The value of surgical staging in patients with apparent early stage epithelial ovarian carcinoma.

OBJECTIVE: The value of surgical staging of apparent early stage epithelial ovarian carcinoma (EOC) is unclear. The aim of this study was to evaluate the importance of surgical staging on the stage of disease and treatment plan. MATERIAL AND METHODS: All patients with apparent stage I EOC undergoing staging from 01/01/2005 to 30/06/2017 in all Danish hospitals and in the Radboud University Hospital Nijmegen, the Netherlands, were evaluated to identify the pathological findings responsible for upstaging and changes in treatment plans. RESULTS: We included 1234 patients with apparent stage I EOC. The staging steps often missed were the biopsy from the right diaphragmatic surface (missed in 96.9% of all patients) and lymph node (LN) sampling or lymphadenectomy (missed in 65.5% of all patients). Upstaging occurred in 393 patients (31.8%) due to microscopic spread to both ovaries (0.8%); ovarian surface (5.8%); positive cytology (10.0%); fallopian tubes (3.1%), ovary (1.5%) and/or uterus serosa (1.2%); pelvic peritoneum (4.3%); LNs (4.7%); omentum (3.7%); abdominal peritoneum (0.6%) and right diaphragmatic surface (2.6%). Of the 393 upstaged patients, 138 (35.1%) had an altered treatment plan due to metastases found by surgical staging. CONCLUSION: Staging was incomplete in most patients, mainly because a biopsy of the diaphragm was omitted. However, surgical staging led to adjuvant treatment in 35.1% of the upstaged patients. Peritoneal biopsies (para-colic gutters and right diaphragm) were of little value, since few patients had an adjustment of treatment plan due to these biopsies. Omitting these biopsies, in the absence of peritoneal abnormalities, is justifiable.

The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer.

This corrects the article DOI: 10.1038/bjc.2012.109.

Vaginal Radical Trachelectomy for early stage cervical cancer. Results of the Danish National Single Center Strategy.

OBJECTIVE: To present and evaluate an unselected national single center strategy with fertility preserving trachelectomy in cervical cancer. In 2003 nationwide single-center referral of women for trachelectomies was agreed upon between all Danish departments performing cervical cancer surgery with the purpose of increasing volume, to increase surgical safety and facilitate follow-up. METHODS: Prospective data were recorded in the Danish Gynecological Cancer Database of all Vaginal Radical Trachelectomies (VRT) performed in Denmark between 2002 and 2013. Oncologic, fertility and obstetrical outcomes of 120 unselected consecutive VRTs were assessed. To obtain complete follow-up about fertility treatment, pregnancy and obstetric outcome the women filled out an electronic questionnaire. Median follow-up: 55.7 months. RESULTS: 85.8% of the patients had stage IB1 disease, 68.3% squamous cell carcinomas, 30.0% adenocarcinomas and 1.7% adenosquamous carcinomas. Six recurrences (5.1%) and 2 deaths (1.7%) occurred. Four women with adenocarcinomas (10.5%) had recurrences, compared to two women with squamous cell carcinomas (2.5%). Seventy-two women (60.0%) desired to conceive and 55 women obtained a total of 77 pregnancies. Of the 72 women 40 were referred to fertility treatment. First and second trimester miscarriage rates were 21.6% and 2.7%, respectively. A total of 53 children were born of which 41 were delivered after gestational week 34. CONCLUSION: This unselected national single center referral study confirms the oncological safety of Vaginal Radical Trachelectomy. The complete follow-up regarding reproductive data, reveals a surprisingly extensive need of fertility treatment and due to the rate of prematurity, these pregnancies must be regarded as high-risk pregnancies.

The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer.

BACKGROUND: Although the role of human papilloma virus (HPV) in cervical squamous cell carcinoma (CSCC) is well established, the role in head and neck SCC (HNSCC) is less clear. MicroRNAs (miRNAs) have a role in the cancer development, and HPV status may affect the miRNA expression pattern in HNSCC. To explore the influence of HPV in HNSCC, we made a comparative miRNA profile of HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC against CSCC. METHODS: Fresh frozen and laser microdissected-paraffin-embedded samples obtained from patients with HPV+/HPV- HNSCC, CSCC and controls were used for microarray analysis. Differentially expressed miRNAs in the HPV+ and HPV- HNSCC samples were compared with the differentially expressed miRNAs in the CSCC samples. RESULTS: Human papilloma virus positive (+) HNSCC had a distinct miRNA profile compared with HPV- HNSCC. Significantly more similarity was seen between HPV+ HNSCC and CSCC than HPV- and CSCC. A set of HPV core miRNAs were identified. Of these especially the miR-15a/miR-16/miR195/miR-497 family, miR-143/miR-145 and the miR-106-363 cluster appear to be important within the known HPV pathogenesis. CONCLUSION: This study adds new knowledge to the known pathogenic pathways of HPV and substantiates the oncogenic role of HPV in subsets of HNSCCs.

