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Summary: Understanding the capacity of temperate trees to acclimate to limited soil water has become essential in the face of increasing drought risk due to climate change. We documented seasonal – or phenological – patterns in acclimation to water deficit stress in stems and leaves of tree species spanning the angiosperm phylogeny.Over 3 yr of field observations carried out in two US arboreta, we measured stem vulnerability to embolism (36 individuals of 7 Species) and turgor loss point (119 individuals of 27 species) over the growing season. We also conducted a growth chamber experiment on 20 individuals of one species to assess the mechanistic relationship between soil water restriction and acclimation.In three‐quarters of species measured, plants became less vulnerable to embolism and/or loss of turgor over the growing season. We were able to stimulate this acclimatory effect by withholding water in the growth chamber experiment.Temperate angiosperms are capable of acclimation to soil water deficit stress, showing maximum vulnerability to soil water deficits following budbreak and becoming more resilient to damage over the course of the growing season or in response to simulated drought. The species‐specific tempo and extent of this acclimatory potential constitutes preadaptive climate change resilience. [ABSTRACT FROM AUTHOR]

Background/aims: Many cytokines are involved in the pathogenesis of retinal proliferative diseases, but none has been shown to be related to a specific disorder. The aim of this study was [...]

Rhino-cerebral zygomycosis (RCZ) is an acute rapidly progressive fungal infection usually occurring in patients with diabetes mellitus and ketoacidosis. Patients typically complain of pain located in the facial, nasal or orbital regions, followed by sudden blindness and cranial nerve palsy. Early diagnosis, correction of risk factors, prompt surgical removal and aggressive antifungal therapy are warranted as life-saving treatments. The following report describes a case of a lethal RCZ which occurred in an apparently healthy woman with latent non-decompensated diabetes mellitus and a fetal-type posterior (FTP) circle of Willis. [ABSTRACT FROM AUTHOR]

SummaryProstaglandin E-induced signal transduction pathways in human T cells from healthy and uveal melanoma-bearing subjects were studied. Transfection experiments showed that PGE2 was able to phosphorylate and activate the fusion trans-activator of the cAMP responsive element-binding protein (CREB). Phosphorylation was at least partially mediated by protein kinase A, as evidenced by the effects of specific kinase inhibitors. Western blotting experiments, which were performed to identify the CREB/ATF2 family members involved in the response to PGE2, revealed a modulation of proteins CREB1, CREB2 and ATF2 and phosphorylation of the 43 kDa form of CREB. Experiments of immunoprecipitation with CREB-binding protein (CBP) demonstrated that, after PGE2 treatment, all of the CREB/ATF isoforms studied, as well as the phosphorylated form of CREB (p-CREB), interacted with CBP. In basal conditions, T cells from patients with conjunctiva basal cell carcinoma showed the presence of p-CREB, which coimmunoprecipitated with CBP. CREB phosphorylation did not modify after PGE2 treatment whereas the p-CREB fraction bound to CBP increased in a delayed manner compared to normal subjects. [ABSTRACT FROM AUTHOR]

Background: Soccer is an intermittent team sport that demands high aerobic capacity. On field, soccer players' aerobic capacity, assessed through the maximal oxygen uptake (VO2max), is usually determined by an intermittent recovery test. The aim of this study was to obtain a construct validity of a new intermittent recovery test (IRT) with a fixed speed and a progressive decrement of rest period., Methods: Twenty-five male soccer players were recruited to perform an incremental continuous test (ICT) and the new IRT, to compare their physiological data. Fifteen male soccer players were involved to perform a test-retest of IRT to assess its reliability., Results: VEpeak, absolute VO2max, relative VO2max and VCO2peak registered during ICT and IRT correlated strongly (Pearson's correlation coefficient ranges from 0.75 to 0.80, with very large as magnitude of effects and with P<0.001). IRT showed reliability from good to excellent regarding VEpeak, absolute VO2max, relative VO2max, VCO2peak and covered distance (ICC values ranged from 0.82 to 0.95)., Conclusions: These findings and its underlying physiological and muscular demands, suggest that IRT can be considered as a valid and reliable test to assess aerobic capacity in soccer players during the competitive period.

