Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

ABREAST: a prospective, real-world study on the effect of nab-paclitaxel treatment on clinical outcomes and quality of life of patients with metastatic breast cancer.

PURPOSE: The efficacy of nab-paclitaxel in patients with metastatic breast cancer (MBC) has been demonstrated in randomized clinical trials. However, real-world evidence on effectiveness remains limited. PATIENTS AND METHODS: The primary objective of this multicenter prospective study was to assess the overall response rate (ORR) of patients with MBC treated with nab-paclitaxel. Secondary objectives included progression-free survival (PFS), overall survival (OS) and quality of life, assessed with the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument. RESULTS: Eligible patients (N = 150; 36% with de novo MBC presentation) with a median age of 64.5 years were enrolled (86% were ER+, 33.3% (50/150) were ≥ 70 years of age and 53% were treated in the third or later line of treatment). A median of 6 cycles were administered but 26% of patients required dose reduction due to toxicity. The ORR was 26.7% [95% confidence interval (CI) 19.6-33.7], the median PFS was 6.2 months (95% CI 5.2-7.3), and the median OS 21.1 months (95% CI 17.2-not estimable). There was no statistical significant difference in the median PFS of patients < and ≥ 70 years of age. The patients' baseline FACT-B total score remained unchanged. The serious and non-serious adverse event incidence rates were 13% and 48%, respectively. CONCLUSIONS: This prospective study provides further evidence on quality of life, efficacy, and safety of nab-paclitaxel in patients with MBC and sheds more light in special subpopulations such as the elderly and those treated beyond the second line.

Bilateral primary ovarian non-Hodgkin's lymphoma and fertility preservation: 5-year follow-up.

AIM: Primary ovarian non-Hodgkin's lymphoma is a very rare disease. Median age at diagnosis is estimated at 42 years, something that leads to fertility preservation issues in many cases. This was a case report study, presenting a rare case of bilateral primary ovarian non-Hodgkin's lymphoma. CASE REPORT: A 38-year old nulliparous woman, underwent exploratory laparotomy because of bilateral ovarian masses. Left salpingooophorectomy, partial omentectomy and excision of an ovarian mass of the right ovary was performed. Great effort in order to preserve healthy ovarian tissue of the right ovary as well as the right fallopian tube was given, due to fertility reasons. Final histology showed bilateral diffuse large B-cell primary ovarian non-Hodgkin's lymphoma. Postoperatively, the patient underwent chemotherapy with the CHOP regimen in combination with rituximab. Five years after initial diagnosis, the patient remains well with normal menstrual cycle, without evidence of recurrence. DISCUSSION: Fertility preservation issues in some cases of rare gynecological malignancies could be managed via minimally invasive oncological approach.

The implication of second-trimester amniotic fluid TNF-alpha, cytochrome C and cell death nucleosomes in the prediction of preterm labor and/or premature rupture of membranes.

AIM: The multifactorial pathway leading to preterm labor possibly includes the implication of apoptosis. This study aimed to clarify the role of amniotic fluid apoptotic molecules (TNF-alpha, cytochrome C and cell death nucleosomes) at midtrimester as possible predictors of preterm labor (PTL) and/or premature rupture of membranes (PROM). METHOD: In this case-control study, comprising 360 women undergoing genetic amniocentesis and out of whom 38 delivered preterm and 18 out of the latter after PROM, the above apoptotic molecules were determined by ELISA. The 38 cases with PTL and 18 cases with PROM were matched for age with 38 and 18 respective controls delivering at term, and the levels of apoptotic molecules were compared. RESULTS: Cell death nucleosome levels were found to be significantly associated with preterm delivery. Specifically, for every unit increase in nucleosomes, women were on average 0.2% more likely to deliver preterm (OR: 1.002, CI: 1.0-1.003, p = 0.018). In contrast, such an association was not found concerning the other two apoptotic molecules (TNF-a and Cytochrome C). CONCLUSION: Second-trimester amniotic fluid cell death nucleosomes' levels are significantly associated with preterm delivery and could possibly serve as predicting markers.

Laparoscopic low anterior resection for early rectal cancer.

