PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers.

BACKGROUND: The PEOPLE trial aimed to identify new immune biomarkers in negative and low programmed death-ligand 1 (PD-L1) (0%-49%) advanced non-small-cell lung cancer (aNSCLC) patients treated with first-line pembrolizumab. Here we report the main outcomes and the circulating immune biomarkers analysis. PATIENTS AND METHODS: The primary endpoint of this phase II trial was the identification of immune biomarkers associated with progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety were secondary endpoints. Absolute cell counts for 36 subsets belonging to innate and adaptive immunity were determined by multiparametric flow cytometry in peripheral blood at baseline and at first radiologic evaluation. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyze immune variables and their correlation with clinical endpoints. RESULTS: From May 2018 to October 2020, 65 patients were enrolled. After a median follow-up of 26.4 months, the median PFS was 2.9 months [95% confidence interval (CI) 1.8-5.6 months] and median OS was 12.1 months (95% CI 8.7-17.1 months). The ORR was 21.5%, DCR was 47.7% and median DoR was 14.5 months (95% CI 6.4-24.9 months). Drug-related grade 3-4 adverse events were 9.2%. Higher T cell and natural killer (NK) cell count at baseline and at the first radiologic evaluation were associated with improved PFS, DCR and OS. On the contrary, higher myeloid cell count at baseline or at the first radiologic evaluation was significantly associated with worse OS and DCR. CONCLUSIONS: Circulating immune biomarkers can contribute to predict outcomes in negative and low PD-L1 aNSCLC patients treated with first-line single-agent pembrolizumab.

Toxicological assessment and developmental abnormalities induced by butylparaben and ethylparaben exposure in zebrafish early-life stages.

Toxicological effects of butylparaben (BuP) and ethylparaben (EtP) on zebrafish (Danio rerio) early-life stages are not well established. The present study evaluated, using zebrafish embryos and larvae, the toxicity of BuP and EtP through benchmark dose (BMD) approach. BuP was more toxic than EtP to zebrafish larvae. In fact, Lethal Concentration 50 (LC50) values at 96 h post-fertilization (hpf) for BuP and EtP were 2.34 mg/L and 20.86 mg/L, respectively. Indeed, BMD confidence interval (lower bound (BMDL) - upper bound (BMDU) was 0.91-1.92 mg/L for BuP and 10.8-17.4 mg/L for EtP. Zebrafish embryos exposed to 1 mg/L, 2.5 mg/L of BuP and 5 mg/L, 10 mg/L, 20 mg/L, 30 mg/L of EtP showed several developmental abnormalities and teratological effects compared to negative control. Exposed zebrafish developed reduced heartbeat, reduction in blood circulation, blood stasis, pericardial edema, deformed notochord and misshaped yolk sac. Embryos exposed to the highest concentrations of the chemicals (2.5 mg/L of BuP, 10 mg/L, 20 mg/L and 30 mg/L of EtP) showed the developmental abnormalities at 48 hpf while those treated with 1 mg/L of BuP and 10 mg/L of EtP reported behavioral changes at 72 hpf, including trembling of head, pectoral fins and spinal cord. This research identified the lethal and sublethal effects of BuP and EtP in zebrafish early-life stages and could be helpful to elucidate the developmental pathways of toxicity of parabens.

Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes.

BACKGROUND: Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. PATIENTS AND METHODS: A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus <30 Gy), and PEB/EP regimens only. RESULTS: Thirteen studies have been selected for MA on relapse outcome. No randomized trials compared RT and CT. There were 4 prospective and 9 retrospective studies, with a total of 607 patients receiving RT and 283 patients CT. The pooled relapse rate (RR) was similar between the RT [0.11, 95% confidence interval (CI) 0.08-0.14, P for heterogeneity = 0.096, I(2) = 38%] and CT groups (0.08, 95% CI 0.01-0.15, P for heterogeneity <0.001, I(2) = 82.5%). However, in the sensitivity analysis, the pooled RR for RT in CSIIB was 0.12 (95% CI 0.06-0.17) while it was 0.05 (95% CI 0-0.11) for CT. Long-term side-effects and incidence of second cancers were more frequently reported following RT. The overall incidence of nontesticular second malignancies was 0.04 (95% CI 0.01-0.02) in the RT group and 0.02 (95% CI 0.003-0.04) in the CT group. CONCLUSIONS: Although RT and CT appeared to be equal options in CSIIA and IIB seminoma, a trend in favor of CT for a lower incidence of side-effects and RR in CSIIB was found. This evidence is limited by the retrospective quality of studies and their small sample size.

