified radical neck dissection with modified lateral temporal bone resection and pectoralis major myocutaneous flap reconstruction. Histopathological examination revealed both low- and high-grade areas. Sections from facial nerve showed tumor invasion. CONCLUSION: The radiological features of isolated perineural spread in intratympanic part of facial nerve can be easily missed if not specifically looked for. Every attempt should be made preoperatively and intraoperatively to determine the complete extent of the tumor for adequate disease clearance. A combined clinico-radiological approach aided by histopathology examination helps in early detection of this carcinoma and in better patient management.

Development of Cancer Care in Northeast India.

Northeast India, a region of geographic, cultural, and ethnic diversity comprises of Assam, Arunachal Pradesh, Manipur, Meghalaya, Mizoram, Tripura, and Sikkim. Geographically, two-thirds of the area is hilly terrain. The North Eastern Region (NER) shows marked diversity in customs, cultures, cuisines, traditions, and languages. The Aizawl district of Mizoram (269.4) and the Papumpare district of Arunachal Pradesh (219.8) have the highest age-adjusted incidence rates (AAR) of cancer among males and females, respectively. Meghalaya has the highest relative proportion of cancers associated with tobacco use, with 70.4% in men and 46.5% in women. This correlates with the high prevalence of tobacco use. The Dr Bhubaneswar Borooah Cancer Institute, Guwahati, was inaugurated in 1973. The Institute currently conducts M.Ch. Surgical Oncology, Head and Neck Oncology and Gynaecologic Oncology, and DM courses in Medical Oncology and Onco-pathology. The year 2019 saw the creation of a high-dose radioisotope therapy ward. Allogenic Bone Marrow Transplantation (BMT) was started in 2021-2022. State Cancer Institute (SCI), Guwahati, houses a medical cyclotron, which is the only one in Northeast India. Assam Cancer Care Foundation (ACCF) is a joint venture between the Government of Assam and the Tata Trusts, with a three-level cancer grid. The Cachar Cancer Hospital and Research Centre (CCHRC) offers holistic, subsidised cancer care to over 4000 new patients every year. North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS) offers endobronchial ultrasound (EBUS) and mediastinoscopy services, enabling accurate staging of lung cancers. While the cancer care facilities in NER have grown over the years, it is not commensurate with the high incidence of cancers in the region.

Study of Programmed Death Ligand 1 and EGFR/HER2 Expression in Non-Small-Cell Lung Carcinoma With a Clinicopathological Spectrum.

Non-small-cell lung carcinoma (NSCLC) is a disease characterized by the upregulation of programmed death ligand 1 (PD-L1) along with alterations in epidermal growth factor receptor (EGFR) and HER2-neu (HER2) amplification in addition to EGFR mutation. In the present study, the expression of PD-L1 and EGFR and HER2-neu in NSCLC was studied and their expression in relation to various clinicopathological parameters was analysed. We studied 49 core biopsy specimens of NSCLC for PD-L1, EGFR and HER2-neu expressions using immunohistochemistry. Scoring was based on the intensity and percentage of tumour cells expressing the immunomarkers. PD-L1, EGFR and HER2-neu expression was seen in 20.4%, 32.7% and 14.2% of NSCLC, respectively. The analysis showed no significant difference in PD-L1 expression in relation to any clinicopathological parameters. Low or negative EGFR expression was significantly associated with positive lymph node status (P=0.04). HER2-neu expression showed a significant difference in relation to tumour histology (adenocarcinoma; P=0.01). Also, there was no difference noted with PD-L1 expression in relation to EGFR and HER2-neu expression. As our study has a small number of cases, the validation of the predictive and prognostic value of these markers in lung cancer patients requires further studies.

High Magnetic Anisotropy of a Square-Planar Iron-Carbene Complex.

