Pembrolizumab as a first line therapy in a patient with extensive mucoepidermoid salivary gland carcinoma. A complete clinical, radiological and pathological response. A very specific case.

BACKGROUND: Patients with advanced salivary gland malignancies (SGCs) have few therapy options. Although results from newly published trials suggest that checkpoint inhibition may be useful in a subgroup of patients, there are no clear criteria for PD-L1 score in SGCs. Chemotherapy benefits were observed to be limited, with a dismal prognosis in unresectable and high-grade SGC. Immunotherapies have demonstrated extraordinary efficacy in a variety of cancers, including non-small cell lung cancer and malignant melanoma. Anti-PD-1 antibody pembrolizumab has been shown to have potent anti-tumor action in a number of clinical trials. CASE PRESENTATION: We report a unique case of advanced high grade mucoepidermoid carcinoma of the parotid salivary gland after Pembrolizumab treatment as a first line therapy. The tumor was downstaged as a result of the pembrolizumab treatment, allowing for a successful surgical excision with no facial nerve sacrifice and no major neoadjuvant treatment adverse effects, and the final specimen pathology was tumor-free. In these types of malignancies, a similar technique resulted in a complete response (CR) radiologically and pathologically has never been discussed before. CONCLUSIONS: In pretreated patients with high-grade salivary gland mucoepidermoid carcinoma, pembrolizumab showed good anticancer activity and provided a clinically, radiologically, and pathological response with a viable treatment choice. More research is needed to bring Pembrolizumab to the front-line of treatment. The time and duration of medication should be compared to the time required for surgery in these investigations.

Novel Totally Laparoscopic Endolumenal Rectal Resection With Transanal Natural Orifice Specimen Extraction (NOSE) Without Rectal Stump Opening: A Modification of Our Recently Published Clean Surgical Technique in a Porcine Model.

Our group has recently described a novel technique for clean endolumenal bowel resection, in which abdominal and transanal approaches were used. In the current study, 2 modifications of this procedure were tested for feasibility in a porcine model. A laparoscopic approach to the peritoneal cavity was employed in rectal mobilization; this was followed by a transanal rectorectal intussusception and pull-through (IPT). IPT was established in a stepwise fashion. First, the proximal margin of resection was attached to the shaft of the anvil of an end-to-end circular stapler with a ligature around the rectum. Second, this complex was pulled transanally to produce IPT. Once IPT was established, a second ligature was placed around the rectum approximating the proximal and distal resection margins. This was followed by a purse string suture through 2 bowel walls, encircling the shaft of the anvil just proximal to the ligatures. The specimen was resected and extracted by making a full-thickness incision through the 2 bowel walls distal to the previously placed purse string suture and ligatures. The anastomosis was achieved by applying the stapler. The technique was found to be feasible. Peritoneal samples, collected after transanal specimen extraction, did not demonstrate bacterial growth. Although, this is a novel and evolving procedure, its minimally invasive nature, as well as aseptic bowel manipulation during endolumenal rectal resection, has the potential to limit the complications associated with abdominal wall incision and surgical site infection.

Acute urinary retention in an adolescent as the presenting symptom of lichen sclerosus et atrophicus.

BACKGROUND: A rare case of acute urinary retention caused by labial fusion in an adolescent is described and the possible causes are discussed. CASE: A 17-year-old girl, not sexually active, presented to our emergency service for acute urinary retention. Genital examination revealed labia minora fusion from the clitoris to the vaginal fourchette; urethra, and clitoris were not visualized. Sexual abuse and trauma were excluded. The labia minora were manually separated in the operating room revealing a normal vagina and urethral meatus. Skin biopsies taken from the fused labia minora revealed Lichen Sclerosus et Atrophicus. SUMMARY AND CONCLUSION: Urinary retention may be seen in the face of complete adhesion of the labia minora, a rare event in postpubertal individuals. In such cases, a suspicion of underlying pathology such as asymptomatic Lichen Sclerosus should be raised and be confirmed by a biopsy.

Endolumenal rectal resection and transanal natural orifice specimen extraction (NOSE) without rectal stump opening: a novel, clean surgical technique in a porcine model.