High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study.

BACKGROUND: In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). PATIENTS AND METHODS: Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m(2)), 2 courses of cisplatin and HD-etoposide (2.4 g/m(2)) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. RESULTS: From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7-165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8-72.8] and 54.8% (95% CI 41.6%-72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9-79.0) and 59.3% (95% CI 46.1-76.3). One toxic death (PEB arm) was recorded. CONCLUSIONS: The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. CLINICALTRIALS.GOV: NCT02161692.

Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ cell tumors: long-term efficacy and safety outcomes.

BACKGROUND: Since 1985, we introduced a modified combination of etoposide, ifosfamide, and cisplatin (PEI) as second-line therapy of adult male germ cell tumors with the aim to reduce toxic effect while maintaining efficacy over the original regimen. PATIENTS AND METHODS: Patients received four cycles of ifosfamide at 2.5 g/m(2) on days 1-2, etoposide, and cisplatin at 100 and 33 mg/m(2), respectively, on days 3-5 every 21 days, followed by surgery. Results were stratified according to the International Germ Cell Consensus Classification Group-2 (IGCCCG-2). RESULTS: From February 1985 to January 2012, 189 patients were treated. 72.6% were IGCCCG-2 intermediate-to-very high risk. Thirty-five patients (18.5%) had a complete response, 67 (35.4%) a marker normalization (PRm-). Median follow-up was 122.1 months (inter-quartile range [IQR]: 71.4-232.0). Two-year progression-free and 5-year overall survival were 34.3% [95% confidence interval (CI) 28.1% to 41.9%] and 42.1% (95% CI 35.3% to 50.2%), respectively. Survival estimates compared favorably with those obtained by conventional dose chemotherapy (CDCT) regimens in each prognostic category. 70.4% of grade 3-4 neutropenia (25.5% febrile neutropenia), 48.1% thrombocytopenia, 21.2% anemia, 3.2% neurotoxic effect, and no severe renal toxic effect were recorded. CONCLUSION: Dose-modified Italian PEI should be considered as an appropriate benchmark for CDCT in the first salvage setting.

CT-guided percutaneous cryoablation of renal masses in selected patients.

PURPOSE: We analysed our experience with computed tomography (CT)-guided percutaneous cryoablation (PCA) in patients who were not surgical candidates or refused surgery for small to medium-sized renal masses. MATERIALS AND METHODS: Two freezing cycles were applied and separated by a passive warming cycle using 1.7- and 2.4-mm cryoprobes under either general anaesthesia or sedation based on patient positioning and respiratory status. Postoperative monitoring included haematological and biochemistry evaluation and CT scan 24 h after PCA. Follow-up consisted of a multislice CT scan at 1 month and every 3 months in the first year then every 6 months thereafter. RESULTS: Thirty-seven patients (38 lesions) underwent 40 PCA procedures; 5/37 (13.5%) had a solitary kidney. Median mass size was 35 (range 12-70) mm. No complications occurred during the procedure. Clavien grade ≥2 anaemia occurred in two patients (5.4 %): one patient required 1 U of packed red blood cells; the other required an arterial embolisation. Serum creatinine did not increase in any case. Two patients showed persisting or recurrent disease at 1 and 9 months, respectively, and both could be re-treated with PCA. All other patients showed a hypodense mass 3 months after PCA, with no contrast enhancement. Subsequent examinations showed that lesion sizes decreased and CT densitometry remained stable or increased minimally, also with no contrast enhancement. CONCLUSIONS: PCA proved relatively easy and safe and could be considered an effective alternative for patients who are not surgical candidates or refuse surgery, as well as in patients with medium-sized lesions.

[Retroperitoneal surgery in the treatment of germ-cell tumors of the testis: retroperitoneal lymph node dissection (RPLND)]. / La linfoadenectomia retroperitoneale (RPLND) nel trattamento delle neoplasie germinali del testicolo.

