An early modern human presence in Sumatra 73,000-63,000 years ago.

Genetic evidence for anatomically modern humans (AMH) out of Africa before 75 thousand years ago (ka) and in island southeast Asia (ISEA) before 60 ka (93-61 ka) predates accepted archaeological records of occupation in the region. Claims that AMH arrived in ISEA before 60 ka (ref. 4) have been supported only by equivocal or non-skeletal evidence. AMH evidence from this period is rare and lacks robust chronologies owing to a lack of direct dating applications, poor preservation and/or excavation strategies and questionable taxonomic identifications. Lida Ajer is a Sumatran Pleistocene cave with a rich rainforest fauna associated with fossil human teeth. The importance of the site is unclear owing to unsupported taxonomic identification of these fossils and uncertainties regarding the age of the deposit, therefore it is rarely considered in models of human dispersal. Here we reinvestigate Lida Ajer to identify the teeth confidently and establish a robust chronology using an integrated dating approach. Using enamel-dentine junction morphology, enamel thickness and comparative morphology, we show that the teeth are unequivocally AMH. Luminescence and uranium-series techniques applied to bone-bearing sediments and speleothems, and coupled uranium-series and electron spin resonance dating of mammalian teeth, place modern humans in Sumatra between 73 and 63 ka. This age is consistent with biostratigraphic estimations, palaeoclimate and sea-level reconstructions, and genetic evidence for a pre-60 ka arrival of AMH into ISEA. Lida Ajer represents, to our knowledge, the earliest evidence of rainforest occupation by AMH, and underscores the importance of reassessing the timing and environmental context of the dispersal of modern humans out of Africa.

New chronology for the Middle Palaeolithic of the southern Caucasus suggests early demise of Neanderthals in this region.

Neanderthal populations of the southern and northern Caucasus became locally extinct during the Late Pleistocene. The timing of their extinction is key to our understanding of the relationship between Neanderthals and anatomically modern humans (AMH) in Eurasia. Recent re-dating of the end of the Middle Palaeolithic (MP) at Mezmaiskaya Cave, northern Caucasus, and Ortvale Klde, southern Caucasus, suggests that Neanderthals did not survive after 39 ka cal BP (thousands of years ago, calibrated before present). Here we extend the analysis and present a revised regional chronology for MP occupational phases in western Georgia, based on a series of model-based Bayesian analyses of radiocarbon dated bone samples obtained from the caves of Sakajia, Ortvala and Bronze Cave. This allows the establishment of probability intervals for the onset and end of each of the dated levels and for the end of the MP occupation at the three sites. Our results for Sakajia indicate that the end of the late Middle Palaeolithic (LMP) and start of the Upper Palaeolithic (UP) occurred between 40,200 and 37,140 cal BP. The end of the MP in the neighboring site of Ortvala occurred earlier at 43,540-41,420 cal BP (at 68.2% probability). The dating of MP layers from Bronze Cave confirms that it does not contain LMP phases. These results imply that Neanderthals did not survive in the southern Caucasus after 37 ka cal BP, supporting a model of Neanderthal extinction around the same period as reported for the northern Caucasus and other regions of Europe. Taken together with previous reports of the earliest UP phases in the region and the lack of archaeological evidence for an in situ transition, these results indicate that AMH arrived in the Caucasus a few millennia after the Neanderthal demise and that the two species probably did not interact.

Neanderthal exploitation of marine mammals in Gibraltar.

Two coastal sites in Gibraltar, Vanguard and Gorham's Caves, located at Governor's Beach on the eastern side of the Rock, are especially relevant to the study of Neanderthals. Vanguard Cave provides evidence of marine food supply (mollusks, seal, dolphin, and fish). Further evidence of marine mammal remains was also found in the occupation levels at Gorham's Cave associated with Upper Paleolithic and Mousterian technologies [Finlayson C, et al. (2006) Nature 443:850-853]. The stratigraphic sequence of Gibraltar sites allows us to compare behaviors and subsistence strategies of Neanderthals during the Middle Paleolithic observed at Vanguard and Gorham's Cave sites. This evidence suggests that such use of marine resources was not a rare behavior and represents focused visits to the coast and estuaries.

