Prognostic relevance of regional lymph-node distribution in patients with N1-positive non-small cell lung cancer: A retrospective single-center analysis.

OBJECTIVE: Lymph node (LN) metastases predict survival in patients with non-small cell lung cancer (NSCLC) treated with curative surgery. Nevertheless, prognostic differences within the same nodal (N) status have been reported. Consequently, the International Association for the Study of Lung Cancer (IASLC) proposed to stratify patients with limited nodal disease (pN1) from low (pN1a) to high (pN1b) nodal tumor burden. This study aimed to validate the IASLC proposal in a large single-center surgical cohort of patients with pN1 NSCLC. MATERIAL AND METHODS: Data from 317 patients with pN1 NSCLC treated between January 2012 and December 2016, were retrospectively analyzed. Associations between distribution of LN metastases and survival were analyzed for different classification models-toward nodal extension (pN1a: one station involved; pN1b: multiple stations involved) and toward location (pN1 in the hilar [LN#10/11] or peripheral zone [LN#12-14]). RESULTS: Tumor-specific survival (TSS) in the entire pN1 cohort was 67.1% at five years. Five-year TSS rates for pN1a and pN1b patients were comparable (67.6% vs. 66.5%, p = 0.623). Significant survival differences from pN1a to pN1b were observed only in patients with adenocarcinoma histology and completed adjuvant chemotherapy (5-year TSS: pN1a, 80.4% vs. pN1b, 49.6%; p = 0.005). TSS for LN metastases in the hilar zone/peripheral zone or in both zones was 68.2% and 59.9%, respectively (p = 0.068). In multivariate analysis, adjuvant chemotherapy, squamous cell histology, and nodal disease limited to one zone nodal disease were identified as independent beneficial prognostic factors (p < 0.05). CONCLUSION: pN1 in only one region (hilar or lobar) was associated with better outcome than metastatic affection of both regions after surgery and adjuvant therapy. A stratification towards single (pN1a) and multiple (pN1b) N1-metastases was found of prognostic relevance only in adenocarcinoma. Prospective multicenter analysis of prognostic subgroups in N1 NSCLC is required to evaluate its clinical impact for consideration in future TNM classification.

PD-L1 expression in large cell neuroendocrine carcinoma of the lung.

OBJECTIVES: Large cell neuroendocrine carcinoma of the lung (LCNEC) is associated with an unfavorable prognosis and only few patients are eligible for surgery. In most patients, chemotherapy is recommended alone or in addition to resection. Novel immunotherapies blocking the PD-L1 pathway have been introduced into therapeutic regimens for NSCLC with great success. In order to evaluate a possible efficacy of an anti-PD-L1 therapy, we analyzed the frequency of PD-L1 expression in LCNEC. MATERIAL AND METHODS: We retrospectively reviewed data from 76 patients with LCNEC treated in our institution between 1998 and 2010. The expression of PD-L1 was examined on the tumor cells and the tumor surrounding tissue by immunohistochemistry. An expression of >1% was considered as positive. Statistical analysis was performed to determine significant predictors for survival. RESULTS: 56 of 76 patients with LCNEC were treated with a potentially therapeutic surgical approach. Tumor-specific survival (TSS) of the entire cohort was 29% at five years. 17 patients (22.3%) had PD-L1 positive tumors and 12 of these had no additional PD-L1 expression in the adjacent immune cell infiltrate. Tumor-flanking immune cells were found PD-L1 positive 28 patients; 16 of these had no additional expression on the tumor cells. The most considerable difference in survival was found when comparing patients with isolated PD-L1 expression on tumor cells and PD-L1 negative immune cell infiltrate to their counterpart (positive immune-cell infiltrate and PD-L1 negative tumor cell surface; 5-year TSS: 0% vs. 60%; p < 0.017). CONCLUSION: PD-L1 expression in LCNEC was associated with poorer survival whereas PD-L1 expression in the tumor microenvironment seemed to have a beneficial effect. Therapeutic approaches have to be evaluated in future.

[Local treatment of solitary intrapulmonary, malignant nodules]. / Lokaltherapie solitärer intrapulmonaler maligner Rundherde.