Germ-cell tumors of the testis (GCTT) are rare, but have a high social impact. In fact they represent no more than 1% of male tumors (about 700 new cases per year in Italy), but electively occur in young patients, 20 to 40 years old, during their fully mature social and working life. More than 80% of patients are cured and return to a normal social, sexual, and working life. Improvements achieved both in diagnosis, with the use of scans (CT, MRI, US and recently PET) and of serum tumor markers alpha-fetoprotein (AFP), beta-fraction of human chorionic gonadotropin (b-HCG) and lactate dehydrogenase (LDH), and mainly in treatment, through the amelioration of radiotherapy and surgical techniques and, especially, with the introduction of Cisplatin, Etoposide and Ifosfamide in chemotherapic regimens, have made germ-cell tumor a model of "curable disease". Retroperitoneal lymph node dissection (RPLND) has indications in patients with clinical stage I (CS1) as well as in advanced disease, where it is integrated in the multimodality treatment. Anatomical studies, as well as a long-term experience, have gradually but consistently modified the surgical techniques of RPLND. Currently, "nerve sparing" RPLND represents a safe management of CS1 nonseminomatous germ cell testicular tumor with minimal morbidity and excellent outcomes. Nonetheless, surveillance and adjuvant chemotherapy are as effective as RPLND, but, in our opinion, associated with some discomforts for the patients. Laparoscopic retroperitoneal lymph node dissection (Lap-RPLND) is gaining popularity as a minimally invasive staging procedure for clinical stage I nonseminomatous testicular carcinoma, but its therapeutic role is still under investigation.

[State of the art and controversies in the treatment of testis germ-cell tumors (TGT)].

Many different, intersecting strategies are available for managing germ-cell cancers,particularly in early-stage disease. Which is 'right' remains a matter of debate, and requires balancing efficacy against late effects, bearing in mind the complexity of treatment strategies and the available expertise.

Electron correlation in C(4N+2) carbon rings: aromatic versus dimerized structures

The electronic structure of C(4N+2) carbon rings exhibits competing many-body effects of Huckel aromaticity, second-order Jahn-Teller (SOJT), and Peierls instability at large sizes. This leads to possible ground state structures with aromatic, bond angle, or bond length alternated geometry. Highly accurate quantum Monte Carlo results indicate the existence of a crossover between C10 and C14 from bond angle to bond length alternation. The aromatic isomer is always a transition state. The gap opening mechanism is the SOJT effect, which coalesces with the Peierls regime as N-->infinity.

[Comparison of orthotopic neobladders: Studer vs modified Camey II]. / Neovesciche ortotopiche a confronto: Studer vs. Camey II modificata.

A comparative study between modified Camey II and Studer ileal orthotopic neobladder was performed. The Camey II was modified as follows: 1) The ureters were implanted, using wallace technique, in an undetubularized ileal loop, 15-18 cm. long, to prevent vesico-ureteral reflux; 2) The neobladder was made using staplers. In such a way, time is saved (about one hour) and results are quite similar, with a low rate of ureteral stenosis in both groups.

Neoadjuvant CMV chemotherapy plus radical cystectomy in locally advanced bladder cancer: the impact of pathologic response on long-term results.

AIMS AND BACKGROUND: Neoadjuvant systemic chemotherapy in infiltrating transitional cell carcinoma of the bladder has proved to be effective and to provide a pathologic complete response in about 30% of patients. No survival benefit has yet been proved. METHODS: We analyzed the outcome of 75 patients with advanced bladder cancer (stages T2-T4 N+/N0 M0) treated from 1985 to 1993 at two institutions in the same geographic area with 2 or 3 cycles of neoadjuvant CMV (cisplatin, methotrexate and vinblastine) chemotherapy plus cystectomy. Transurethral resection of the tumor was expressly avoided in order to keep the tumor intact as a marker lesion to evaluate response to chemotherapy. RESULTS: At the time of analysis, the median follow-up of 67 assessable patients was 51.5 +/- 3.9 (SE) months. Forty-six patients (69%) had clinical evidence of extravesical spread of the bladder tumor and 6 of lymph node metastases at presentation. After cystectomy, a pathologic complete response (pT0, pN0) was achieved in only 6 cases (9%) and a pathologic partial response in 32 patients (48%). The overall 5-year survival rate of all patients was 61 +/- 6%. Those patients who had a major response to chemotherapy (pCR +pPR) had a 5-year disease-free survival rate of 74%, which was statistically higher (P = 0.0021) than the 44% for the remaining nonresponding patients (pNR). Overall, 43% of the patients with stage T2-T3a disease achieved tumor downstaging (CR, 5%; PR, 38%) compared with 63% of the patients with T3b-T4 (CR, 11%; PR, 52%), although there was no significant difference in 5-year survival curves between the two groups. CONCLUSIONS: A pathologic complete response was achieved in less than 10% of the cases without a preoperative tumor resection. Unfortunately, most of the responses were only partial. Even though the study appears to suggest a survival advantage for those patients who achieved a downstaging, CMV chemotherapy had a limited curative potential in most of the patients. It seems unlikely that determinant proof will be obtained that neoadjuvant chemotherapy may improve survival over a nontreatment control arm. The intrinsic chemoresistance or the suboptimal response to chemotherapy of bladder cancer remains the most adverse prognostic factor.

