Long-term decline of the Amazon carbon sink.

Atmospheric carbon dioxide records indicate that the land surface has acted as a strong global carbon sink over recent decades, with a substantial fraction of this sink probably located in the tropics, particularly in the Amazon. Nevertheless, it is unclear how the terrestrial carbon sink will evolve as climate and atmospheric composition continue to change. Here we analyse the historical evolution of the biomass dynamics of the Amazon rainforest over three decades using a distributed network of 321 plots. While this analysis confirms that Amazon forests have acted as a long-term net biomass sink, we find a long-term decreasing trend of carbon accumulation. Rates of net increase in above-ground biomass declined by one-third during the past decade compared to the 1990s. This is a consequence of growth rate increases levelling off recently, while biomass mortality persistently increased throughout, leading to a shortening of carbon residence times. Potential drivers for the mortality increase include greater climate variability, and feedbacks of faster growth on mortality, resulting in shortened tree longevity. The observed decline of the Amazon sink diverges markedly from the recent increase in terrestrial carbon uptake at the global scale, and is contrary to expectations based on models.

Threats to intact tropical peatlands and opportunities for their conservation.

Large, intact areas of tropical peatland are highly threatened at a global scale by the expansion of commercial agriculture and other forms of economic development. Conserving peatlands on a landscape scale, with their hydrology intact, is of international conservation importance to preserve their distinctive biodiversity and ecosystem services and maintain their resilience to future environmental change. We explored threats to and opportunities for conserving remaining intact tropical peatlands; thus, we excluded peatlands of Indonesia and Malaysia, where extensive deforestation, drainage, and conversion to plantations means conservation in this region can protect only small fragments of the original ecosystem. We focused on a case study, the Pastaza-Marañón Foreland Basin (PMFB) in Peru, which is among the largest known intact tropical peatland landscapes in the world and is representative of peatland vulnerability. Maintenance of the hydrological conditions critical for carbon storage and ecosystem function of peatlands is, in the PMFB, primarily threatened by expansion of commercial agriculture linked to new transport infrastructure that is facilitating access to remote areas. There remain opportunities in the PMFB and elsewhere to develop alternative, more sustainable land-use practices. Although some of the peatlands in the PMFB fall within existing legally protected areas, this protection does not include the most carbon-dense (domed pole forest) areas. New carbon-based conservation instruments (e.g., REDD+, Green Climate Fund), developing markets for sustainable peatland products, transferring land title to local communities, and expanding protected areas offer pathways to increased protection for intact tropical peatlands in Amazonia and elsewhere, such as those in New Guinea and Central Africa which remain, for the moment, broadly beyond the frontier of commercial development.

The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma.

Forty consecutive patients with stage III and IV invasive ovarian carcinoma were treated on a phase II protocol consisting of optimal debulking surgery, induction cisplatin, cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy, 6-month interval laparoscopy, reinduction cisplatin, PAC chemotherapy, and second-look procedure. All 40 patients have either disease progression or have completed the 12-month protocol. Eighty-seven percent of the patients (35) underwent optimal (less than or equal to 2 cm residual) debulking surgery before chemotherapy, in spite of the fact that 50% (20) were referred to Roswell Park Memorial Institute (RPMI) as inoperable after initial surgery elsewhere. There were no postoperative deaths and chemotherapy was started in less than or equal to 14 days in 97% of the patients. Of the 40 patients, 30% (12) achieved a pathologic complete remission (11) or a clinical complete remission (one patient refused second-look surgery). The estimated 3-year survival rate was 62%, but the 3-year progression-free survival rate was only 29%. The median survival time was 48 months. The estimated 3-year progression-free survival rate was 31% for residual disease less than or equal to 2 cm. For the five patients with residual disease greater than 2 cm, four died within 3 years. The median survival time of patients with less than or equal to 2 cm residual disease was 48 months, as compared with 21 months for those with greater than 2 cm residual disease. Although the estimated 3-year survival rate of 62% is noteworthy, the 3-year progression-free survival rate of only 29% is probably indicative that in spite of extensive debulking surgery and cisplatin-based chemotherapy as used in this protocol, the long range proportion of patients "cured" will remain small.

Surgically documented response to intraperitoneal cisplatin, cytarabine, and bleomycin after intravenous cisplatin-based chemotherapy in advanced ovarian adenocarcinoma.