Magnesium depletion enhances cisplatin-induced nephrotoxicity.

PURPOSE: Nephrotoxicity and magnesium (Mg)-depletion are well-known side effects to cisplatin (CP) treatment. The purpose of this present study was to investigate the role of Mg on CP induced changes in renal function. CP induced renal dysfunction was achieved by treatment with CP or vehicle (2.5 mg/kg) once weekly for 3 weeks. Since the CP-induced renal damage, including tubular reabsorption defects, is most prominent within the outer medulla (OM), changes in the expression pattern of OM aquaporins and sodium transporters including the Na,K-ATPase (alpha-subunit), type III Na,H-exchanger (NHE3), aquaporin 1 (AQP1) and 2 (AQP2) and the Na,K,2Cl-cotransporter (NKCC2) were investigated by semi-quantitative Western blotting. EXPERIMENTAL DESIGN: Rats had access to either a diet with standard Mg or to a Mg-depleted diet. Cisplatin was administered to female Wistar rats once a week for 3 weeks according to four regimens: (1) Cisplatin 2.5 mg/kg body weight i.p., to rats on a diet with standard Mg, (2) Cisplatin 2.5 mg/kg body weight i.p., to rats on a diet with low Mg, (3) Isotonic NaCl 2.5 ml/kg body weight i.p., to rats on a diet with standard Mg, (4) Isotonic NaCl 2.5 ml/kg body weight i.p., to rats on a diet with low Mg. RESULTS: CP had no effect on plasma creatinine or urea in rats with standard Mg intake, but the expression of all five transporters was significantly reduced when compared to vehicle treated rats on standard Mg-intake. Vehicle treated rats on low Mg-intake had a significant reduction in the expression of Na,K-ATPase, NHE3 and NKCC2, but unchanged expression levels of AQP1 or AQP2 when compared to standard treated controls. Forty percent of the CP-treated rats on low Mg-intake died during the experiment and the remaining animals had marked increased plasma creatinine and urea. Furthermore, the Western blot analysis revealed an almost complete disappearance of all four transporters, suggesting a dramatic synergistic effect of CP and Mg-depletion on renal function including the expression pattern of outer medullary sodium transporters and aquaporins. CONCLUSIONS: This study indicates a substantial additive effect of Mg-depletion on cisplatin induced renal toxicity as evidenced by significant changes in plasma creatinine and urea, renal failure induced mortality and loss of renal transporters. This should give cause for concern since the nephrotoxicity observed during cisplatin treatment might be substantiated by the known Mg-loss associated with cisplatin treatment especially in patients suffering from intense gastro-intestinal side effects.

Magnesium and potassium homeostasis during cisplatin treatment.

PURPOSE: Administration of cisplatin causes changes in magnesium and potassium metabolism. The purpose of this study was to investigate day-to-day changes in renal and intestinal homeostasis of magnesium (Mg) and potassium (K) during repeated cisplatin treatments in rats to provide guidelines for human supplementation studies. EXPERIMENTAL DESIGN: Rats were housed in metabolic cages with access to a diet containing excess Mg and K. Treatment was administered once a week for 3 weeks and comprised either cisplatin 2.5 mg/kg body weight i.p or, as sham treatment, isotonic NaCl 2.5 ml/kg body weight i.p. Urine and feces were collected every 24 h. Blood samples for measurement of plasma Mg and K were obtained from a permanent arterial catheter prior to each treatment cycle and at the termination of the study. RESULTS: Cisplatin exerted a significant negative effect on total Mg balance. This effect was cumulative with repeated doses of cisplatin. The observed difference was mainly due to the difference in Mg balance between the treatment day and the following 2-3 days. The cumulated urinary excretion of Mg did not differ significantly between the two groups at the end of follow-up. A significant decrease was observed in cumulated intestinal absorption in treated rats compared to control rats at the end of follow-up. Lowered intestinal absorption accounted for 90% of the difference in total Mg balance between the two groups as compared to the renal loss. Cisplatin treatment also exerted a negative effect on total K balance, although the difference between cisplatin-treated and control rats was not significant at the end of follow-up. CONCLUSIONS: The Mg loss associated with cisplatin treatment was mainly the result of lowered intestinal absorption and not, as presently thought, the result of increased renal elimination. Instead, an increased renal reabsorption capacity was observed in response to decreased intestinal absorption. The study further showed that Mg and K metabolism are subject to predictable changes in intestinal absorption and renal excretion with each cisplatin treatment, and that knowledge of these changes can be used in planning supplementation. Thus, the experimental observations support intravenous supplementation on the day of treatment and 2-3 days after treatment followed by oral supplementation until the next treatment.