Among Earth-abundant catalyst systems, iron-carbene intermediates that perform C-C bond forming reactions such as cyclopropanation of olefins and C-H functionalization via carbene insertion are rare. Detailed descriptions of the possible electronic structures for iron-carbene bonds are imperative to obtain better mechanistic insights and enable rational catalyst design. Here, we report the first square-planar iron-carbene complex (MesPDPPh)Fe(CPh2), where [MesPDPPh]2- is the doubly deprotonated form of [2,6-bis(5-(2,4,6-trimethylphenyl)-3-phenyl-1H-pyrrol-2-yl)pyridine]. The compound was prepared via reaction of the disubstituted diazoalkane N2CPh2 with (MesPDPPh)Fe(thf) and represents a rare example of a structurally characterized, paramagnetic iron-carbene complex. Temperature-dependent magnetic susceptibility measurements and applied-field Mössbauer spectroscopic studies revealed an orbitally near-degenerate S = 1 ground state with large unquenched orbital angular momentum resulting in high magnetic anisotropy. Spin-Hamiltonian analysis indicated that this S = 1 spin system has uniaxial magnetic properties arising from a ground MS = ±1 non-Kramers doublet that is well-separated from the MS = 0 sublevel due to very large axial zero-field splitting (D = -195 cm-1, E/D = 0.02 estimated from magnetic susceptibility data). This remarkable electronic structure gives rise to a very large, positive magnetic hyperfine field of more than +60 T for the 57Fe nucleus along the easy magnetization axis observed by Mössbauer spectroscopy. Computational analysis with complete active space self-consistent field (CASSCF) calculations provides a detailed electronic structure analysis and confirms that (MesPDPPh)Fe(CPh2) exhibits a multiconfigurational ground state. The majority contribution originates from a configuration best described as a singlet carbene coordinated to an intermediate-spin FeII center with a (dxy)2{(dxz),(dz2)}3(dyz)1(dx2-y2)0 configuration featuring near-degenerate dxz and dz2 orbitals.

Expression of PDL1 and Her2neu in Gastric and Gastroesophageal Junction Adenocarcinoma.

The process of tumorigenesis in gastric carcinoma involves multiple genetic alterations including overexpression of PD-L1, amplification of Her2neu, and mutation of p53. In the present study, the expressions of PD-L1 and Her2neu were analyzed in relation to clinicopathological parameters including p53 in gastric and gastroesophageal junction adenocarcinoma. We examined 100 biopsy and resection samples of gastric and gastroesophageal junction carcinomas for PD-L1, Her2neu, and p53 protein expressions using immunohistochemistry. Scorings were done based on intensity and percentage of tumor cells expressing the markers. Follow-up and survival analyses were done wherever data was available. PD-L1 and Her2neu were seen in 37% and 38% respectively. The analysis showed PD-L1 expression was significantly associated with depth of invasion (p = 0.0007), nodal metastasis (p = 0.0003), and AJCC staging (p = 0.0085). Her2neu negative including equivocal expression was significantly associated with histological grading (p = 0.0043), Lauren classification (p = 0.0042), depth of invasion (p = 0.04), and nodal metastasis (p = 0.017). Combined analysis of PD-L1 and Her2neu showed significant association with histological grading (p = 0.017), Lauren classification (p = 0.005), depth of invasion (p = 0.0035), and nodal metastasis (p = 0.00073). Univariate Cox regression analysis showed that depth of invasion, nodal metastasis, distant metastasis, AJCC staging, and p53 were negative prognostic factors for patients' overall survival. In multivariate analysis, distant metastasis and Her2neu negativity including equivocal cases were independent prognostic factors. PD-L1 positivity was seen in cases with advanced pathological features, which suggest its role in the tumorigenesis of gastric and gastroesophageal junction adenocarcinoma. Her2neu positivity showed no correlation with advanced pathological features as well as no prognostic significance, which could be attributed to tumor heterogeneity, endoscopic nature of the biopsies, and non-confirmation of equivocal cases by fluorescent in situ hybridization.

Impact of COVID-19 on cancer care in India: a cohort study.