DEFINITION: Intrapulmonary nodules generally represent an incidental finding in the roentgenogram or computed tomography (CT) scan of the chest. They are defined as single, well-circumscribed, radiographic opaque lesions that measures up to 3 cm in diameter and are surrounded completely by aerated lung. The probability of malignancy directly correlates with increasing diameter. Lesions that have a diameter of 1 cm or larger require direct evaluation. THERAPY: Surgery is the first option for patients with a malignant lesion, given an acceptable perioperative risk; for high-risk patients either radiofrequency ablation (RFA) or stereotactic body radiation therapy (SBRT) should be offered. In these cases the malignant histology has to be established beforehand or verified by radiologic proven growth. OUTCOME: Complete surgical resection is superior to RFA and SBRT with respect to local tumor control.

Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low-Dose Treosulfan.

Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9 ± 784.1 ng/mL at baseline to 8.8 ± 11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug-related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option.

[Dyspnea, cough and tachycardia]. / Luftnot, Husten und Tachykardie.

Pneumopericardium is known as a rare complication following cardiothoracic surgery or intravenous line placement. Baseline examination including chest x-ray may lead to diagnosis. To prevent cardiac tamponade, pericardiotomy or adaequate pericardial drainage is crucial. We revealed pneumopericardium as the reason for new dyspnea and tachycardia in a 56-year-old man 3 weeks after lobectomy and lymphadenectomy because of a non-small cell lung cancer. Early decision for transpleural pericardiotomy prevented a possibly lethal course.

Estradiol, testosterone, dehydroepiandrosterone and androstenedione: novel derivatives and enantiomers. Interactions with rat liver microsomal cytochrome P450 and antioxidant/radical scavenger activities in vitro.

Interactions of 27 steroids, among them 17 derivatives such as ethers, sulfates and amidosulfonates derived from 17 beta- and 17 alpha-estradiol, from testosterone and alpha- and beta-dihydrotesosterone and from dehydroepiandrosterone with rat liver microsomal cytochromes P450 (P450) were investigated in vitro by assessing binding to P450 and effects on P450 mediated monooxygenase functions as measured by different model reactions: ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD) and ethylmorphine N-demethylation (EMND). With the exception of 17 alpha-estradiol-3-dimethylamidosulfonate, estrone, its -3-methylether and -3-amidosulfonate and testosterone, all other steroids displayed type I or reverse type I binding to P450. All steroids inhibited EROD activity in micromolar concentrations. An additional strong inhibition of ECOD and EMND activities was only demonstrated for the androgens and progestins. Estriol, estrone and mestranol displayed less inhibitory actions on the model reactions than estradiol. No major differences in comparison to the parent compounds were noted with the other derivatives. The only exceptions were 17 beta-(8,9-dehydro-14 alpha,15 alpha-methylene)estradiol, which displayed stronger effects than estradiol, and dehydroepiandrosterone-3-sulfate, which was less effective than dehydroepiandrosterone. Possible antioxidant properties of the steroids were examined by the stimulated lipid peroxidation (LPO), H2O2 production, and lucigenin (LC) and luminol (LM) amplified chemiluminescence (CL) using rat liver microsomes. Additionally, the influence on rat whole blood chemiluminescence (WB-CL) was assessed. All the estrogens, but not their methylethers and amidosulfonates inhibited LPO in micromolar concentrations. The effects on the other oxidase model reactions or on WB-CL were less distinct. Only ethinylestradiol and 17 beta-(8,9-dehydro-14 alpha,15 alpha-methylene)estradiol displayed a strong inhibitory action on all model reactions. With the exception of dehydroepiandrosterone-3-sulfate, which in general had only weak effects, the androgen and progestin derivatives, in contrast, strongly decreased H2O2 formation and LM- and LC-CL, but were mostly ineffective on LPO and WB-CL.

Comparison of the response of human FaDu squamous cell carcinoma in nude mice after hypofractionated-accelerated regimens and "curative" fractionation schedules.

BACKGROUND: It has been suggested that tumors respond differently after irradiation with 10 or more fractions than with less fractionated regimens and that extrapolation from experiments with only a few fractions to "curative" regimens may be invalid. To test this hypothesis, we compared hypofractionated-accelerated treatments with "curative" fractionation schedules in human squamous cell carcinoma in nude mice. MATERIAL AND METHODS: FaDu tumors were transplanted subcutaneously into the hindleg of NMRI nu/nu mice. TCD50 values, i.e., the dose necessary to control 50% of the tumors locally, were determined after irradiation under ambient blood flow conditions with 5 and 10 fractions in 5 days, 10 fractions in 10 days, and 30 fractions in 15 days, 6 weeks or 10 weeks. RESULTS: TCD50 values of the hypofractionated regimens were not significantly different and varied from 41 to 46 Gy. The number of fractions given in the same overall time had no measurable effect on local tumor control. The TCD50 after 30 fractions in 6 weeks was 30 Gy higher than after the hypofractionated regimens. This effect was caused by a substantial increase of TCD50 with overall treatment time, the dose recovered per day was 0.82 Gy (95% CI 0.66; 0.96). alpha/beta eff determined from all data was 58 Gy (13; infinite). CONCLUSIONS: The results of the present study compare well with our previous findings after different "curative" fractionation schedules in the same tumor. Thus, our study does not support that tumors respond differently after application of 10 or more fractions compared to less fractionated regimens. The biological mechanisms that govern the radiation response of FaDu tumors appear to be the same for hypofractionated-accelerated and "curative" regimens. Since only one tumor was investigated, these results cannot be generalized at the present time.