Five-year results of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy plus radical cystectomy in locally advanced bladder cancer.

Neoadjuvant systemic cisplatin, methotrexate and vinblastine chemotherapy has been used in the treatment of 69 patients with advanced bladder cancer (stages T2-T4 N+/N0 M0). Sixty patients were evaluable for response at a median follow-up of 48 months. Preoperative resection of the tumor was purposely avoided in order to keep a marker lesion. After planned radical cystectomy, pathological complete responses (pCRs) and partial responses (pPRs) were documented in 5 (8.3%) and 29 cases (43.4%), respectively. These patients had a 5-year disease-free survival rate of 80%, which was statistically superior (p = 0.0013) to 35% for the remaining nonresponding patients. One patient (20%) with a pCR died of systemic disease after 14 months, while the remaining 4 patients (80%) are alive and free of disease after a median follow-up of 57 months. A higher percentage of pCRs and pPRs was observed in the group of patients with stage T3b-T4 tumor (pCR 11%, pPR 63%) in contrast to the patients with stage T2-T3a disease (pCR 4.5%, pPR 45.5%), even if no significant difference in the 5-year survival rate was observed between the 2 groups. Patients with a G2 tumor before chemotherapy survived longer (5-year survival rate of 78%) than those with G3 disease (5-year survival rate of 61%), but no significant difference was achieved.

Biological markers in transurethral biopsies from bladder-cancer - preliminary-results.

A biologic profile including proliferative.activity, evaluated as H-3-thymidine labeling index (H-3-dT LI), DNA ploidy, p53 tumor-suppressor gene and P-glycoprotein (P-170), as an expression of the multidrug resistance gene, was defined for 50 primary transitional cell carcinomas of the bladder. H-3-dT LI was evaluated by autoradiography on histologic sections after incubation of fresh tumor biopsies with H-3-thymidine. Ploidy was defined by flow cytometric analysis of DNA content on nuclei suspensions obtained from frozen material. Expression of p53 protein and P-170 glycoprotein was detected by immunohistochemistry using the PAb1801 and C219 monoclonal antibody respectively, on sections from paraffin-embedded tumor biopsies. Invasive tumors showed a higher median H-3-dT LI (12.7% vs 4.2%) and a higher frequency of aneuploidy (73% vs 43%) and more frequently expressed p53 (82% vs 36%) than superficial tumors. Further analysis showed that proliferative activity was higher in invasive than in superficial cancers only in p53-positive or aneuploid tumors and not in p53-negative or diploid tumors. Moreover, proliferative activity and p53 overexpression, but not ploidy, were directly related to histologic grading and tumor stage. Generally, P-170 was not significantly related to any biologic or clinico-pathologic factor. Kinetic and phenotypic biologic markers are differently related to clinico-pathologic factors. A panel of biologic features can be easily evaluated on small transurethral biopsies at diagnosis, during endocavitary treatment or follow-up in bladder cancer patients.

Systemic preoperative chemotherapy with cisplatin, methotrexate and vinblastine for locally advanced bladder cancer: local tumor response and early followup results.