BACKGROUND: The COVID-19 pandemic has disrupted health-care systems, leading to concerns about its subsequent impact on non-COVID disease conditions. The diagnosis and management of cancer is time sensitive and is likely to be substantially affected by these disruptions. We aimed to assess the impact of the COVID-19 pandemic on cancer care in India. METHODS: We did an ambidirectional cohort study at 41 cancer centres across India that were members of the National Cancer Grid of India to compare provision of oncology services between March 1 and May 31, 2020, with the same time period in 2019. We collected data on new patient registrations, number of patients visiting outpatient clinics, hospital admissions, day care admissions for chemotherapy, minor and major surgeries, patients accessing radiotherapy, diagnostic tests done (pathology reports, CT scans, MRI scans), and palliative care referrals. We also obtained estimates from participating centres on cancer screening, research, and educational activities (teaching of postgraduate students and trainees). We calculated proportional reductions in the provision of oncology services in 2020, compared with 2019. FINDINGS: Between March 1 and May 31, 2020, the number of new patients registered decreased from 112 270 to 51 760 (54% reduction), patients who had follow-up visits decreased from 634 745 to 340 984 (46% reduction), hospital admissions decreased from 88 801 to 56 885 (36% reduction), outpatient chemotherapy decreased from 173634 to 109 107 (37% reduction), the number of major surgeries decreased from 17 120 to 8677 (49% reduction), minor surgeries from 18 004 to 8630 (52% reduction), patients accessing radiotherapy from 51 142 to 39 365 (23% reduction), pathological diagnostic tests from 398 373 to 246 616 (38% reduction), number of radiological diagnostic tests from 93 449 to 53 560 (43% reduction), and palliative care referrals from 19 474 to 13 890 (29% reduction). These reductions were even more marked between April and May, 2020. Cancer screening was stopped completely or was functioning at less than 25% of usual capacity at more than 70% of centres during these months. Reductions in the provision of oncology services were higher for centres in tier 1 cities (larger cities) than tier 2 and 3 cities (smaller cities). INTERPRETATION: The COVID-19 pandemic has had considerable impact on the delivery of oncology services in India. The long-term impact of cessation of cancer screening and delayed hospital visits on cancer stage migration and outcomes are likely to be substantial. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Eccrine Porocarcinoma with Squamous Differentiation in a Patient with Oculocutaneous Albinism.

Eccrine porocarcinoma is a rare malignant skin appendage tumor of sweat gland origin. Eccrine porocarcinoma arising in a patient of oculocutaneous albinism is extremely rare and only two cases have been reported in English literature to the best of our knowledge. Out of the two cases of eccrine porocarcinoma in oculocutaneous albinism, one case had squamous differentiation. We report a case of eccrine porocarcinoma with squamous differentiation in a 39-year-old male, who presented with a nodular lesion on the upper left chest wall. He also had nodal and distant cutaneous metastasis.

Calculation of a clinical predictive factors identifying peritoneal disease on a staging laparoscopy in gastric cancers.

INTRODUCTION: Staging laparoscopy (SL) is the current standard staging workup for loco-advanced gastric cancers (GCs). Materials and Methods: We analyzed the data of all patients with loco-regionally advanced, nonmetastatic GCs, who underwent SL for the evaluation of peritoneal carcinomatosis (PC). MATERIALS AND METHODS: We analyzed the data of all patients with loco-regionally advanced, nonmetastatic GCs, who underwent SL for the evaluation of peritoneal carcinomatosis (PC). RESULTS: Between December 2013 and October 2016, 363 patients underwent SL, of which 75 (20.7%) were found to have PC on SL. Age ≤40 years, CA 19-9 > upper limit of normal, and low serum albumin levels (≤3.5 g/dl) correlated significantly with the presence of PC on SL. There was a statistically significant difference in the median overall survival between patients with radiologically detected PC and SL detected PC (8.67 months vs. 15.3 months;P < 0.0001). CONCLUSION: SL upstaged disease status in 20.7% of patients. Clinical factors, identified in this study, need further validation in larger prospective cohorts before being used in clinical practice. Patients with radiologically detected PC have lower survival as compared to those with PC on SL.