Thirty-one evaluable patients with stages III and IV invasive ovarian adenocarcinoma were treated on a phase II protocol of second-line intraperitoneal cisplatin, cytarabine, and bleomycin. All 31 patients received first-line intravenous (IV) cisplatin-based chemotherapy; the size of the residual cancer was documented surgically before intraperitoneal chemotherapy in all patients. Response to intraperitoneal chemotherapy was documented by a third-look laparotomy in all patients not evidencing progression of disease clinically. There were eight responses (26%): five surgical complete responses and three surgical partial responses. Responders were patients with stage III ovarian cancer, small residual disease of less than or equal to 1 cm (primarily less than or equal to 5 mm), and patients who previously had responded to cisplatin-based IV chemotherapy. Of the 15 patients with stage III ovarian cancer, residual disease less than or equal to 1 cm, and those who had responded to first-line IV cisplatin-based chemotherapy, 53% (eight) responded to second-line intraperitoneal chemotherapy. Intraperitoneal chemotherapy as used in this phase II protocol would appear to be an effective second-line treatment in advanced ovarian cancer in this specific subset of patients.

Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery.

PURPOSE: The purpose of this study is to delineate the factors which (a) contribute to an increase in the severe, radiation induced complication rate and (b) have a significant effect on survival in patients with International Federation of Gynecologists and Obstetricians (FIGO) Stage I-IVA cervical cancer undergoing pretherapy surgical staging. METHODS AND MATERIALS: From 1971-1991, 189 patients underwent pretherapy surgical staging via a retroperitoneal approach (67) or transperitoneal approach (122). Seventy-nine patients had previously experienced a laparotomy. Patients subsequently received a median of 85 Gy to point A. In patients receiving paraaortic radiation, a median of 45 Gy was administered. One hundred and thirty-two (69.8%) patients received hydroxyurea as a radiation sensitizer. RESULTS: Pretherapy surgical evaluation revealed that 21 of 89 (23.6%) Stage II patients and 32 of 85 (37.6%) Stage III patients had paraaortic lymph node metastases. Multivariate logistic regression analysis detailed the significant factors favorably influencing the radiation-induced complication rate to be a retroperitoneal approach of pretherapy surgical staging and no previous laparotomy. Survival was significantly prolonged in patients receiving hydroxyurea, evaluated via a retroperitoneal incision, with negative paraaortic lymph nodes, and with an early stage of disease. CONCLUSION: A retroperitoneal approach to pretherapy surgical staging and absence of previous surgery reduced the incidence of subsequent radiation-induced complications. Despite improvements in the detection of occult disease, prolonged survival is impaired when the therapeutic measures currently available are used.

Survival in patients with paraaortic lymph node metastases from endometrial adenocarcinoma clinically limited to the uterus.

PURPOSE: The purpose of this study was (a) to evaluate the incidence of paraaortic lymph node metastasis from adenocarcinoma of the endometrium clinically limited to the uterus (1971 FIGO Stages I and II) and (b) to report the 5 year disease-free survival of patients with histologically documented paraaortic lymph node metastasis from endometrial adenocarcinoma clinically limited to the uterus treated on two separate protocols. METHODS AND MATERIALS: From June 1979 to June 1990, 109 patients underwent staging paraaortic lymphadenectomy or paraaortic lymph node biopsy at the time of total abdominal hysterectomy and bilateral salpingo-oophorectomy for adenocarcinoma of the endometrium clinically limited to the uterus. Patients with histologically documented paraaortic lymph node metastasis were treated on two protocols: (a) pelvic radiation (5,040 cGy) plus progestins or (b) pelvic radiation therapy (5,040 cGy) plus paraaortic radiation (4,500 cGy). RESULTS: Paraaortic lymph node metastases was primarily associated with grade 3 tumors (34.4%) and deep myometrial invasion (42%) and was present in 17.4% (19) of 109 patients. None of the women treated with pelvic radiation therapy and progestins survived five years disease-free. In contrast, the 5 year disease-free survival was 27% for patients treated by pelvic and paraaortic radiation. CONCLUSIONS: Since all patients with macroscopic metastases to the paraaortic lymph nodes developed recurrent cancer and only a small percentage of those with microscopic metastases to the paraaortic lymph nodes survived disease-free at 5 years, improved survival for patients with paraaortic lymph node metastases will necessitate the addition of effective cytotoxic chemotherapy to pelvic and paraaortic radiation.

Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines.

A series of hydroxamates was prepared from an aminoproline scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors, such as compound 47, display broad-spectrum activity with sub-nanomolar potency for some enzymes. Modifications of the P1' portion of the molecule played a key role in affecting both potency and selectivity within the MMP family. Longer-chain aliphatic substituents in this region of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is rationalized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrease with longer and more hydrophilic substituents. Finally, a rat model of osteoarthritis was used to evaluate the efficacy of these compounds, and a direct link was established between their pharmacokinetics and their in vivo efficacy.

Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.

A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.

Rapid liquid chromatographic-mass spectrometric assay for oxymetazoline in whole rat blood.