A total of 44 patients with infiltrating, locally advanced bladder cancer (stages T 3a-b, T 4a-b and N+/N0) were treated with the systemic chemotherapy regimen of cisplatin, methotrexate and vinblastine (CMV) in the neoadjuvant setting, of whom 39 were evaluable for response. After planned radical cystectomy and 2 to 3 cycles of chemotherapy no tumor was found on the pathological specimen of 4 patients (10%), the tumor was downstaged in 19 (49%) and no change was observed in 16 (41%). Toxicity included leukopenia in 29 patients (66%), 1 of whom died of granulocytopenic sepsis, nausea and vomiting in 39 (89%) and mild to moderate mucositis in 18 (41%). Median followup is 12 months with a range of 6 to 39 months. Of 32 patients followed for longer than 6 months 6 (19%) experienced progression or recurrence of disease. We conclude that preoperative CMV chemotherapy is effective in inducing downstaging of the tumor, although systemic toxicity limits its use to cautiously selected patients.

[Neoadjuvant chemotherapy with MVC (methotrexate, vinblastine, cisplatin)in the treatment of infiltrating transitional carcinoma of the bladder]. / Chemioterapia neoadiuvante MVC (methotrexate, vinblastina, cisplatino) nel trattamento del carcinoma transizionale infiltrante della vesicica.

Of 19 patients with advanced transitional bladder cancer (T2-T4, N0-N+, M0) who received two or three cycles of pre-emptive MVC (Methotrexate, Vinblastine, Cisplatin), pathological partial (PR) and complete (CR) remissions were observed in 67% (50% and 17% respectively). The toxicity of chemotherapy was generally acceptable but 5 patients required hospitalization for neutropenia and thrombopenia . In one of them chemotherapy was stopped for severe sepsis. No death was observed. In 11 patients follow-up is greater than 12 months. In this group, 10 patients are actually alive and disease-free, while the other one was dead owing to brain metastasis, after eight months from surgery.

Micturitional dysfunction after anterior resection for rectal cancer. Rehabilitative treatment.

A clinical study was made of 21 patients (13 men and eight women) who had undergone anterior resection of the rectum for cancer at the National Tumour Institute of Milan between April 1984 and April 1985. After surgery, 13 patients (including three men with benign prostatic hypertrophy) showed voiding dysfunctions (hesitancy, dysuria, and weak stream) and bladder areflexia. Two of them also had positive Lapides' tests. An early rehabilitative treatment was started after surgery and the entire group was thoroughly reexamined one year later. Only the two patients with positive Lapides' tests still had bladder areflexia with residual urine greater than 100 ml. One of them also had a urinary tract infection. None of them showed decreased renal function.

Sacral chordoma and rehabilitative treatment of urinary disorders.

Sacral chordoma is one of the rarest tumors of the central nervous system (less than 1% of the entire group). Mictional disorders are among the most frequent symptoms and are caused by the extrinsic compression brought to bear on the cauda equina and by surgical demolition of the sacrum. Seven patients who had undergone sacral resection for chordoma, starting from S2, were followed for at least one year. It was observed that mictional disorders were often early symptoms signalling the presence of chordoma. Several patients were affected by a complete bladder denervation (infrasacral lesion) after surgery. Early rehabilitative treatment given after surgery for one year restored normal bladder functions in all the patients whose bladder denervation seemed to be not total (negative Lapides' test). Even when a complete infrasacral lesion of the bladder has been ascertained, early rehabilitative treatment may well prevent serious renal damage.

The role of partial cystectomy in the management of transitional bladder cancer.

A study on 81 patients who underwent partial cystectomy for bladder cancer is presented. The low postoperative mortality (2.46%) and the high 5-year survival (72%) show that this type of surgery is effective and without major complications. Thirty-eight patients were treated with endovesical thiotepa (OTT); the remaining 41 patients were untreated after surgery. Results showed that survival and number of relapses were similar in the two groups. This fact seems to prove that chemotherapy with OTT is not essential after segmental cystectomy. To explain this assertion, several hypotheses are presented.

Renal cell carcinoma and transitional cell carcinomas of the pelvis and bladder in a patient affected by chronic renal failure due to abuse of phenacetin.

This is a report on a case of 2 concurrent neoplasms of different histology within the same kidney: a renal cell carcinoma and a transitional cell carcinoma of the renal pelvis in a patient affected by chronic renal failure due to abuse of phenacetin. There was also a transitional cell carcinoma of the urinary bladder.