Minimally invasive surgery has been continuously evolving over the past 20 years. The use of natural orifice specimen extraction (NOSE) is one of the most recent contributions to minimally invasive methods. The anus has been widely used in NOSE procedures. However, an open rectal stump carries the highest risk of contamination compared with other translumenal approaches to the peritoneal cavity. In this study, the feasibility of a novel NOSE method was tested in a porcine model. This technique combined abdominal and transanal approaches. The abdominal approach was used in rectal mobilization; this was followed by a transanal recto-rectal intussusception and pull-through (IPT). IPT was established in a stepwise fashion. First, the proximal margin of resection was attached to the shaft of the anvil of an end-to-end circular stapler with a ligature around the rectum. Second, this complex was pulled transanally to produce IPT. Once IPT was established, a second ligature was placed around the rectum, approximating the proximal and distal resection margins. The specimen was resected and extracted by making a full-thickness incision through 2 bowel walls distal to the previously placed ligatures. Anastomosis was achieved by applying the stapler. The technique was found to be feasible. A substantial length of bowel was resected in all experiments. Peritoneal samples, collected after transanal specimen extraction, did not demonstrate bacterial growth. Although more investigation is warranted, this procedure has the potential to limit surgical site infections by using aseptic bowel manipulation during colorectal resection and transanal specimen extraction.

Lack of HER-2 gene amplification in non-Hodgkin lymphoma using chromogenic in situ hybridisation test.

HER-2 is overexpressed in 25% of breast cancers and provides a poor prognostic factor, affecting treatment decisions including administration of trastuzumab. Single reports show a lack of HER-2 in non-Hodgkin lymphomas (NHLs) using immunohistochemical (IHC) test. The present study evaluates HER-2 in NHLs using the chromogenic in situ hybridisation (CISH) test, which is more accurate than IHC, to seek new prognostic factors. The secondary aim of the study is to investigate efficacy of using trastuzumab in the treatment of NHLs in future studies. Fifty eight formalin-fixed, paraffin-embedded tissue specimens presenting various NHLs were examined using CISH test. Sixty six percent of all patients were diagnosed at stages III and IV. Histologically, 30 (52%) were low grade and 28 (48%) were intermediate and high grade. HER-2 was negative in all NHLs. Because there is no HER-2 gene amplification in NHL, HER-2 cannot be used as a prognostic factor and should not play a role in biological targeting therapy in non-Hodgkin lymphoma.

Orlistat reverse fatty infiltration and improves hepatic fibrosis in obese patients with nonalcoholic steatohepatitis (NASH).

Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0-3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAic remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.

The beneficial effect of aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of cirrhosis.

The aim of this study was to examine the effect of the antithrombotic drugs aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of liver cirrhosis and to determine if these two drugs are beneficial in animals with advanced fibrosis or with established cirrhosis undergoing partial hepatectomy. Thioacetamide-induced cirrhotic rats received saline (N=10), aspirin (N=7), or enoxaparin (N=11) for a 5-week treatment period. Hepatic fibrosis was assessed according to METAVIR score. Liver regeneration was monitored using PCNA immunostaining. Compared to untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the aspirin (43%; chi(2)=54, P<0.001) and enoxaparin (36%; chi(2)=43, P<0.001) treated groups. Postoperatively, total serum bilirubin levels were lower in the aspirin (1.4+/-0.18 mg/dl; P<0.01) and enoxaparin (1.8+/-0.35 mg/dl; P<0.05)-treated groups compared to untreated cirrhotic controls (3.2+/-0.6 mg/dl). Hepatic regenerative activity was significantly improved in the aspirin group (57.3%+/-6.8%, versus 34.2%+/-7.2% in untreated cirrhotic controls; P<0.01) but unchanged in the enoxaparin group. We conclude that aspirin and enoxaparin hold promise as a useful therapy for patients with extensive fibrosis.

Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease.