A rapid HPLC-electrospray mass spectrometric assay for the quantitation of oxymetazoline in whole rat blood has been developed. Sample preparation was a single liquid-liquid extraction after addition of a deuterated internal standard (IS) and pH adjustment. An aliquot of reconstituted extract was injected onto a narrow-bore octadecyl reversed-phase column at a flow-rate of 400 microliters/min. Using a 20:1 post-column split, 5% of the eluent was introduced into the mass spectrometer interface. Elution of the analyte and IS occurred in less than 2 min. This rapid separation was made possible because of the sample cleanup and the selectivity of the mass spectrometric detection. The [M+H]+ ions for oxymetazoline (m/z 261) and [2H9]oxymetazoline (m/z 270) were detected using selected ion monitoring. The linear range of the assay was 0.67-167 ng/g of blood and the limit of quantitation with a 0.30-g sample was 1.0 ng/g. The assay permitted the analysis of nine samples per hour with the requisite sensitivity and selectivity and was used to determine the blood pharmacokinetics of oxymetazoline in rats dosed via intravenous and intranasal routes.

Phase II trial of cisplatin, adriamycin, and etoposide for metastatic endometrial adenocarcinoma.

Twenty patients with metastatic or recurrent endometrial adenocarcinoma not amenable to surgery or radiation were treated with monthly cisplatin (20 mg/m2 x 3), etoposide (75 mg/m2 x 3), Adriamycin (40 mg/m2) (PAV) and Megace. Patient characteristics were as follows: grade 3 differentiation, 55%; papillary subtype, 15%; prior radiotherapy, 70%; prior chemotherapy, 10%; and prior hormonal therapy, 20%. Hematologic toxicity was significant but acceptable: WBC nadirs, 50%; platelet nadirs, 40%. There was no hematologic mortality. There was a 75% objective response rate and a 55% complete response rate with PAV. The median survival was 15+ months, the 2-year survival was 42%, and the 2-year progression-free survival was 20%. PAV appears to be an active combination with acceptable toxicity in the treatment of metastatic or recurrent endometrial cancer, and we believe that phase III evaluation is indicated.

Prospective trial of cisplatin, adriamycin, and dacarbazine in metastatic mixed mesodermal sarcomas of the uterus and ovary.

Twenty-four patients with advanced or recurrent uterine (13) and ovarian (11) mixed mesodermal sarcomas received a combination of cisplatin. Adriamycin and dacarbazine (PAD) as initial therapy after surgical debulking. Of the 13 patients with metastatic uterine sarcoma, six (46.1%) remained without evidence of disease (NED) from 8 to 36 months from the start of PAD. The estimated 1-, 2-, and 3-year survivals for these patients were 68%, 68%, and 51%, respectively. Of the 11 ovarian sarcoma patients, five (45.4%) were NED at 5, 7, 32, 56, and 59 months from the start of PAD. The estimated 1-, 2-, and 3-year survivals for these patients were 70%, 35%, and 35%, respectively. The PAD regimen is an active regimen in patients with metastatic uterine and ovarian mixed mesodermal sarcomas and progression-free survival may be improved by maximum debulking surgery prior to the initiation of PAD chemotherapy.

Impact on progression-free survival of adjuvant cyclophosphamide, vincristine, doxorubicin (adriamycin), and dacarbazine (CYVADIC) chemotherapy for stage I uterine sarcoma. A prospective trial.

To assess the impact on progression-free survival of the use of the multiagent chemotherapy regimen of cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dacarbazine (CYVADIC) as adjuvant treatment for patients with stage I uterine sarcoma: 20 evaluable patients who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for stage I uterine sarcoma received adjuvant multiagent chemotherapy with vincristine sulfate 1 mg/m2 days 1 and 4, doxorubicin (Adriamycin) 40 mg/m2 and cyclophosphamide 400 mg/m2 day 2, and dacarbazine 200 mg/m2 days 1 through 4 for a total of 9 monthly cycles or until recurrence of disease was documented. Patients were followed for a median of 65 months (range: 5-116 months). Myelotoxicity was monitored by weekly complete blood counts, cardiac toxicity by monthly radionuclide angiography, and neurotoxicity by monthly physical examination. Survival and progression-free survival were calculated by the method of Kaplan and Meier (17). The Fisher exact test was employed to determine the significance of recurrence rates between histologic groups (18). These 20 patients received 172 of a planned 180 cycles of chemotherapy. Dose reductions in response to myelotoxicity were necessitated in four cycles among three patients. Mild neurotoxicity was observed in six patients (30%) and moderate neurotoxicity in one patient (5%). A decrease in cardiac ejection fraction of > 10% was observed in two patients (10%). No deaths ascribable to complications arising from chemotherapy were observed. Seven patients (35%) developed recurrence of disease. Recurrence rates for pure sarcomas and mixed mesodermal tumors did not differ significantly (P = .65). Progression-free survival for the population at 2 years was 80% and at 5 years was 65%. This study describes the largest prospective trial of adjuvant combination chemotherapy for patients with stage I uterine sarcoma reported to date. Adjuvant chemotherapy employing the combination of cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dacarbazine (CYVADIC) failed to impact significantly on long-term survival in this group of patients with stage I uterine sarcoma.