Background: The symptoms and complications related to chronic liver disease (CLD) have been shown to affect patient well-being. Currently there is limited research data on how CLD severity may affect both health-related quality of life (HRQOL) and the development of depressive symptoms in CLD patients. Moreover, the ongoing advances in CLD treatment, and its effect on HRQOL, highlight the need for further studies. Therefore, the aim of the present study was to evaluate if the CLD severity may affect the HRQOL and the development of depressive symptoms., Methods: A cross-sectional study was conducted. Patients with CLDs were identified at their regular visits to the outpatient clinic of the Sant'Orsola-Malpighi Hospital in Bologna, between September 2016 and July 2017. HRQOL was measured with Short Form 12 (SF-12) and Nottingham Health Profile (NHP) questionnaires; depressive symptoms were measured with Beck Depression Inventory-II (BDI). CLD severity was measured using the MELD score and the sample was stratified into five classes according to it. Group comparisons were conducted using the Kruskal-Wallis test., Results: Two hundred and fifty-four patients were included. Mean age was 62.84 years (SD 11.75) and 57.9% were male. Most participants were affected by compensated cirrhosis (140.2%) and chronic hepatitis (40.2%), with a disease duration ≥ 5 years (69.3%). Regarding the MELD score, 67.7% of patients belonged to Class I, 29.9% to Class II, and 2.4% to Class III. There were not patients belonging to the Classes IV and V. No statistically significant differences were found in all SF-12 and NHP domains between the MELD classes, except for CLD impact on sexual life and holidays (p = 0.037 and p = 0.032, respectively). A prevalence rate of 26% of depressive symptoms was reported, no statistically significant differences were found in BDI-II total scores between the three MELD classes., Conclusions: All domains of HRQOL and depression were altered in CLDs patients, nevertheless CLD severity was not confirmed as an affecting factor for HRQOL., (© 2021. The Author(s).)

Objectives: To determine whether emergency department (ED) length of stay before ward admission is associated with incident delirium in older adults., Design: Prospective cohort study., Setting: Hospital., Participants: Individuals aged 75 and older without delirium at ED entry, coma, aphasia, stroke, language barrier, psychiatric disorder, or alcohol abuse (N = 330)., Measurements: On ED admission, individuals underwent standardized evaluation of comorbidity (Cumulative Illness Rating Scale), cognitive impairment (Short Portable Mental Status Questionnaire), functional independence (activities of daily living, instrumental activities of daily living), pain (Numeric Rating Scale), and acute clinical conditions (Acute Physiology and Chronic Health Evaluation II). During the first 3 days after ward admission, the presence of delirium (defined as ≥1 delirium episodes within 72 hours) was assessed daily using a rapid assessment for delirium (4AT scale). ED length of stay was calculated as the time (hours) between ED registration and when the person left the ED., Results: ED length of stay longer than 10 hours (odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.13-4.41), moderate to severe cognitive impairment (OR = 5.47, 95% CI = 2.76-10.85), and older age (OR = 1.07, 95% CI = 1.01-1.13) were associated with delirium onset., Conclusion: ED length of stay longer than 10 hours was associated with greater risk of delirium in hospitalized older adults, after adjusting for age and cognitive impairment., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Aim of the Study: The lymph node sentinel method is today used for staging the axillary lymph node stations. Ultrasonography is widely available and inexpensive method to study axillary status., Methods: One hundred fourteen patients were studied consecutively using axillary ultrasonography and ultrasound guided fine needle aspiration of the lymph node. We used ATL Ultramark 9 with 5-7.5 MHz multiple frequency linear probe or Aloka SSDD-1400 with 7.5 MHz linear probe., Results: One hundred fourteen patients were examined; six were excluded because of definitive histological diagnosis of non-infiltrating carcinoma. 106 had monofocal carcinomas, 2 had bifocal carcinoma in 104/108 ultrasonography was carried out successfully. The axillary cytological examination was positive in 18 cases (17.3%) who were subjected to axillary examination. 86 patients were subjected to sentinel lymph node biopsy: positive 13 cases (6 micrometastases). 31 cases/104 (29.8%) showed positive axilla. Sensitivity of ultrasonography was 58%, 100%specificity. Predictive positive value 100%, Negative value 84.9% for an accuracy of 87.5%., Discussion: Ultrasonography is useful in all cases eligible to sentinel lymph node examination; the minimum cost of the procedure and of the human resources is amply rewarded by the direct indication for surgical axillary dissection in case of a positive result (17.3% in our experience).