Two hominin incisor teeth from the middle Pleistocene site of Boxgrove, Sussex, England.

In 1995-1996 two isolated hominin lower incisors were found at the middle Pleistocene site of Boxgrove in England, with Lower Palaeolithic archaeology. Boxgrove 2 is a permanent lower right central incisor and Boxgrove 3 a permanent lower left lateral incisor. They were found separately, but close to one another and appear to belong to the same individual. The Boxgrove 1 tibia discovered in 1993 came from a different stratigraphic context and is thus believed to represent a different individual. This paper describes the morphology of the incisors, which is similar to other middle Pleistocene hominin specimens and, as with the tibia, suggests that they could be assigned to Homo heidelbergensis (recognising that the taxonomic status of this species is still a matter of debate). The incisors show substantial attrition associated with secondary dentine deposition in the pulp chamber and clearly represent an adult. They also show extensive patterns of non-masticatory scratches on the labial surfaces of both crown and root, including some marks which may have been made postmortem. The roots were exposed in life on their labial sides by a large dehiscence, extending almost to the root apex. This is demonstrated by deposits of calculus, polishing, and scratching on the exposed surfaces. The dehiscence may have been caused by repeated trauma to the gingivae or remodelling of the tooth-supporting tissues in response to large forces applied to the front of the dentition.

Genetic and fossil evidence for the origin of modern humans.

The origin of living Homo sapiens has once again been the subject of much debate. Genetic data on present human population relationships and data from the Pleistocene fossil hominid record are used to compare two contrasting models for the origin of modern humans. Both genetics and paleontology support a recent African origin for modern humans rather than a long period of multiregional evolution accompanied by gene flow.

Frequency of psychological distress in gynecologic cancer patients seen in a large urban medical center.

Psychological distress in cancer is a well-documented phenomenon, but additional information is needed about demographic and disease correlates in diverse populations with different forms of cancer. This study focused on gynecologic cancers. Using the Distress Thermometer and the Hospital Anxiety and Depression Scale, this study examined distress levels in 94 women with gynecologic cancer who were being treated as outpatients at a large urban medical center. The distress levels in this sample were lower than in comparable studies, raising questions about openness to reporting distress. Those who reported higher levels of distress were more likely to also report a mental health diagnosis or psychiatric medication. This suggests that an alternate form for distress screening may involve inquiring about mental health treatment. In this sample, younger women and those with higher educational achievement or private health insurance had higher levels of distress. Conversely, there were no relations between distress levels and disease characteristics, indicating that, for example, women with early stage disease have just as much risk of distress as those with later-stage disease.

High-throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide.

Treatment of cancer cells lacking p53 function with G2 checkpoint inhibitors sensitizes them to the toxic effects of DNA damage and has been proposed as a strategy for cancer therapy. However, few inhibitors are known, and they have been found serendipitously. We report the development of a G2 checkpoint inhibition assay that is suitable for high-throughput screening and its application to a screen of 1300 natural extracts. We present the isolation of a new G2 checkpoint inhibitor, the structurally novel compound isogranulatimide. In combination with gamma-irradiation, isogranulatimide selectively kills MCF-7 cells lacking p53 function.

Phase I dose escalation of paclitaxel in patients with advanced ovarian cancer receiving cisplatin: rapid development of neurotoxicity is dose-limiting.