Severe intracellular magnesium and potassium depletion in patients after treatment with cisplatin.

The purpose of this study is (1) to evaluate skeletal muscle magnesium (Mg) and potassium (K) during treatment with cisplatin; (2) to evaluate the predictive value of plasma (P)-Mg for intracellular Mg during cisplatin treatment; and (3) to evaluate whether changes in intracellular K influence skeletal muscle Na,K-ATPase. In all, 65 patients had a needle muscle biopsy obtained before and 26 patients both before and after cisplatin treatment. Biopsies were analysed for Mg, K, and Na,K-ATPase concentrations, and P-Mg and P-K determined. Treatment with a total dose of approximately 500 mg (270 mg m(-2) surface area) cisplatin over 80 days was associated with reductions in muscle [Mg] (95% CI) (8.95 (8.23-9.63) to 7.76 (7.34-8.18) mumol g(-1) wet wt. (P<0.01), and muscle [K] (90.81 (83.29-98.34) to 82.87 (78.74-87.00) mumol g(-1) wet wt. (P<0.05), as well as in P-Mg 0.82 (0.80-0.85) to 0.68 (0.64-0.73) mmol l(-1) (P<0.01 but not in P-K (4.0 (3.8-4.1) vs 3.8 (3.7-4.0) mmol l(-1)). No simple correlations were observed between P-Mg and muscle [Mg], or between P-K and muscle [K], either before (n=65) or after (n=26) treatment with cisplatin. The changes in [Mg] and [K] were not associated with changes in the muscle Na,K-ATPase concentration. Following treatment with cisplatin, an approximately 15% decline in P-Mg was accompanied by an approximately 15% loss of muscle [Mg], as well as an approximately 10% reduction of muscle [K] and fatigue and muscle weakness previously ascribed to hypomagnesaemia may therefore also be well explained by muscle K depletion observed despite normal levels of P-K. There was no correlation between P-Mg and SM-Mg or between P-K and SM-K. Thus, P-Mg and P-K are not reliable indicators for Mg and K depletion during treatment with cisplatin. However, the majority of patients will present Mg and K depletion after cisplatin therapy and of these only very few patients will present a low P-Mg or P-K. Therefore, routine supplementation should be considered in all patients receiving cisplatin.

Cisplatin and hypomagnesemia.

Hypomagnesemia is a well known side-effect in patients receiving cisplatin-containing chemotherapy. Cisplatin induces hypomagnesemia through its renal toxicity possibly by a direct injury to mechanisms of magnesium reabsorption in the ascending limb of the loop of Henle as well as the distal tubule. Since the magnesium reabsorption process still remains to be fully characterized, the effect by cisplatin on this process remains uncertain. Hypomagnesemia is a frequent complication to chemotherapy with cisplatin affecting up to 90% of patients if no corrective measures are initiated. The clinical importance of this hypomagnesemia remains uncertain. Possible symptoms of hypomagnesemia can be impossible to distinguish from symptoms related to the underlying disease or the treatment with chemotherapy. Existing studies on how to supplement magnesium during treatment with cisplatin have focused mainly on the effect on serum magnesium values and erythrocyte magnesium concentrations but both parameters are poor indicators of body magnesium stores. As long as the relationship between hypomagnesemia and possible complications thereof remains poorly elucidated, it seems reasonable to try to avoid hypomagnesemia. The best results seem to be provided by adding magnesium to the pre- and posthydration fluids.

Hernias in trocar ports following abdominal laparoscopy. A review.

BACKGROUND: With increasing numbers of laparoscopies in gynecologic surgery as well as the use of larger trocars more post-operative hernias can be expected. Most hernias occur as Richter's hernias without peritoneal lining and contain small or large intestines or omentum. The incidence is around 1%, but rising with increasing size of trocars. About one fourth of hernias are umbilical, the rest located extraumbilical. RESULTS: The diagnosis is typically based on the presence of vomiting or nausea with an extended and painful abdomen within two weeks of surgery and can be established by a small bowel series. However, the course can be prolonged and ileus can occur up to one year following laparoscopy. In the majority of cases the hernial content was small intestines or omentum. CONCLUSIONS: In order to reduce the frequency of trocar hernias it is recommended to apply small trocars. Fascial closure must be done when trocars of 10 mm or larger have been employed and the surgeon must ensure that peritoneal tissue is not drawn into the trocar canals when removing the probes. Also, umbilical hernias must be ruled out and, if found, closure must include the complete fascial defect. There are several techniques available for fascial closure. It is concluded that all precautions including fascial suturing must be taken to reduce the 1% incidence of post-laparoscopy hernias.