Background: The current study was designed to assess the activity and safety of a novel combination therapy for patients with recurrent or refractory aggressive non-Hodgkin lymphoma (NHL)., Methods: Forty-three consecutive patients with recurrent or refractory aggressive NHL were treated with lomustine (chloroethylnitrosourea [CCNU]; 60 mg/m2 on Day 1), ifosfamide (1.5 g/m(2 on Days 1, 2 and 21, 22), bleomycin (5 mg/m2 on Days 1, 5 and 21, 25), vincristine (1.4 mg/m2 on Days 1, 8 and 21, 28), and cisplatin (25 mg/m2 on Days 3, 4, 5 and 23, 24, 25), every 42 days (CIBO-P regimen)., Results: Thirty-nine patients (91%) were evaluable for response. The median patient age was 63 years. Thirty-five percent of the patients had received > or = 2 lines of previous chemotherapy and 40% had elevated lactate dehydrogenase levels at the time of treatment initiation. The overall objective response rate was 77% (95% confidence interval [95% CI], 63-90%), including 19 (49%) complete (CR) and 11 (28%) partial responses. CIBO-P induced responses in primary refractory disease and in patients treated for second or subsequent disease recurrences. A CR with previous therapy was the most important factor associated with a significantly higher CR rate. The median duration of response was 6 months (95% CI, 4.4-7.7 months) and the median survival duration was 10.7 months (95% CI, 5.9-18.1 months). Five patients (11.6%) remained disease free for > or = 24 months. By multivariate analysis, a CR with previous therapy and average dose intensity of CIBO-P drugs were independent prognostic factors for time-to-treatment failure, whereas a CR with previous therapy and serum lactate dehydrogenase were independent predictors for survival. Myelosuppression was the most frequent serious complication of this regimen. However, none of the patients had hemorrhage with thrombocytopenia, and only 2 patients (5%) had febrile neutropenia., Conclusions: In the current study, CIBO-P was a novel, highly active, and safe combination therapy for patients with refractory disease with a poor prognosis or for patients with multiply recurrent aggressive NHL.

A 33-year-old woman underwent a liver transplantation and splenectomy in 1985 and had followed immunosuppressive therapy until 1995. Afterwards a non-Hodgkin lymphoma was diagnosed and chemotherapy was started. In January 2000, because of suspect transplantation rejection she was treated with steroid and immunosuppressive therapy. Fever occurred after two months and Cytomegalovirus (CMV) infection was diagnosed. Ganciclovir was started with clinical remission. In November 2000 fever recurred without clinical symptoms. Lymphoma recurrence was excluded and CMV was detected by PCR in several biological fluids. Blood cultures were positive for a bacterium that was identified as Campylobacter fetus. The patient was successfully treated with intravenous ciprofloxacin. For persistent CMV viremia therapy with gancyclovir was stopped and foscarnet was used (60mg/Kg/tid i.v. for two weeks). Bacteremia due to C. fetus is rare, occurring mainly in immunocompromised patients. In our patient the immunosuppressive therapy, chemotherapy for lymphoma and CMV infection had made the patient susceptible to bacteremia with this infrequently found bacterium. The clinical microbiologist should be aware of this infection in immunocompromised hosts.