PURPOSE: To determine the maximum-tolerable dose (MTD) of paclitaxel in a phase I dose-escalation study when combined with cisplatin in patients with advanced ovarian cancer receiving filgrastim for prophylaxis of myelosuppression. PATIENTS AND METHODS: A total of 23 patients with stage II (bulky residual), III, or IV epithelial ovarian cancer were treated (following debulking surgery) with paclitaxel as a 3-hour infusion followed by cisplatin (75 mg/m2) administered over 4 hours on day 1, repeated every 21 days for six cycles. Filgrastim (5 micrograms/kg/d) was administered subcutaneously (SC) beginning on day 2 of each cycle through neutrophil recovery (absolute neutrophil count [ANC] > 10,000/microL). Patients were assigned to one of six escalating dose levels of paclitaxel: 150 (n = 3), 175 (n = 3), 200 (n = 3), 225 (n = 4), 250 (n = 4), and 275 mg/m2 (n = 6). RESULTS: At each paclitaxel dose level (150, 175, 200, 225, 250, and 275 mg/m2), the numbers of patients who completed six cycles without dose reduction were three (100%), three (100%), two (66%), two (50%), three (75%), and zero (0%), respectively. The numbers of patients who experienced a grade III/IV adverse event (hematologic or nonhematologic) were zero (0%), two (66%), two (66%), one (25%), four (100%), and five (80%), respectively. Reasons for dose reduction included neurotoxicity (225 mg/m2, n = 1; 275 mg/m2, n = 2), neutropenia (225 mg/m2, n = 2), diarrhea (275 mg/m2, n = 2), and nephrotoxicity (225 mg/m2, n = 1). Reasons for not completing six cycles at full or reduced dose included neuropathy (200, 225, and 275 mg/m2, n = 1 each) physician request (275 mg/m2, n = 1), and death (275 mg/m2, n = 1). Hematopoietic toxicity was minimal. Six patients developed grade III/IV neutropenia. No patient developed thrombocytopenia below a level of 50,000/microL. CONCLUSION: The MTD of paclitaxel was determined to be 225 mg/m2 when administered as a 3-hour infusion and combined with cisplatin (75 mg/m2). Nonhematologic dose-limiting toxicities were neuropathy and diarrhea. The neuropathy often had a rapid onset, especially at the higher dose levels.

Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin.

Since 1984, we have treated 26 patients with malignant ovarian germ cell tumors with a combination of bleomycin, etoposide (VP-16), and cisplatin (BEP) at The University of Texas MD Anderson Cancer Center (UTMDACC). The median age of the patients was 19 years (range, 8 to 32). All patients underwent initial surgery (unilateral salpingo-oophorectomy in 14, unilateral salpingo-oophorectomy plus abdominal hysterectomy in one, and bilateral salpingo-oophorectomy with or without hysterectomy in 11 patients). Twenty patients had no residual disease, three had less than or equal to 2 cm (one each, dysgerminoma, mixed, and immature teratoma), and three had more than 2 cm lesions (two dysgerminomas, one endodermal sinus tumor). Fourteen patients had pure dysgerminoma (five, stage I; one, stage II; six, stage III; and two, recurrent), and 12 had nondysgerminomatous tumors (five, stage I; two, stage II; three, stage III; and two, recurrent). All four patients with clinically measurable disease had a complete response. All four patients who underwent second-look laparotomy had negative findings. Twenty-five patients (96%) remain in sustained remission 10.4 to 54.4 months from the start of chemotherapy. One patient died of progressive disease 14 months after beginning chemotherapy. We conclude that the BEP regimen has excellent activity and acceptable toxicity in patients with malignant ovarian germ cell tumors.

Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus.

Eighteen patients with metastatic mixed mesodermal sarcoma of the uterus received cisplatin therapy at the University of Texas (UT) M.D. Anderson Hospital and Tumor Institute at Houston. The dose of cisplatin varied from 75 mg/m2 to 100 mg/m2. Previous therapy included surgery in 11 patients, radiotherapy in two patients, and surgery plus radiotherapy in four patients. One patient had no prior therapy. Seven patients had also received prior chemotherapy with doxorubicin. Of 12 patients with measurable disease, one (8%) had a complete response and four (33%) had a partial response for an overall response rate of 42%. The median progression-free survival of patients treated with cisplatin as first- and second-line therapy was 4.5 and 5.5 months, respectively. Cisplatin demonstrated moderate activity with mild toxicity in this group of patients with metastatic mixed mesodermal uterine sarcomas. Further studies including cisplatin-containing combination regimens seem to be warranted.

Pelvic endometriosis simulating colonic malignant neoplasm.

