Risk factors and outcomes of conversion in minimally invasive distal pancreatectomy: a systematic review.

PURPOSE: The reported conversion rates for minimally invasive distal pancreatectomy (MIDP) range widely from 2 to 38%. The identification of risk factors for conversion may help surgeons during preoperative planning and patient counseling. Moreover, the impact of conversion on outcomes of MIDP is unknown. METHODS: A systematic review was conducted as part of the 2019 Miami International Evidence-Based Guidelines on Minimally Invasive Pancreas Resection (IG-MIPR). The PubMed, Cochrane, and Embase databases were searched for studies concerning conversion to open surgery in MIDP. RESULTS: Of the 828 studies screened, eight met the eligibility criteria, resulting in a combined dataset including 2592 patients after MIDP. The overall conversion rate was 17.1% (range 13.0-32.7%) with heterogeneity between studies associated with the definition of conversion adopted. Only one study divided conversion into elective and emergency conversion. The main indications for conversion were vascular involvement (23.7%), concern for oncological radicality (21.9%), and bleeding (18.9%). The reported risk factors for conversion included a malignancy as an indication for surgery, the proximity of the tumor to vascular structures in preoperative imaging, higher BMI or visceral fat, and multi-organ resection or extended resection. Contrasting results were seen in terms of blood loss and length of stay in comparing converted MIDP and completed MIDP patients. CONCLUSION: The identified risk factors for conversion from this study can be used for patient selection and counseling. Surgeon experience should be considered when contemplating MIDP for a complex patient. Future studies should divide conversion into elective and emergency conversion.

The role of older age and obesity in minimally invasive and open pancreatic surgery: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The aim of this study was to assess the impact of older age (≥70 years) and obesity (BMI ≥30) on surgical outcomes of minimally invasive pancreatic resections (MIPR). Subsequently, open pancreatic resections or MIPR were compared for elderly and/or obese patients. METHODS: A systematic review was conducted as part of the 2019 Miami International Evidence-Based Guidelines on MIPR (IG-MIPR). Study quality assessment was according to The Scottish Intercollegiate Guidelines Network (SIGN). A meta-analysis was performed to assess the impact of MIPR or open pancreatic resections in elderly patients. RESULTS: After screening 682 studies, 13 observational studies with 4629 patients were included. Elderly patients undergoing laparoscopic distal pancreatectomy (LDP) had less blood loss (117 mL, p < 0.001) and a shorter hospital stay (3.5 days p < 0.001) than elderly patients undergoing open distal pancreatectomy (ODP). Postoperative pancreatic fistula (POPF) B/C, major complication and reoperation rate were not significantly different in elderly patients undergoing either laparoscopic or open pancreatoduodenectomy (OPD). One study compared robot PD with OPD in obese patients, indicating that patients with robotic surgery had less blood loss (mean 250 ml vs 500 ml, p = 0.001), shorter operative time (mean 381 min vs 428 min, p = 0.003), and lower rate of POPF B/C (13% vs 28%, p = 0.039). CONCLUSION: The current available limited evidence does not suggest that MIPR is contraindicated in elderly or obese patients. Additionally, outcomes in MIPR are equal or more beneficial compared to the open approach when applied in these patient groups.

Validation of a nomogram to predict the risk of cancer in patients with intraductal papillary mucinous neoplasm and main duct dilatation of 10 mm or less.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is premalignant pancreatic lesion. International guidelines offer limited predictors of individual risk. A nomogram to predict individual IPMN malignancy risk was released, with good diagnostic performance based on a large cohort of Asian patients with IPMN. The present study validated a nomogram to predict malignancy risk and invasiveness of IPMN using both Eastern and Western cohorts. METHODS: Clinicopathological and radiological data from patients who underwent pancreatic resection for IPMN at four centres each in Eastern and Western countries were collected. After excluding patients with missing data for at least one malignancy predictor in the nomogram (main pancreatic duct diameter, cyst size, presence of mural nodule, serum carcinoembryonic antigen and carbohydrate antigen (CA) 19-9 levels, and age). RESULTS: In total, data from 393 patients who fit the criteria were analysed, of whom 265 were from Eastern and 128 from Western institutions. Although mean age, sex, log value of serum CA19-9 level, tumour location, main duct diameter, cyst size and presence of mural nodule differed between the Korean/Japanese, Eastern and Western cohorts, rates of malignancy and invasive cancer did not differ significantly. Areas under the receiver operating characteristic (ROC) curve values for the nomogram predicting malignancy were 0·745 for Eastern, 0·856 for Western and 0·776 for combined cohorts; respective values for the nomogram predicting invasiveness were 0·736, 0·891 and 0·788. CONCLUSIONS: External validation of the nomogram showed good performance in predicting cancer in both Eastern and Western patients with IPMN lesions.