The histamine content of tears of healthy sex- and age-matched subjects and patients affected by allergic or nonallergic inflammatory ocular diseases was determined through a new competitive reverse-phase high-performance liquid chromatography (HPLC) method. Tear samples from 50 healthy subjects, 30 patients affected by seasonal allergic conjunctivitis, 12 patients with bacterial conjunctivitis associated with Haemophilus influenzae and 8 patients with bacterial conjunctivitis associated with Streptococcus pneumoniae were analyzed for histamine concentration by O-phthaldialdehyde precolumn derivatization-based HPLC. In physiological conditions, the tear histamine content was low (2.26 ng/ml) and did not vary in relation to age and sex. Histamine levels were significantly higher in all the patients studied, to a greater extent in those affected by allergic (23.61 ng/ml) or Haemophilus influenzae-associated (21.53 ng/ml) conjunctivitis., (Copyright 2004 S. Karger AG, Basel)

We designed the P-CHOP regimen, which involves the addition of cisplatin (P) to the standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen, and investigated its activity and its toxicities in a single institution phase II study. Twenty-two consecutive patients with untreated, aggressive, stage I-IV non-Hodgkin lymphoma were enrolled in the study. Cisplatin was administered at a dose of 40 mg/m2 on days 1 and 2, every 3 weeks; the dose and schedule of the other agents were identical to those used in the standard CHOP regimen. The complete remission (CR) rate was 86% in eligible and 80% in all the treated patients, which compares favorably with the CR rates of two recent randomized studies of CHOP versus other regimens. P-CHOP is an innovative regimen for the front-line treatment of aggressive non-Hodgkin lymphoma. It is feasible and warrants further research, which would ideally take the form of a randomized comparison of P-CHOP and CHOP, possibly with the addition of rituximab in both arms.

Background and Aims: To evaluate the feasibility in clinical practice of alternating chemo-radiotherapy in locally advanced head and neck cancer patients., Patients and Methods: From August 1993 to April 1998 at the Division of Medical Oncology of Parma, 48 consecutive patients were observed, and 38 (79%) started the Merlano chemo-radiotherapy. The characteristics of the patients were: males (32, 84%); median age, 57 years; PS <2 (32, 84%). The primary sites were the oropharynx (18, 47%), oral cavity (8, 21%), hypopharynx (7, 19%), larynx (5, 13%); stage IV disease was present in 29 (76%) patients. Twenty-five (66%) patients were married, and 24 (63%) resided outside of the city., Results: The compliance was very low: 21 patients (55%) performed all the programmed cycles of chemotherapy, whereas only 5 patients (13%) performed the chemo-radiotherapy at full doses without any delay. The objective responses were 3 (8%) complete and 21 (55%) complete plus partial responses. Failures were 2 (5%) stable disease and 2 (5%) progressive disease, and the response was not assessable in 10 (26%). The median duration of the response was 8 months. The median overall survival and the time to progression were 18 and 13 months, respectively; the 5-year overall and relapse-free survival were 36% and 26%, respectively. Nine (24%) patients were still alive as of August 30, 2001, 8 (21%) of them without progression. Twenty-six patients (68%) died with a local-regional relapse. One patient (3%) died for a second cancer. Grade 3-4 hematologic toxicity was leukopenia (n = 25, 66%) and thrombocytopenia (n = 9, 24%); grade 3-4 non-hematologic toxicity was diarrhea (n = 3, 8%) and mucositis (n = 2, 5%). Two patients (5%) died for intestinal infarction and perforation possibly related to treatment., Conclusions: Compliance to the chemo-radiotherapy was very poor. The response rate was lower than that reported in clinical trials, whereas overall survival was comparable. The alternating chemo-radiotherapy is a very complex treatment that cannot be easily applied in clinical practice; a careful selection of patients is mandatory not only considering oncologic and medical criteria, but also the level of awareness of the patient and his family.