AIM: To assess whether treatment with insulin-sensitizing agents (ISAs) in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet (MCDD) rat model of non-alcoholic fatty liver disease (NAFLD). METHODS: Rats (n = 6 per group) were treated with different drugs, including MCDD only, MCDD diet with either metformin (200 mg/kg), rosiglitazone (3 mg/kg), metformin plus rosiglitazone (M+R), ezetimibe (2 mg/kg), valsartan (2 mg/kg), or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS: Fatty liver (FL) rats demonstrated severe hepatic fatty infiltration (> 91% fat), with an increase in hepatic TG (+ 1263%, P < 0.001), hepatic cholesterol (+ 245%, P < 0.03), hepatic MDA levels (+ 225%, P < 0.001), serum TNF-alpha (17.8 +/- 10 vs 7.8 +/- 0.0, P < 0.001), but a decrease in hepatic alpha tocopherol (-74%, P<0.001) as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis (-54%), hepatic TG (-64%), hepatic cholesterol (-31%) and hepatic MDA (-70%), but increased hepatic alpha tocopherol (+ 443%) as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis (-32% vs -54%, P < 0.001) and in hepatic MDA levels (-55% vs -70%, P < 0.01), but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION: Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.

An immunohistochemical study of the secretory immune system in human fetal membranes and decidua of the first trimester of pregnancy.

PROBLEM: We analyzed the presence and distribution of components of the secretory immune system (SIS) in human fetal membranes (amnion, yolk sac, chorion) and decidua from the first trimester of pregnancy. MATERIALS AND METHODS: Specimens from 17 embryos (4-8 weeks of pregnancy) and nine fetuses (9-12 weeks) were divided into those that had not been exposed to massive foreign antigenic effects (Group I, n = 18) and those that had suffered acute chorioamnionitis (Group II, n = 8). RESULTS: Positive immunostaining for secretory component (SC), joining (J) chain, IgG, IgA, and macrophages was seen from 4 to 5 weeks of development and then during the whole first trimester of pregnancy in the syncytio- and cytotrophoblasts, the amniotic epithelium, the yolk sac endoderm and decidual cells. Macrophages with J chain, IgG and IgA were found in embryonic tissues on week 4, whereas lymphocytes, including those synthesizing IgA and IgM, appeared only at the end of the first trimester of pregnancy. In the decidua, lymphocytes and macrophages were recognized during the whole period of study. In cases with chorioamnionitis (Group II), reactivity of IgG and IgA in the mentioned cells of fetuses decreased sharply while the rate of immunoreactivity of SC and J chain as well as the number of T and B lymphocytes did not change. In the decidua, the number of immune reactive cells sharply increased with the appearance of plasma cells. CONCLUSIONS: In the fetal membranes and decidua all the SIS components are present. We suggest that two SIS, maternal and fetal, participate in the formation of the barrier between a mother and the fetus. Both these systems have different origin and cellular content as well as different immune reactions.

Secretory immune system in human intrauterine development: immunopathomorphological analysis of the role of secretory component (pIgR/SC) in immunoglobulin transport (review).

Several proteins, such as polymeric immunoglobulin (Ig) receptor/secretory component (pIgR/SC), immunoglobulins (Igs) and joining (J) chain, and cellular components of the secretory immune system (SIS) of the human embryo and fetus were analyzed and compared with reviewed information concerning SIS organization and function. All organs and structures, including extracorporeal ones, of 18 embryos (4-8 weeks of development) and 45 fetuses (9-38 weeks) were studied using methods of pathomorphology, immunohistochemistry and morphometry. This approach enabled us to analyze the problem in the whole organism during its entire development. SC, Igs and J chain were already widely distributed in 4-week-old embryos and were later seen in the mucosa and glands of the digestive, respiratory and urogenital tracts, ovaries, testis, endocrine glands, extracorporeal tissues, blood-brain and other blood-organ barrier structures, as well as in serous membranes. The presence of protein transport and later of cellular components suggests an active role for SIS not only in mucous membranes, but also in blood-tissue barriers. Loss of morphological contact between epithelial structures and mucous membranes during organogenesis of some endocrine organs (hypophysis, pancreatic islets, etc.) is followed by the disappearance of SC as a result of cessation of Ig exocytosis. Secretion of Igs increased in the epithelium and glands of the digestive and respiratory tracts following massive antigenic attack in cases of acute chorioamnionitis. All of this demonstrates that SIS is a widely branching immune system which appears and acts early in the human embryo, before the lymphoid system is formed, using IgG and IgA of maternal origin. IgA and IgM-synthesized lymphocytes appear in 9-week-old fetuses.