ANTECEDENTES: La neoplasia mucinosa papilar intraductal (intraductal papillary mucinous neoplasm, IPMN) es una lesión pancreática premaligna. Las guías internacionales incluyen un número limitado de factores predictivos de riesgo individual. Para predecir el riesgo individual de malignidad del IPMN se ha propuesto un nomograma con un buen rendimiento diagnóstico, basado en una gran cohorte de pacientes asiáticos con IPMN. Este estudio validó el nomograma para predecir el riesgo de cáncer y de invasión de la IPMN utilizando cohortes tanto orientales como occidentales. MÉTODOS: Se recogieron datos clínico-patológicos y radiológicos de pacientes en los que se realizó una resección de páncreas por IPMN en 4 centros en países orientales y en 4 centros de países occidentales. Se excluyeron los pacientes en los que en el nomograma faltaba ≥ 1 factor(es) predictivo(s) de malignidad (diámetro del conducto pancreático principal, tamaño del quiste, presencia de nódulo mural, niveles séricos de CEA y CA19-9, y edad). RESULTADOS: En total, se analizaron datos de 393 pacientes que cumplían con los criterios de inclusión, de los cuales 265 eran de centros orientales y 128 de centros occidentales. Aunque la edad media, el sexo, el valor logarítmico del nivel sérico de CA19-9, la localización del tumor, el diámetro del conducto principal, el tamaño del quiste y la presencia de un nódulo mural difirieron entre las cohortes de Corea/Japón y las cohortes oriental y occidental, las tasas de malignidad y de cáncer invasivo no fueron significativamente diferentes. Las áreas bajo la curva operativa del receptor (area under the receiver operating curve, AUC) que mostró el nomograma para predecir la malignidad fueron: cohorte oriental: 0,745; cohorte occidental: 0,856 y cohortes combinadas: 0,776; y para predecir la invasión tumoral fueron: cohorte oriental: 0,736; cohorte occidental: 0,891, y cohortes combinadas: 0,788. CONCLUSIÓN: La validación externa del nomograma mostró un buen rendimiento en la predicción de cáncer, tanto en pacientes orientales como occidentales con lesiones IPMN.

Transforming growth factor-ß regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM.

Recent studies indicate that a subset of cancer cells possessing stem cell properties, referred to as cancer-initiating or cancer stem cells (CSCs), have crucial roles in tumor initiation, metastasis and resistance to anticancer therapies. Transforming growth factor (TGF)-ß and their family members have been implicated in both normal (embryonic and somatic) stem cells and CSCs. In this study, we observed that exposure to TGF-ß increased the population of breast cancer (BC) cells that can form mammospheres in suspension, a feature endowed by stem cells. This was mediated by the micro (mi)RNA family miR-181, which was upregulated by TGF-ß at the post-transcriptional level. Levels of the miR-181 family members were elevated in mammospheres grown in undifferentiating conditions, compared with cells grown in two-dimensional conditions. Ataxia telangiectasia mutated (ATM), a target gene of miR-181, exhibited reduced expression in mammospheres and upon TGF-ß treatment. Overexpression of miR-181a/b, or depletion of ATM or its substrate CHK2, was sufficient to induce sphere formation in BC cells. Finally, knockdown of ATM enhanced in vivo tumorigenesis of the MDA361 BC cells. Our results elucidate a novel mechanism through which the TGF-ß pathway regulates the CSC property by interfering with the tumor suppressor ATM, providing insights into the cellular and environmental factors regulating CSCs, which may guide future studies on therapeutic strategies targeting these cells.

H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3.

Hyperactivation of phosphatidylinositol-3 kinase (PI3K) can occur as a result of somatic mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The HER2 oncogene is amplified in 25% of all breast cancers and some of these tumors also harbor PIK3CA mutations. We examined mechanisms by which mutant PI3K can enhance transformation and confer resistance to HER2-directed therapies. We introduced the PI3K mutations E545K and H1047R in MCF10A human mammary epithelial cells that also overexpress HER2. Both mutants conferred a gain of function to MCF10A/HER2 cells. Expression of H1047R PI3K, but not E545K PI3K, markedly upregulated the HER3/HER4 ligand heregulin (HRG). HRG siRNA inhibited growth of H1047R but not E545K-expressing cells and synergized with the HER2 inhibitors trastuzumab and lapatinib. The PI3K inhibitor BEZ235 markedly inhibited HRG and pAKT levels and, in combination with lapatinib, completely inhibited growth of cells expressing H1047R PI3K. These observations suggest that PI3K mutants enhance HER2-mediated transformation by amplifying the ligand-induced signaling output of the ErbB network. This also counteracts the full effect of therapeutic inhibitors of HER2. These data also suggest that mammary tumors that contain both HER2 gene amplification and PIK3CA mutations should be treated with a combination of HER2 and PI3K inhibitors.

Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators.

Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) beta1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-beta1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-alpha and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-beta-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-beta signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.

Combined characterization of composite tabular silver halide microcrystals by cryo-EFTEM/EELS and cryo-STEM/EDX techniques.

The combination of cryo-energy filtering transmission electron microscopy (EFTEM)/electron spectroscopic diffraction (ESD)/electron energy-loss spectroscopy (EELS) and cryo-energy-dispersive X-ray (EDX) analysis in the scanning transmission (STEM) and scanning (SEM) modes was applied for the characterization of composite tabular Ag(Br,I) microcrystals. A low-loss fine structure in EEL spectra between 4 and 26 eV was attributed to excitons and plasmons possibly superimposed with interband transitions and many-electron effects. The contrast tuning under the energy-filtering in the low-loss region was used to image the crystal morphology, defect structure (random dislocations and ¿111¿ stacking faults) and bend and edge contours as well as electron excitations in the microcrystals. Sharp extra reflections at commensurate positions in between the main Bragg reflections and diffuse honeycomb contours in ESD patterns of the microcrystals taken near the [111] zone were assigned to the number of defects in the shell region parallel to the grain edges and polyhedral clusters of interstitial silver cations, respectively. The imaginary part of the energy-loss function, Im (-1/epsilon), and the real and imaginary parts, epsilon1 and epsilon2, of the dielectric permittivity were determined by means of a Kramers-Kronig analysis. An assignment of exciton peaks based on calculations of electronic band structure of silver bromide is proposed. Inner-shell excitation bands of silver halide were detected in line with EDX-analyses. The energy-loss near-edge structure (ELNES) of the AgM4,5-edge governed by spin-orbital splitting between the 3d3/2- and 3d5/2-states has been evaluated. Combined silver and halide distributions were obtained by a three-window method (EFTEM) and by EDX/STEM including area mapping and line profiling of iodide.

Cervical cytologic smear false negative fraction. Reduction in a small community hospital.

OBJECTIVE: To determine the false negative fraction (FNF) at a small community hospital and its relation to the discovery of a significant error. STUDY DESIGN: All cervical cytologic smears (6,889) initially interpreted over a one-year period (1992) as "normal" or "near normal" were retrospectively rescreened and interpreted by outside institutions, without knowledge of the initial interpretation, to calculate yearly and quarterly FNFs. RESULTS: The overall FNF for 1992 was 12.3% and was 19.1%, 22.2%, 3.8% and 6.1% per successive quarters in 1992. A significant error was discovered at the start of the third quarter that subsequently received both local and national media attention. CONCLUSION: This study gives further proof that the FNF can be reduced to < 5% by motivated cytotechnologist/ pathologist teams, although it may not be possible to maintain this low an FNF.

Changes in phrenic, hypoglossal and recurrent laryngeal nerve activities after intravenous infusions of aminophylline in cats.

Aminophylline is known to have respiratory stimulant properties, and it has been suggested that it may also be effective in sleep apnoea. However, its role in this disorder remains uncertain. Theoretically, increasing upper airway motoneural activity in order to maintain airway patency might alleviate obstructive sleep apnoea. On the other hand, increasing the respiratory drive may also prove beneficial in treating central sleep apnoea. In these studies, we attempted to determine the effect of aminophylline on neural activities of the upper airway and diaphragm. We administered intravenously either a low dose (4 mg.kg-1) or a high dose (16 mg.kg-1) of aminophylline to decerebrated, vagotomized and paralysed cats, and continuously recorded the phrenic hypoglossal and recurrent laryngeal nerve activities for 3 h. Results showed that a high dose of aminophylline induced a marked increase in phrenic nerve activity, but not hypoglossal or recurrent laryngeal nerve activity. In a group treated with a low dosage of aminophylline, a significant increase of activity was found in all three nerves. Furthermore, phrenic nerve activity increased more with a high dose than with a low dose. We confirmed that aminophylline has dose-dependent and selective effects on respiratory neural activity. A low dose acts on the upper airway and diaphragm, but a high dose induces a marked increase in central respiratory drive. According to our results, low dose aminophylline might be beneficial in obstructive sleep apnoea, whereas, a high or low dose might improve some cases of central sleep apnoea.

Fine needle aspiration diagnosis of orbital plasmacytoma with amyloidosis. A case report.

Fine needle aspiration (FNA) cytology of the orbit was used to diagnose an unusual case of multiple myeloma with secondary amyloid deposition in a 27-year-old man who presented with bilateral keratoconjunctivitis and left-sided ptosis. The FNA smears revealed immature plasma cells, extracellular eosinophilic material (amyloid) and numerous multinucleate giant cells. Subsequent histologic studies of excised tissue confirmed the cytologic diagnosis of plasmacytoma with secondary amyloidosis. Amyloid was further confirmed by electron microscopy. The patient was subsequently diagnosed as having multiple myeloma. The cytologic features of amyloidosis and plasmacytoma are presented. The differential diagnosis and the diagnostic utility of FNA cytology in the evaluation of these orbital lesions are also discussed. This apparently was the first case of orbital amyloidosis diagnosed by FNA cytology.