Background: According to the overview of Early Breast Cancer Trialists' Collaborative Group, anthracycline containing regimens are superior to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant chemotherapy for breast carcinoma, but no comparative information is available in terms of primary chemotherapy. In the current randomized controlled trial, the authors compared CMF with a chemotherapy regimen including CMF, epirubicin, and vincristine (CMFEV)., Methods: Two hundred eleven patients with Stages I and II palpable breast carcinoma and tumor diameter > 2.5 cm or < or = 2.5 cm with cytologically proven axillary lymph node involvement were randomized to receive CMF (arm A) or CMFEV regimen (arm B) for four cycles before surgery. After surgery, patients in both arms received adjuvant CMF for three cycles; the postmenopausal patients also received tamoxifen for two years., Results: There were no significant differences in the complete response (CR) and in the CR plus partial response (PR) rates between the two arms. In the subset analysis, among premenopausal patients, significantly higher rates of CR (26% vs 4%, P = 0.004) and of CR + PR rates (80% vs 54%, P = 0.007) were observed in the CMFEV, as compared to the CMF arm. Multivariate analysis confirmed the presence of a significant interaction between menopausal status and type of treatment on the probability of achieving CR (P = 0.02) or CR + PR (P = 0.01). There were no major differences in the side effects of the two treatments, with the exception of more frequent alopecia in the experimental arm., Conclusions: The results of the current study are in line with those of previous published randomized clinical trials comparing regimens without and with anthracycline as adjuvant treatment, indicating an agreement between the short term response to primary chemotherapy and the long term results observed in the adjuvant setting., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10678)

In a retrospective analysis of a series of clinical trials by Levin and Hryniuk in 1987, the average relative dose intensity of first-line chemotherapy for advanced ovarian cancer correlated significantly with clinical response and survival, and cisplatin was the only drug for which the outcome correlated with the individual drug relative dose intensity. There was a need to test whether and to what extent this evidence would be confirmed in a prospective evaluation. In this study 101 patients with advanced ovarian carcinoma were randomized to receive the same total dose of cisplatin but at the conventional 3-weekly schedule (CTWS) (100 mg/m2 every 3 weeks for six cycles) (51 patients) or at an experimental accelerated weekly schedule (AWS) (100 mg/m2 every week for two triplets of three cycles separated by a 5-week interval) (50 patients). To benefit from a multidrug regimen at the same extent, patients in both arms sequentially received four cycles of doxorubicin and cyclophosphamide. The median follow-up period of this study is 9.7 years. In 42 and 40 patients of the two arms having evaluable response, the clinical complete response rates to cisplatin were 14% and 22% and the complete plus partial response rates were 48% and 55% in the CTWS and in the AWS arm, respectively. These differences were not statistically significant. However, the survival curves were similar during the first 2 years but clearly diverged thereafter in favor of the AWS arm (p = 0.07). At 5 years, 12% and 30% of the patients were still alive in the CTWS and in the AWS arm, respectively. Hematologic toxicity was not relevant in either arm of the study. Nonhematologic toxicity, especially ototoxicity, was substantial and significantly higher in the AWS arm. Although statistically nonsignificant, this AWS regimen of cisplatin is associated with long-term better survival compared to the CTWS regimen in advanced ovarian carcinoma. This accelerated approach administering cisplatin should be further investigated, especially in patients with low residual disease after primary surgery.

We designed three new four-drug cisplatin-containing combinations and evaluated their activity in a randomized phase II study including patients with locally advanced (stage III) and locally recurrent breast carcinoma. All combinations included methotrexate (M) on day 1 and cisplatin (P) on day 2 (MVAC-like combinations) and differed from one another by the addition of Epirubicin (Epi), Vincristine (V), Etoposide (E), Mitomycin (Mi). Based on the administered agents, they were named MPEMi, MPEpiE, MPEpiV. The combinations were randomly assigned to 101 patients, 57 with locally advanced and 44 with locally recurrent breast carcinoma. Response was evaluated after 4 cycles. The complete response (CR) rates were 7% and 43% and the CR plus partial response (PR) rates were 84% and 89% in locally advanced and in locally recurrent disease, respectively. In locally advanced disease, a pathologic CR (pCR) was assessed in seven of 57 patients (12%). There were no significant differences among the three combinations. The toxicities were at times severe, but generally tolerable, as demonstrated by the high cumulative doses of the drugs received by the patients. In conclusion, these three innovative chemotherapy regimens induced high CR plus PR rates in the neoadjuvant treatment of stage III and of locally recurrent breast carcinoma, and a high rate of pCR in stage III disease. These regimens warrant testing in phase III trials.