Cancer chemotherapy drug wastage in a tertiary care hospital in India-A 3-month prospective and 1-year retrospective study.

This study prospectively quantified wastage of cancer chemotherapeutic drugs in an oncology unit to find the associated cost in 3 months. Retrospective analysis of drug usage for 12 months was also conducted to determine the expected drug loss in 1 year. The effect of vial sharing was evaluated under the assumption of sharing. A significant drug wastage of 19.72% (95% confidence interval [CI], 14.52-24.93%) in 3 months and 17.14% (95% CI 14.69-19.59%) in 1 year occurred in our oncology unit. Number of vials purchased (r = 0.362, p < 0.01), weight (r = -0.146, P < .01) and body surface area (r = -0.26, P < .01) correlated with the drug wasted. Vial sharing assumption showed a 9% (95% CI, 2.5-15.5%) reduction in cost in 1 year.

Synthesis and Catalytic Properties of Dirhodium Paddlewheel Complexes with Tethered, Axially Coordinating Thioether Ligands.

Novel mixed-ligand rhodium(II) paddlewheel complexes incorporating tethered axial thioether ligands have been synthesized and characterized. The thioether moiety is essential for high yields and the suppression of byproducts in cyclopropanation reactions using an electron-deficient diazoacetate. Crystal structures, UV-vis analysis, and cyclic voltammetry experiments shed light on the catalytic performance of the complexes.

Primary Extraskeletal Osteosarcoma Arising from the Optic Nerve: A Rare Case Report.

Orbital location of extraskeletal osteosarcoma is extremely rare with only 4 cases reported so far in the English literature. We present the case of a 32-year-old female who presented with proptosis and complete loss of vision of the left eye. Contrast-enhanced computed tomography scan showed a densely calcified lobulated lesion in the left optic nerve showing strong enhancement. A left fronto-occipito-zygomatic osteotomy was conducted and a greyish brown tumor was identified. Histopathological and immunohistochemical examination of the curetted material revealed it to be extraskeletal osteosarcoma. A left partial maxillectomy with ethmoidectomy and left orbital exenteration was done and the patient was advised chemotherapy with radiotherapy.

Roles of progesterone receptor membrane component 1 and membrane progestin receptor alpha in regulation of zebrafish oocyte maturation.

Although previous studies suggest membrane progesterone receptor alpha (mPRα/Paqr7) mediates 17, 20ß-dihydroxy-4-pregnen-3-one (DHP) induction of oocyte maturation (OM) in zebrafish, critical information needed to establish mPRα as the receptor mediating OM is lacking. The relative potencies of progestins and specific mPRα agonists in inducing OM matched their relative binding affinities for zebrafish mPRα, supporting its role in OM. Microinjection of pertussis toxin blocked DHP induction of OM and the progestin-induced decrease in cyclic AMP levels, suggesting mPRα activates an inhibitory G protein (Gi). Microinjection of morpholino antisense oligonucleotides to zebrafish pgrmc1 blocked induction of OM by DHP which was accompanied by decreased levels of Pgrmc1 and mPRα on the oocyte plasma membranes. Similarly, treatment of denuded oocytes with a PGRMC1 inhibitor, AG205, blocked the gonadotropin-induced increase in plasma membrane mPRα levels and attenuated DHP induction of OM. Co-incubation with two inhibitors of epidermal growth factor Erbb2, ErbB2 inhibitor II and AG 879, prevented induction of OM by DHP, indicating the likely involvement of Erbb2 in mPRα-mediated signaling. Treatment with AG205 reversed the inhibitory effects of the Erbb2 inhibitors on OM and also inhibited insulin-like growth factor-1 induction of OM. Close associations between Pgrmc1 and mPRα, and between Pgrmc1 and Erbb2 were detected in zebrafish oocytes with in situ proximity ligation assays. The results suggest progestin induction of OM in zebrafish is mediated through an mPRα/Gi/Erbb2 signaling pathway that requires Pgrmc1 for expression of mPRα on oocyte membranes and that Pgrmc1 also is required for induction of OM through Erbb2.