[Enuresis--symptom of delayed micturition development or an obstructive urinary tract anomaly?]. / Enuresis--Symptom einer verzögerten Miktionsreifung oder einer obstruktiven Harntraktsanomalie?

In a review of the literature the question of origin of enuresis was studied. Most authors agree that diminished bladder capacity and involuntary detrusor contractions are the main cause of primary enuresis. Urodynamic investigations are necessary to differentiate developmental delay in bladder function form true anatomic infravesical obstruction. Therapeutic measures are successful in 2/3 of enuretics. Enuresis has a great tendency of spontaneous disappearance around 15% per year.

[The risk of cancer in neuropathic bladders]. / Karzinomrisiko der neuropathischen Blase.

Neuropathic bladder is on number six in a list of predisposing factors for bladder cancer. The incidence is reported to be between 0.25 and 9.7%. For these patients mortality is about twenty times higher than in patients with normal bladder function. Chronic infection of the urinary tract and long-term indwelling catheter increase the risk of cancer. Pure squamous cell and squamous cell carcinoma with elements of transitional cell carcinoma is noticed to be surprisingly frequent. In comparison, carcinoma in defunctionalized bladder is rare. For prophylaxis, instead of using a long-term catheter, intermittent catheterization is supposed to be applied as well as consequent cystoscopic examination once a year and 'mapping' of a neuropathic bladder which exists longer than 10 years.

The time-distance diagram: a new method to analyze ureteral peristalsis by cineradiography.

We assessed ureteral peristalsis in dogs by cineradiography and analyzed the films in a single frame follow-up by measuring the position of bolus front and rear end in relation to the bladder and the kidney. The data were plotted as function of time in a time-distance diagram. The bolus rear end which is the active contractile rings, as proven by electromyography, travels with constant velocity. The bolus front shows remarkable changes in propagation velocity which can be explained by differences in wall forces that resist the opening of the ureteral lumen. Thus, the time-distance diagram describes precisely the constantly changing dynamics of ureteral peristalsis along the entire ureter.

Fromino-glutamic acid (Figlu) excretion and abortion.

PIP: The relationship between excretion of forminoglutamic acid (figlu) in the urine and spontaneous abortion in the first and second trimesters of pregnancy was investigated in 135 nonanemic women after spontaneous abortion and curettage. The 135 were subdivided into Group A, 95 cases with no known reason for spontaneous abortion, and Group B, 40 women in whom probable abortion cause was known; Group C was control. In Group A, figlu was detected in urine of 40 (42.1%). In Group B, where abortion causes ranged from diabetes, to toxoplasmosis, to cervical incompetence, figlu was positive in only 2 (5%) cases. 3/35 controls (8.6%) were positive for figlu. The percentage of positive figlu findings in Group A was significantly higher when compared with Group B (P .001) and with Group C (P .001). In Group A, the positive figlu excretion was statistically unrelated to previous abortions (P .05), previous pregnancies (P .05), or age groups (P .05). Further, when the 40 Group B cases and the 35 Group C cases were compared with the above, there was no change in the results. If increased figlu excretion can be considered an index of folic acid deficiency, then it is possible that this deficiency may be an etiological factor in cases of spontaneous abortion.^ieng

Gamma-glutamyl transpeptidase as an aid in the diagnosis of liver metastases.

Serum gamma-glutamyl transpeptidase (GGTP) activity was examined in 79 patients. Of these, 49 had diverse malignant tumors, some of which had metastasized to the liver, and 18 had benign diseases of the liver, gallbladder and bile ducts. Enzyme activity increased significantly in all but two patients in whom liver metastases were found. All but one of the patients with malignant tumors, but without liver metastases, showed normal GGTP activity. GGTP activity was elevated in all cases of jaundice. In the absence of jaundice, elevated GGTP activity is suggestive of the presence of liver metastases.