Background: Fine-needle aspiration (FNA) biopsy has been used increasingly in the diagnosis and biologic characterization of breast carcinomas in patients who receive preoperative chemotherapy. Because proliferative activity of breast carcinoma has been shown to be of prognostic significance, the authors compared immunocytochemical Ki-67 growth fraction and flow cytometric S-phase fraction (SPF), both evaluated on FNA samples., Methods: The proliferative activity of 134 FNA samples from primary breast carcinoma patients was studied using both immunocytochemistry with the monoclonal antibody Ki-67 and SPF determined by DNA flow cytometry., Results: Ki-67 and SPF were evaluable in 114 and 107 cases, respectively, and both were evaluable in 95 cases. Of the 134 FNA samples studied, 37% were diploid and 63% were aneuploid. The distribution of both Ki-67 and SPF was different in diploid and aneuploid tumors. The median Ki-67 value as well as the median SPF were significantly higher in aneuploid versus diploid tumors (P < 0.001). Median Ki-67 and SPF values were used to discriminate between low versus high proliferating tumors. The overall concordance between Ki-67 and SPF was 75% (P < 0.001). A good correlation was found between Ki-67 and SPF (correlation coefficient = 0.72; P < 0.001)., Conclusions: The results of the current study suggest that Ki-67 growth fraction and SPF determined by FNA may be used as measurements of the proliferative activity of breast carcinoma. The authors recommend these determinations be used as preoperative procedures in patients with a cytologic diagnosis of breast carcinoma who are candidates for neoadjuvant chemotherapy and/or endocrine therapy.

Aims and Background: The study was designed to define the activity of the combination of cisplatin and etoposide as third-line chemotherapy for advanced breast cancer and to investigate the role of the dosage of cisplatin on the effectiveness of the combination., Methods: Ninety-five eligible patients with advanced breast cancer who had failed or relapsed on two previous lines of chemotherapy were randomized to receive cisplatin at a high dose (100 mg/m2 i.v. day 1, arm A) or a low dose (60 mg/m2 day 1, arm B), combined with etoposide (100 mg/m2 i.v. days 4, 6 and 8). Cycles were repeated every 3 weeks., Results: Of the 78 patients evaluable for response (39 in arm A and 39 in arm B), 9 (12%) showed complete or partial response, 5 (13%) in the high-dose arm and 4 (10%) in the low-dose arm. One complete response was seen in the high-dose arm and none in the low-dose arm. The only 2 patients with brain involvement showed an objective response (one CR in arm A and one PR in arm B). Median time to progression was 14 weeks in arm A and 10 weeks in arm B, median duration of remission 28 and 34 weeks, and survival 36 and 35 weeks, respectively. The differences were not significant. As expected, the patients in the high-dose arm experienced more severe toxicity. One toxic death was observed in each arm due to sepsis in agranulocytosis. The difference was statistically significant regarding nausea and vomiting. Neurotoxicity and ototoxicity were not relevant problems in this patient setting., Conclusions: Considering the very poor prognostic factors presented by these patients, the combination showed a certain activity, and further evaluation in earlier stages of disease is warranted. A particular responsiveness on brain metastases is suggested. The dose of cisplatin was not proven to be of significant importance.