INTRODUCTION: Early rectal cancer (ERC) is adenocarcinoma that has invaded into, but not extended beyond, the submucosa. Endoscopic or minimal access surgical procedures, such as laparoscopic resection, have emerged as a useful tool in the surgical treatment of such diseases. The aim of this study is to present and analyze the feasibility, the short- and long-term results of laparoscopic colorectal surgery (LCS) in patients with ERC. PATIENTS AND METHODS: Between 2002 and 4/2011, a total of 164 patients with colorectal cancer underwent laparoscopic surgery (LS). Of these, 7 patients (4.2%) had ERC and underwent laparoscopic anterior resection (LAR). The median follow-up was 41 months. RESULTS: The mean operative time was 2.5 h. None of the laparoscopic procedures was converted to open surgery. Liquids and solid food were started on median postoperative days 1 and 3, respectively. The median length of postoperative stay was 5 days. Postoperative complications occurred in 2 patients (28.5%), including wound infection in one patient (14.2%) and atelectasis in one patient (14.2%). None of the patients required an urgent re-operation. There was no mortality related to LS. CONCLUSIONS: LS for ERC can be used as a strategy sited between endoscopic mucosal resection and open anterior resection with beneficial long- and short-term results. It appears as a technically and oncologically safe procedure when performed by surgeons with sufficient experience in laparoscopic techniques.

The stapled hemorrhoidopexy syndrome: a new clinical entity?

PURPOSE: Haemorrhoidal disease is a rather common disease of unknown cause. A new technique for treating prolapsing haemorrhoids known as the stapled hemorrhoidopexy (SH) or the "Longo procedure" is widely used. Serious adverse events were reported in 2000 and some discussion over the syndrome but nothing since. METHODS: Two hundred and five patients underwent SH by our surgical team at the Interbalkan European Medical Center. Modified SH was performed. RESULTS: Despite the low incidence of postoperative complications (11/205), 36.58% of patients developed syndrome comprised of urgency to defecate, sensation of anal foreign body and incomplete defecation and mild cramp like anal discomfort, immediately after surgery or in the following 48 h. There is not statistically significant relationship between the presence of the syndrome and the gender, the presence of muscle fibres in the resected "ring" the degree of haemorrhoidal disease, age and ring length. CONCLUSION: Observations led us to conclude that the stapled hemorrhoidopexy syndrome (SHS) is probably caused by the irritating presence of the titanium staples in the rectal mucosa and by the resection itself.

Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study.

BACKGROUND: We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. METHODS: Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. RESULTS: In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). CONCLUSION: Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.

The role of urocortin in gynecological and obstetrical conditions.

AIM: The objective of the review is to present the possible role of urocortin, a novel peptide of the corticotrophin releasing factor family, in different conditions of obstetrics and gynecology such as preterm labor, preeclampsia or ovarian steroidogenesis. METHOD-RESULTS: A MEDLINE search was commenced with the terms "urocortin", "preterm labor", "preeclampsia", "ovary", "endometrium", "myometrium", "placenta", "plasma", "amniotic fluid". Seventy-three articles were found to be relevant on the field and the potential role of urocortin in such conditions is presented. CONCLUSION: Amounting data suggest that urocortin could play a significant role in human reproduction (steroidogenesis in the ovary, maintenance of the placental function and labor). Further investigation on the field is necessary in order to clarify the natural role of this newly identified molecule in the field of obstetrics and gynecology.

Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer.

This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and

Crossover analysis using immunofluorescent detection of MLH1 foci in frozen-thawed testicular tissue.

To date, the effects of freezing on spermatogenesis have not yet been fully investigated at a molecular level. Antibody localization studies have identified the MutL homolog 1 (MLH1) protein, a mis-match repair protein, at the prophase I stage of meiosis, which allows the detection of recombination foci during pachytene. This study investigated the effect of long-term testicular tissue cryopreservation on meiotic prophase I, identified by recombination foci frequency and synaptonemal complex (SC) integrity. Frozen-thawed testicular tissues from 12 males who had each fathered a child were used. Because vasectomy or reverse vasectomy procedures are rare in the locale of the investigation, it was not possible to obtain fresh testicular tissue and use the males as their own controls. Immunocytogenetic analysis of 612 spermatocytes at the pachytene stage was performed. The results indicated a mean number of MLH1 foci of 49.2 (SD +/- 5.9), and no correlation was found between the freezing period, the MLH1 frequency and the SC integrity. The results suggest that freezing of testicular tissue taken post-puberty does not appear to be detrimental to the crossover process as identified by occurrence of MLH1 loci.

Combination chemotherapy with paclitaxel and gemcitabine followed by concurrent chemoradiotherapy in non-operable localized non-small cell lung cancer. A hellenic cooperative oncology group (HeCOG) phase II study.