Secretory component, J chain, and immunoglobulins in human embryos and fetuses of the first trimester of pregnancy: immunohistochemical study.

In our previous studies, we described the development of the secretory (mucosal) immune system (SIS) in human fetuses in the second trimester of pregnancy. In the present study, we examined the presence and distribution of components of this system in human embryos and early fetuses in the first trimester. An immunohistochemical study was performed on 17 embryos and 9 fetuses (4 to 12 wk of development) using antibodies against secretory component (SC), joining (J) chain, immunoglobulins (IgA, IgM, IgG), subsets of T and B lymphocytes, and macrophages. Cells positive for SC, J chain, and IgG were found in epithelial tissues from wk 4 of pregnancy. In the internal organs, such as the myocardium and endocardium, capillary endothelium, epithelium of the kidney tubules and some others, only J chain and immunoglobulins were seen. IgA was weakly reactive in tissues where SC and/or J chain were presented. IgM was very weak or absent. Among the cellular components of the SIS, only macrophages were seen in 4-wk-old embryos. CD3+ and CD20+ lymphocytes were found at wk 7 to 8. IgA- and IgM-positive lymphocytes appeared at the end of wk 9. The SIS is widespread in embryonic and early fetal periods and begins to function before the appearance of the common immune system in the developing organism. The first functional components of the SIS, such as IgG and IgA observed in this study, are most probably of maternal origin.

Liver regeneration is not altered in patients with nonalcoholic steatohepatitis (NASH) when compared to chronic hepatitis C infection with similar grade of inflammation.

Fatty infiltration is associated with an increased incidence of complications and mortality after liver resection and transplantation. The aim of this study was to document the regenerative response in patients with hepatic steatosis and mild inflammatory activity (NASH) and to identify potential levels of impaired regeneration. Ki-67 immunostaining was similar in patients with NASH (ages 44.6 +/- 15 years, labeling index, 0.4 +/- 0.3%) when compared to patients with chronic hepatitis C infection (ages 50.7 +/- 17 years, labeling index; 0.4 +/- 0.7%). The labeling index was not increased in patients with a higher level of inflammation, a higher level of fibrosis, and a higher level of fat in either study group. In conclusion, liver regeneration is not altered in patients with nonalcoholic steatohepatitis, suggesting that the delayed postoperative liver failure seen in these patients may be related to another mechanism.

Lymphoid-epithelial secretory immune system in human fetuses in the second trimester of gestation.

The development of the secretory immune system (SIS) in the respiratory, digestive, and urogenital tracts and other organs of fetuses in the second trimester of gestation is described. Tissues of all internal organs of human fetuses (n = 36) that had died between 13 and 25 weeks of gestation were studied immunohistochemically for the presence of secretory component (SC), J chain, IgA, IgM, IgG, macrophages, and different subsets of lymphocytes. We found protein elements of the SIS in fetuses during the entire second trimester in the epithelium of the digestive, respiratory, and urinary tracts; in hepatocytes; in the epithelium of the bile duct, renal tubules, and all the urinary tract; in the salivary glands, pancreas, and thyroid; in the epithelium of the Fallopian tubes and uterus; in the epididymis and the rete testes; in the skin; and in other organs. Immunocompetent cells, including IgA- and IgM-secreting cells, were located in these organs under the epithelium and sometimes between epithelial cells. In fetuses with acute infection, the number of immunocompetent cells was higher, reflecting a whole-immune system reaction, including the SIS. We conclude that the fetal SIS is a ramified, defensive immune system that is distributed throughout most organs of epithelial origin in second-trimester fetuses, and that it reacts against intrafetal infiltration by foreign antigens.