To evaluate the efficacy of a three-drug regimen vs. a two-drug CDDP based combination in the treatment of NSCLC, we conducted a three-arm randomized parallel trial comparing (a) CDDP (120 mg/m2 day 1) + etoposide (100 mg/m2 days 1-3) every 3 weeks (PE--arm A); (b) CDDP (120 mg/m2 every 4 weeks) + mitomycin (8 mg/m2 days 1, 29, 71) + vindesine (3 mg/m2 days 1, 8, 15, 22 every 2 weeks) (MVP--arm B); and (c) CDDP (120 mg/m2 day 1) + mitomycin (6 mg/m2 day 1) + ifosfamide (3 g/m2 day 2) every 3 weeks (MIC--arm C). From May 1989 to April 1992, 393 consecutive previously untreated patients with NSCLC Stage IIIB and IV entered the trial; 373 were evaluable for survival and 360 for response. The response rate was significantly better for both the three-drug regimens compared with PE (Table 3). Logistic regression model showed a significantly better response in patients with a good P.S. and in Stage IIIB. Main toxicity consisted of myelosuppression: neutropenia Grade III-IV was recorded in 14% (arm A), 15% (arm B) and 21% (arm C). Thrombocytopenia Grade III-IV was worst in arm C: 10% vs. 5% (arm A) and 3% (arm B). Nephrotoxicity Grade III-IV was more common in arm C: 3.5%. Toxic deaths were 11 (3%: three in arm A, five in arm B, three in arm C). From our data, the three-drug containing regimens, MVP and MIC, appear more active than the two-drug combination PE in treatment of advanced NSCLC.

Background: Endocrine factors may affect the clinical course of malignant melanoma and the response to the treatment of this disease. The presence of estrogen receptors in melanomas has been suggested, and occasional responses to antiestrogen therapy have been reported., Methods and Results: We randomly assigned 117 patients with metastatic malignant melanoma to treatment with dacarbazine alone or dacarbazine in combination with tamoxifen. The overall rate of response, measured objectively, was higher (28 percent vs. 12 percent, P = 0.03) and survival was longer (median, 48 vs. 29 weeks, P = 0.02) among the patients who received dacarbazine plus tamoxifen than among those who received dacarbazine alone. Among women, both the response rate (38 percent vs. 10 percent, P = 0.04) and the median survival (69 vs. 30 weeks, P = 0.008) were better with dacarbazine plus tamoxifen than with dacarbazine alone, whereas among men the differences were smaller and not statistically significant. Among the patients given dacarbazine alone, there were no significant differences between women and men in response rate (10 percent vs. 13 percent) or survival (30 vs. 27 weeks), whereas among those given dacarbazine plus tamoxifen, women had better outcomes, as indicated by both response rate (38 percent vs. 19 percent, P = 0.15) and survival (69 vs. 31 weeks, P = 0.02). When we analyzed the Quetelet body-mass index (the weight in kilograms divided by the square of the height in meters) as an indirect indicator of the levels of endogenous estrogens in postmenopausal women and in men, survival was not affected by the body-mass index in the group given dacarbazine alone, whereas in the group given dacarbazine plus tamoxifen, survival was longer among patients whose Quetelet index was above the median value than among those with a Quetelet index lower than the median value (60 vs. 26 weeks, P less than 0.001)., Conclusions: In the treatment of metastatic malignant melanoma, dacarbazine plus tamoxifen is more effective than dacarbazine alone, as indicated by both the response rate and the median survival; the difference in efficacy is among women.

Purpose: A randomized study comparing low-dose aminoglutethimide (AG) with and without hydrocortisone (HC) was performed to investigate whether corticosteroid replacement contributes to the therapeutic effects of the drug administered as a front-line endocrine therapy in postmenopausal advanced breast cancer., Patients and Methods: Postmenopausal patients who had not had prior endocrine therapy for advanced disease and with estrogen receptor (ER) or progesterone receptor (PgR) status positive or unknown were eligible. AG was administered at a dose of 250 mg twice a day orally (125 mg twice a day during the first month) with or without HC (20 mg twice a day orally). Seventy-nine and 74 patients were assessable for response on the AG plus HC arm and on the AG arm, respectively. The two treatment groups were well balanced and patients were largely untreated. Approximately 60% had not received any adjuvant treatment, and approximately 75% had not received any medical treatment after relapse., Results: The overall responses (complete response [CR] plus partial response [PR]) were 44% and 41% for the AG plus HC and the AG arm, respectively, showing no significant difference. Time to progression (median, 8.1 and 6.3 months), duration of response (median, 15.8 and 13.7 months), and duration of survival (median, 34.2 and 36.3 months) were not significantly different between the two treatment arms. Side effects were infrequent and mild in both arms, with no significant differences., Conclusion: We conclude that half of the conventional daily dose of AG has optimal therapeutic activity as a front-line endocrine treatment of postmenopausal advanced breast cancer and that HC does not significantly contribute to the therapeutic effects.