Three women had endometriosis that involved the rectosigmoid colon; their clinical presentation suggested primary colonic malignant neoplasm. Intestinal obstruction, weight loss, and, in two patients, rectal bleeding with radiologic evidence of a mass lesion that involved the rectosigmoid were present at initial evaluation. All patients eventually underwent colonic resection as definitive therapy. Endometriosis of the pelvic colon may mimic primary intestinal disease, mistakenly suggesting malignant neoplasm. Such symptoms in a young woman should prompt a search for endometriosis, which is a more likely diagnosis. Adequate therapy frequently requires surgical intervention.

Intrapartum maternal lumbosacral plexopathy.

Maternal intrapartum neurologic injuries are infrequently reported in modern obstetric practice. Two cases are presented and methods of evaluating the level of injury to differentiate this syndrome from peroneal nerve palsies are suggested. The long-term prognosis of lumbosacral plexus injuries encountered during labor and delivery appears to be favorable. Nonetheless, future intrapartum management of these patients should be conservative.

Fetal growth sustained by parenteral nutrition in pregnancy.

Severe maternal nutritional deprivation has been associated with intrauterine growth retardation, premature labor, and increased perinatal mortality and morbidity. The authors present four cases in which total parenteral nutrition was used successfully to support fetal growth in such diverse complications as twin pregnancy with maternal jejunoileal bypass, regional enteritis, and acute pancreatitis. Maintenance of fetal growth as evidenced by serial sonographic examination allows achievement of fetal lung maturation before delivery. In all the cases presented there was no perinatal mortality or morbidity. The main clinical implication of the report is the possible application of total parenteral nutrition to maintain adequate growth in fetuses small for gestational age because of maternal nutritional deprivation.

Endodermal sinus tumor of the ovary associated with pregnancy.

The association of endodermal sinus tumor of the ovary with pregnancy is a rare event. Reported is a patient with stage Ic endodermal sinus tumor diagnosed in the 25th week of gestation. She received two cycles of combination chemotherapy consisting of vinblastine, bleomycin, and cisplatin, and delivered a healthy male infant by cesarean section at 32 weeks' gestation. She subsequently completed three more cycles of chemotherapy and remains alive and well. This is the first reported case of a patient with endodermal sinus tumor treated with combination chemotherapy during pregnancy that had a successful outcome for both mother and infant. The literature concerning the association of endodermal sinus tumor and pregnancy and the use of chemotherapy during pregnancy is reviewed.

Adenoid cystic carcinoma of Bartholin gland.

Five cases of adenoid cystic carcinoma of the Bartholin gland, a rare vulvar tumor, are reviewed with respect to clinical and pathological characteristics. Histologic transition from normal Bartholin gland to adenoid cystic carcinoma was evident in two cases. Two patients developed the tumor in association with pregnancy. Local recurrences are common and may precede distant metastases, pulmonary being the most common. Patients with repetitive local recurrence or pulmonary metastases may have slowly progressive disease and survive for many years. This is reflected in the disparity between the progression-free interval and survival curves. The recommended primary treatment is wide local excision, obtaining clear margins, and an ipsilateral inguinal lymphadenectomy.

Sarcoma botryoides of the female genital tract.

Results of treating 14 patients with sarcoma botryoides of the female genital tract are reviewed. Nine patients were younger than four years old and five were older than 14. Primary tumors were in the vagina (eight), cervix (three), vulva (one), and cervicovaginal region (two). All but one patient underwent surgery, including wide local excision (one), vaginectomy (one), hysterectomy (one), hysterectomy and vaginectomy (two), anterior exenteration (two), and total pelvic exenteration (six). A combination of vincristine, actinomycin-D, and cyclophosphamide was the chemotherapy regimen most frequently administered. Only one of the nine patients receiving chemotherapy died from recurrence. One patient with disease too extensive for surgery received intraarterial vincristine and radiation therapy; 16 years later she developed an adenosquamous carcinoma of the uterus. Sarcoma recurred in three patients. This review of patients treated between 1956 and 1983 reflects the evolution of therapy over 30 years. Conservative surgery alone was inadequate; therefore, radical (exenterative) surgery was adopted; recently less extensive surgery has been combined with chemotherapy, producing satisfactory results.

Stage IB cervical carcinoma treated with radical hysterectomy and pelvic lymphadenectomy: role of adjuvant radiotherapy.