UNLABELLED: Concurrent chemoradiotherapy has become a standard therapy for locoregionally advanced inoperable nonsmall cell lung cancer (NSCLC). The purpose of this phase II trial was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy following induction with non-platinum chemotherapy in patients with inoperable locally advanced NSCLC. PATIENTS AND METHODS: All patients with locally advanced inoperable NSCLC ECOG performance status (PS): 0-1 following staging received paclitaxel 200 mg/m2 in a 3-h infusion on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 every 21 days for two cycles. The patients with a response or stable disease (SD) continued to receive paclitaxel 60 mg/m2 weekly and radiotherapy 63 Gy given at 1.8 Gy once a day for 7 weeks. RESULTS: Forty-three eligible patients entered the study. The median age was 63 years (range 42-76), male 93%, IIIB 63% and IIIA 37%. Following induction 15 (36.5%) of the patients responded: complete response (CR), 2%; partial response (PR), 33%; and 19 (46.5%) SD. From those with SD, 7 (37%) improved to a PR following concurrent chemoradiotherapy. With a median follow-up of 44 months (95% CI: range 36-53) the median survival was 20.8 months (95% CI: range 15.4-26.3) and time-to-progression 8.4 months (95% CI: range 6.2-10.6). The median survival of those who had improved response from SD to PR was 31.4 months (95% CI: range 18.7-44.1) versus 20.8 months (95% CI: range 5.5-11.3) for those who had no improvement (p=0.20). The commonest grade 3/4 toxicity in induction was neutropenia 12% with 2 febrile neutropenic patients whereas in the concurrent chemoradiotherapy neutropenia, neurotoxicity and oesophagitis were observed in 6% of the patients. CONCLUSION: Concurrent chemoradiotherapy following induction chemotherapy in patients with stage III NSCLC is feasible with reasonable efficacy and acceptable toxicity.

Dose-finding study of fixed dose gemcitabine and escalating doses of ifosfamide given on days 1 and 8 in patients with advanced non-small cell lung cancer.

UNLABELLED: This is a dose-finding study of fixed dose gemcitabine and escalating doses of ifosfamide, in chemo naïve patients with advanced non-small cell lung cancer. The purpose of the study was to determine the optimal dosage and the maximal tolerated dose (MTD) of a specified schedule of gemcitabine and ifosfamide. Patients received gemcitabine 1250 mg/m2 and ifosfamide between 1.6 and 2.2 g/m2, intravenously, on days 1 and 8, repeated every 3 weeks for a maximum of four cycles. RESULTS: Sixteen patients entered the study. Three patients were entered at the first dose level of ifosfamide (1.6 g/m2) and none experienced any dose limiting (DLT) toxicity. In dose level 2 (1.8 g/m2), two patients had grade IV haematological toxicities, but they reached 21 days without any other dose limiting toxicity (DLT). Three further patients entered at this level but they were withdrawn due to disease progression. The sixth patient entered without any DLT. Three patients entered dose level 3 (2.0 g/m2), without any grade IV toxicity. The first patient entered into dose level 4 (2.2 g/m2), had progressive disease within 21 days and was withdrawn and another three were entered and had no DLT during the first 21 days. Four (33%) of the patients had stable disease and 67% had progressive disease. CONCLUSION: The MTD of the ifosfamide gemcitabine combination was not reached in the present study, as no DLT was observed. This combination at the dose levels of this protocol has little or no activity in patients with advanced NSCLC.

A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1).

BACKGROUND: Phase III studies suggest that non-small-cell lung cancer (NSCLC) patients treated with cisplatin-docetaxel may have higher response rates and better survival compared with other platinum-based regimens. We report the final results of a randomised phase III study of docetaxel and carboplatin versus MIC or MVP in patients with advanced NSCLC. PATIENTS AND METHODS: Patients with biopsy proven stage III-IV NSCLC not suitable for curative surgery or radiotherapy were randomised to receive four cycles of either DCb (docetaxel 75 mg/m(2), carboplatin AUC 6), or MIC/MVP (mitomycin 6 mg/m(2), ifosfamide 3 g/m(2) and cisplatin 50 mg/m(2) or mitomycin 6 mg/m(2), vinblastine 6 mg/m(2) and cisplatin 50 mg/m(2), respectively), 3 weekly. The primary end point was survival, secondary end points included response rates, toxicity and quality of life. RESULTS: The median follow-up was 17.4 months. Overall response rate was 32% for both arms (partial response = 31%, complete response = 1%); 32% of MIC/MVP and 26% of DCb patients had stable disease. One-year survival was 39% and 35% for DCb and MIC/MVP, respectively. Two-year survival was 13% with both arms. Grade 3/4 neutropenia (74% versus 43%, P < 0.005), infection (18% versus 9%, P = 0.01) and mucositis (5% versus 1%, P = 0.02) were more common with DCb than MIC/MVP. The MIC/MVP arm had significant worsening in overall EORTC score and global health status whereas the DCb arm showed no significant change. CONCLUSIONS: The combination of DCb had similar efficacy to MIC/MVP but quality of life was better maintained.

A phase II trial with RFS2000 (rubitecan) in patients with advanced non-small cell lung cancer.