Immunoscintigraphy using 111InCyt103 prior to second look laparotomy in ovarian cancer. A pilot study.

A prospective pilot study was performed in order to determine the efficacy of 111InCyt103 (ONCOScintr CR/OV) in the detection of the presence and location, or absence of disease among patients with epithelial ovarian cancer who demonstrated no clinical or biochemical (Ca 125: < 35 mu/ml) evidence of disease at the end of first-line therapy. Among 15 patients who underwent second-look laparotomy, the overall accuracy of the test was 60%. The test demonstrated a sensitivity of 62.5% and a specificity of 57.1%. The predictive value of a positive test was 62.5% and of a negative test was 57.1%. The correct location of disease was predicted in 57% of patients with macroscopically appreciable tumors. ONCOScintr CR/OV offers little appreciable advantage over current modalities in discriminating between the presence or absence of disease among patients with epithelial ovarian cancer who demonstrate no clinical evidence of disease at the end of first-line therapy.

The addition of etoposide and ifosfamide to cisplatin as second line therapy in ovarian carcinoma.

Forty-five patients with progressive or recurrent ovarian carcinoma received cisplatin, etoposide, and ifosfamide as salvage chemotherapy. The primary purpose of this trial was to evaluate if etoposide and ifosfamide added to cisplatin was effective second line therapy in the 20 patients with progressive or recurrent ovarian cancer after first line cisplatin-based chemotherapy. The overall response in the 20 patients was 20%, all of which were complete responses. However, responses were seen only in patients who had previously responded to first line cisplatin-based chemotherapy and then developed recurrent cancer, whereas none of the patients whose cancer progressed during first line cisplatin-based chemotherapy responded. The addition of etoposide and ifosfamide to cisplatin as second line therapy does not potentiate cisplatin in patients demonstrating first line cisplatin resistance and most likely does not contribute to the second line responses in those patients who demonstrated first line cisplatin sensitivity. This combination is also ineffective as third, forth, fifth or sixth line salvage chemotherapy with a response rate of only 8%.

Response to Taxol chemotherapy in resistant ovarian carcinoma.

Taxol was administered to 25 patients with progressive ovarian cancer who had failed three or more lines of chemotherapy. A response rate of 27% was noted in 22 evaluable patients (5 partial responders; 1 complete responder). Median duration of response was only eight weeks. The impact of Taxol's use in this disease awaits the result of trials in which it is administered as first line therapy.

Lack of activity of 5-fluorouracil plus mitomycin-C as salvage therapy in cisplatin-resistant epithelial ovarian cancer: results of a phase II trial.

Twenty-five patients with progressive, cisplatin-resistant epithelial ovarian cancer received 5-Fluorouracil (5-FU) 500 mg/m2 days one through three and Mitomycin-C 10 mg/m2 every 28 days in a phase II trial. Myelotoxicity manifested as thrombocytopenia resulted in dose reduction, delay of therapy, or discontinuation of treatment in 24% of patients. Only two patients (8%) demonstrated a partial response to therapy. Neither response was durable. The majority of patients (76%) demonstrated progression of disease following a single course of therapy. As utilized in this trial, the combination of 5-FU and Mitomycin-C is not an active salvage regimen for patients with cisplatin-resistant, progressive epithelial ovarian cancer.

Seroepidemiologic survey for Coxiella burnetii among hospitalized US troops deployed to Iraq.

Q fever is a zoonotic illness which frequently has a non-specific clinical presentation. Cases among deployed US military personnel have been reported in increasing numbers indicating an emerging at-risk occupational group. Banked serum specimens were utilized to estimate seroprevalence and risk factors among military personnel deployed to Iraq. Coxiella burnetii antibody testing was performed and epidemiologic data were analysed from 909 servicemembers. The overall number who seroconverted to Q fever was 88 (10%). The most common ICD-9 code assigned to Q fever cases was fever not otherwise specified (NOS) (45%). A combat occupational specialty was a risk factor for Q fever seroconversion (OR = 1.8, 95% CI: 1.1-2.8) as well as receiving a primary diagnosis of fever NOS (OR = 2.6, 95% CI: 1.6-4.1). These findings indicate that Q fever is a significant infectious disease threat to military personnel deployed to Iraq. A heightened awareness among physicians is necessary to ensure prompt diagnosis and treatment.