A retrospective review of 194 patients with stage IB cervical carcinoma treated with radical hysterectomy between January 1977 and December 1984 revealed 30 patients (15%) with pelvic node metastases. Twenty patients with pelvic node metastases received postoperative radiotherapy and ten patients did not. Five of 20 patients who received adjuvant radiotherapy had recurrence, compared with five of ten patients who did not receive radiotherapy. No pelvic recurrences occurred in the adjuvant radiotherapy group compared with two in the no radiotherapy group. Only one serious complication occurred in a patient receiving radiotherapy. Adjuvant postoperative radiotherapy may reduce pelvic recurrences and improve survival in patients with pelvic node metastases treated with radical hysterectomy and pelvic lymphadenectomy.

Treatment of metastatic stromal tumors of the ovary with cisplatin, doxorubicin, and cyclophosphamide.

From September 1981 until June 1986, eight patients with metastatic ovarian stromal tumors were entered into a prospective phase II study to determine the efficacy of a chemotherapy regimen combining cisplatin, doxorubicin, and cyclophosphamide. Patients received cisplatin 40-50 mg/m2 intravenously (IV), doxorubicin 40-50 mg/m2 IV, and cyclophosphamide 400-500 mg/m2 IV, all on day 1 every 28 days. The median age was 43 years (range 24-65 years). Two patients had stage II disease, one had stage III, and five had recurrent disease (original stage: four stage I and one stage III). The median number of chemotherapy cycles was six (range four to 14). Three patients (38%) had a complete response to therapy (two confirmed by second-look laparotomy), and two patients (25%) achieved a partial response (one verified by second-look laparotomy). The overall response rate was 63%. Toxicity was minimal. Four patients are disease-free at 13+ to 48+ months, one patient is alive with disease at six+ months, and three patients are dead of tumor at four, 17, and 36 months from the start of chemotherapy. These results indicate that the combination of cisplatin, doxorubicin, and cyclophosphamide has modest activity in the treatment of metastatic ovarian stromal tumor.

Ureteral assessment after radical hysterectomy.

Postoperative intravenous pyelography was performed in 233 patients with stage IB cervical carcinoma treated with radical hysterectomy and pelvic lymphadenectomy between January 1962 and December 1985. Four patients developed symptoms of ureteral injury, two (0.8%) ureteral fistulae, and one (0.4%) stricture and obstruction due to recurrent carcinoma. No ureteral injuries were observed in 229 asymptomatic patients. A 5.2% incidence of transient severe ureteral dilatation occurred in asymptomatic patients, but resolved within a median of 94 days. A significant urinary tract anomaly was observed in 3.4% of preoperative pyelograms. All of these anomalies were apparent at surgery and presented no intraoperative difficulties. Three patients (1.3%) sustained intraoperative ureteral transections, which were diagnosed and repaired without sequelae. In patients with early cervical carcinoma having primary operative treatment, the role of routine preoperative and postoperative intravenous pyelography is questionable.

Re-treatment of patients with recurrent epithelial ovarian cancer with cisplatin-based chemotherapy.

Nineteen patients with recurrent epithelial ovarian cancer who had responded to initial cisplatin-based combination chemotherapy were re-treated with cisplatin-based therapy. The median disease-free interval, as measured from the last cycle of primary chemotherapy to the diagnosis of relapse, was 26.3 months (range 5-81 months). Eighteen of the 19 patients had measurable disease at the time of relapse. Nine patients had a clinical complete response to the cisplatin-based re-treatment, and nine patients had a partial response (surgically documented in one case). The overall response rate to secondary cisplatin-based chemotherapy was therefore 100% in patients with measurable disease. Toxicity of re-treatment was acceptable. The median progression-free survival, as measured from the diagnosis of relapse to the time of disease progression, was 10.6 months (range 4-24 months). The median survival from diagnosis of relapse was 19.3 months (range 5-39 months). At the time of analysis, three patients were alive without evidence of disease, four were alive with tumor, and 12 were dead of cancer. These data suggest that re-induction with cisplatin-based chemotherapy should be considered for patients who develop recurrent disease after favorable responses to primary cisplatin-based chemotherapy.