In this prospective randomized study, first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median, 32 v 31 weeks), duration of response (48 v 39 weeks), and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE, and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned, a trend of superiority over CMF was observed, which was of borderline significance. Due to the lack of survival advantage and to toxicity, this combination is not recommended for routine clinical use. However, its high level of activity should be taken into account for further research.

Twenty patients with recurrent or metastatic gastric adenocarcinoma and prior chemotherapy were treated with cisplatin, 60-120 mg/m2 as a 6-hr infusion repeated every 3 weeks. There were 4 partial responses in 18 evaluable patients. Seven patients had stable disease. Time to progression ranged from 6 to 28 weeks. Median WBC nadir was 3.2 X 10(3)/mm3 (range, 1.5-7.1) and platelet nadir 120 X 10(3)/mm3 (range, 13-220). A transient increase in serum creatinine was observed in 6 cases, and nausea and vomiting in all. We conclude that this drug is active in stomach cancer and that it warrants further trials in combination chemotherapy.

Twenty-four evaluable extensively pretreated advanced breast cancer patients received a combination of platinum and etoposide. Platinum was given i.v. at the dose of 80 mg/mq at day 1. Etoposide was given at the dose of 120 mg/mq i.v. at day 1, and p.o. at the dose of 200 mg/mq at day 3 and 5. Treatment was repeated every 3 weeks. CR was never obtained. PR was observed in four patients (17%), MR in two, NC in seven and PD in 11 patients. PR plus MR occurred in six patients (25%). Considering the extensive pretreatment of patients, the results seem to indicate that this combination is active and can be included among the possible options in treating chemotherapy refractory advanced breast cancer. Moreover, it deserves further evaluation in an earlier phase of the disease.

From July 1980 to June 1983, 61 postmenopausal women with progressive metastatic breast cancer were treated with aminoglutethimide, 250 mg 4 times daily, plus cortisone acetate, 25 mg twice daily. Of 51 evaluable patients, an objective remission was observed in 22 (43%) (partial remission in 19, complete in 3), stable disease in 14 (27%), and progressive disease in 15 (30%). The median duration of response was 60 weeks (range 12+; 94+). The response rate was higher when the dominant disease site was soft tissue (50%) or bone (56%) rather than viscera (29%). Side effects were common but usually slight and transient. Somnolence (69%), dizziness (41%), nausea (35%) and skin rash (27%) were the most frequent. Serum levels of gamma-GT, alkaline phosphatase and total cholesterol rose during aminoglutethimide treatment, whereas levels of uric acid and indirect bilirubin decreased. Aminoglutethimide plus cortisone acetate appears to be an active and relatively safe treatment in advanced breast cancer and may be recommended as second-line endocrine treatment.

From April 1982 to December 1987, 71 patients with small cell lung cancer entered a randomized clinical trial, and underwent bone marrow biopsy (BMB) as part of staging procedures. We identified 8 patients (11%) with bone marrow metastases, 6 with extensive disease independently of BMB, and 2 with extensive disease on the basis of the BMB only. BMB determined a change in the stage in only 3% (2/71) of the cases. No differences were found in the hematological parameters of the patients with or without bone marrow metastases. The median survival of the patients with bone marrow involvement was the same (41 weeks) as those with extensive disease but without bone marrow involvement. We conclude that unilateral BMB without aspiration detects a substantial proportion of bone marrow metastases in patients with extensive disease. This fact does not worsen the prognosis. A small proportion of patients with apparently limited disease has bone marrow involvement. The technique therefore contributes, to a small extent, to the definition of the clinical stage of the disease. However, bone marrow involvement is an important data of natural history, and therefore new methods to better assess this peculiar site of the disease are needed.