Rubitecan (RFS2000, 9 nitrocamptothecin,) is a new oral topoisomerase I inhibitor. We report a phase II, single-arm, open-label study of RFS2000 as first line treatment for non-small cell lung cancer (NSCLC). Seventeen treatment-naïve patients with stage IIIB (9/17) and IV (8/17) NSCLC (11 male and 6 female) were treated, the median age was 62 years (range 52-86), and the majority of patients (14/17) were of performance status 1. RFS2000 was given orally, daily for 5 days, repeated every week. The starting dose was 1.5 mg/m(2)/day, and dose adjustment was permitted based upon toxicity. Fifteen patients had a dose escalation to 1.75 mg/m(2)/day and 7 had a second dose escalation to the protocol maximum level of 2.0 mg/m(2)/day. RFS2000 was tolerated well. Almost all adverse events were grade 1 and 2. The most frequently encountered adverse events were diarrhoea, nausea, anorexia, and lethargy. Neutropenia and thrombocytopenia were not observed in any patient. There were no responders to RFS2000 treatment, 10 patients had stable disease as their best response, whilst five had tumour progression. Two patients were not assessable for tumour response. The median survival time was 257 days (95% CI = 222-352). RFS2000 appears to be inactive at dose levels of 1.5-2.0 mg/m(2)/day in advanced NSCLC patients. Since only mild toxicity and no myelosuppression were encountered, these dose level are too low for this treatment-naïve patient population with NSCLC. Further studies at an increased dose would be required to identify whether this agent has merit in the treatment of NSCLC.

Randomized phase II study of two gemcitabine schedules for patients with impaired performance status (Karnofsky performance status

PURPOSE: This randomized phase II study compared two treatment schedules of gemcitabine in patients with non-small-cell lung cancer (NSCLC) and impaired Karnofsky performance status (KP). Primary objectives were to record changes from baseline KP and to assess symptom palliation. Secondary objectives were overall survival, tumor response, and toxicity. PATIENTS AND METHODS: Patients with stage IIIb and IV NSCLC and KP

Concentrations of angiogenic factors in follicular fluid and oocyte-cumulus complex culture medium from women undergoing in vitro fertilization: association with oocyte maturity and fertilization.

OBJECTIVE: To determine the concentration of angiogenic factors (vascular endothelial growth factor [VEGF], basic fibroblast growth factor [bFGF], and angiogenin) in the follicular fluid (FF) and oocyte-cumulus complex culture medium (CM) of women undergoing IVF and to investigate the association of the concentrations with the maturity and fertilization of the oocyte. DESIGN: Prospective study. SETTING: Academic tertiary-care institution. PATIENT(S): IVF patients with unexplained or tubal factor infertility. INTERVENTION(S): Analysis of VEGF, bFGF, and angiogenin FF and CM concentrations. MAIN OUTCOME MEASURE(S): Oocyte maturity and fertilization and FF and CM angiogenic factor concentrations. RESULT(S): VEGF, bFGF, and angiogenin were determined in FF and CM. FF angiogenin concentrations were significantly higher when the oocyte was mature versus immature. CM VEGF concentrations were significantly higher when the oocyte was nonfertilized versus fertilized. Positive correlations were observed between angiogenic factors in CM. CONCLUSION(S): VEGF, bFGF, and angiogenin (determined for the first time) are secreted in the FF and CM. Elevated CM VEGF concentrations, probably implying oocyte-cumulus complex hypoxia, are negatively associated with oocyte fertilization. Elevated FF angiogenin concentrations are positively associated with oocyte maturity, possibly indicating angiogenin's biological role beyond neovascularization.

Cell cycle genes c-mos and cyclin-B1 are expressed in a specific pattern in human oocytes and preimplantation embryos.

Little is known about the molecular mechanisms governing the development of human oocyte and pre-embryo. We characterized the expression pattern of c-mos, cyclin B1 and beta-actin mRNA in oocytes and granulosa cells from human and monkey, and in human early embryos, using both qualitative and semi-quantitative reverse transcriptase polymerase chain reaction. The proto-oncogene c-mos was expressed in an oocyte-specific manner and no mRNA for c-mos could be detected in the granulosa cells. Similarly, strong expression of cyclin-B1 was seen in the oocytes. In human pre-embryos, the expression of cyclin-B1 and beta-actin increased from the 6-cell stage onwards, indicating active transcription and thus activation of embryonic genome either at or before the 6-cell stage. The expression of c-mos was transient and very little c-mos mRNA could be detected in the human embryos beyond the 6-cell stage. Thus, both its time-specific and site-specific expression suggest meiosis-specific functions for the proto-oncogene c-mos in human oocytes. As judged by the disappearance of c-mos, the maternal pool of mRNA seems to be degraded towards the 6- to 8-cell stage. The transient expression of c-mos and high levels of cyclin-B1 mRNA suggest that mechanisms similar to those found in lower organisms govern the growth and development of the human oocyte and preimplantation embryo.