Mucin-positive epithelial mesothelioma.

Mucin-positive epithelial mesothelioma is a rare, frequently unrecognized entity that should not be misinterpreted as metastatic adenocarcinoma, as each is associated with differing treatment and prognosis. Presented herein is a case of an acidic and neutral mucin-positive papillary mesothelioma of the right pleura, with cytologic, histologic, histochemical, immunohistochemical, and ultrastructural evaluation.

Primary nasal amelanotic melanoma: MR appearance.

The appearance on magnetic resonance (MR) images of a primary amelanotic malignant melanoma of the nasopharynx is reported. The factors affecting the MR appearance of melanomas of the head and neck are reviewed. The case is compared with a previously reported case of primary nasopharyngeal melanotic melanoma, and the importance of considering the tumor in all nasopharyngeal neoplasms is emphasized.

Complete response of carcinosarcoma of the ovary to therapy with doxorubicin, ifosfamide, and dacarbazine.

Although carcinosarcoma occurs in various locations throughout the body, it rarely originates in the ovary. Chemotherapy has been minimally beneficial. This case describes a patient with carcinosarcoma of the ovary who responded minimally to chemotherapy used for epithelial carcinomas but had a complete response after receiving chemotherapy used for sarcomas. The patient relapsed within 1 year after receiving cisplatin therapy. She was treated with mesna, ifosfamide, Adriamycin, and dacarbazine (MAID) chemotherapy and after one cycle of chemotherapy she had no evidence of tumor. She has received six cycles of chemotherapy without evidence of progression 13+ months since beginning MAID therapy. MAID chemotherapy may be useful in the treatment of carcinosarcoma of the ovary.

Case report 654: Disseminated tuberculosis.

A case of disseminated tuberculosis with a psoas abscess and associated destruction of bone in a 28-year-old man has been presented. Multiple skeletal lesions and hilar adenopathy were observed. The initial diagnosis from pathological specimens was equivocal, since acid-fast bacilli were not demonstrated. However, special stains of biopsy specimens subsequently confirmed the diagnosis. The initial radiographs suggested disseminated malignancy. Good therapeutic results were obtained, utilizing surgical and chemotherapeutic methods. This case demonstrates the ability of disseminated tuberculosis to mimic other disease processes and shows the difficulty that may exist in establishing a diagnosis of tuberculosis, even with biopsy specimens.

Flow cytometric S fraction as a predictor of clinical outcome in cystosarcoma phyllodes.

Clinicopathologic characteristics were evaluated in 20 cases of cystosarcoma phyllodes in relation to clinical outcome. Flow cytometric DNA studies were carried out in 15 of these 20 cases. Stromal overgrowth and an infiltrating tumor border emerged as prominent histopathologic features that were associated with an unfavorable clinical outcome. Flow cytometric S fractions greater than 0.05 were associated with poor clinical outcome. There was no correlation between tumor ploidy and clinical outcome. There were no direct correlations between clinicopathologic features and flow cytometric measurements. Our data suggest that flow cytometric S fractions may be a useful predictor of clinical outcome in cystosarcoma phyllodes that can complement the traditional histologic analysis of these rare breast tumors.

Dermatophilus congolensis and "hairy" leukoplakia.

The authors report the first human case (to our knowledge) of infection of the oral mucosa by Dermatophilus congolensis. Septate branching filaments morphologically identical to those of D. congolensis were identified in the lingual epithelium of a male homosexual employed as an animal handler. This actinomycete is the cause of dermatophilosis, a proliferative exudative dermatitis affecting many animal species. Clinical features suggested "hairy" leukoplakia (HL), a hyperkeratotic tongue lesion for which human papillomavirus (HPV) and Epstein-Barr virus (EBV) have been implicated as etiologic agents. Immunoperoxidase staining for HPV capsid antigen was negative. Direct immunofluorescent staining with a conjugate specific for D. congolensis identified the bacterial structures as those of this species while excluding morphologically similar organisms.

Fine needle aspiration cytology of sclerosing hemangioma of the lung, a mimicker of bronchioloalveolar carcinoma.

A rare "sclerosing hemangioma" of the lung in a 24-year-old man was initially interpreted as a bronchioloalveolar carcinoma by fine needle aspiration (FNA) cytology. The similarity of these two tumors in fine needle aspirates is discussed. Benign sclerosing hemangioma should be considered in the differential diagnosis when numerous atypical proliferating bronchiolar or alveolar cells are obtained by FNA.