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Abstracts by Bruce Shriver and Tom Swartz
The finished DNA
sequence of human chromosome 12, by Steven E. Scherer, et al, Nature,
N. 440, pp. 346-351. From the abstract, “Human chromosome 12 contains more
than 1,400 coding genes and 487 loci that have been directly implicated in
human disease. The q arm of chromosome 12 contains one of the largest blocks
of linkage disequilibrium found in the human genome. Here we present the
finished sequence of human chromosome 12, which has been finished to high
quality and spans approximately 132-megabases, representing  4.5%
of the human genome. Alignment of the human chromosome 12 sequence across
vertebrates reveals the origin of individual segments in chicken, and a
unique history of rearrangement through rodent and primate lineages. The
rate of base substitutions in recent evolutionary history shows an overall
slowing in hominids compared with primates and rodents.”
Challenging Perceptions in Chronic Pain
Challenging Perceptions in Chronic Pain
CME,
by
Frank Porreca, PhD; Stephan A. Schug,
MD; and Nicholas Bellamy, MD . This CME activity is based on
transcripts and slides of presentations as delivered by the faculty at the
"Challenging Perceptions in Chronic Pain" symposium held at the Sydney
Convention and Exhibition Center in Sydney, Australia.
This activity has been planned and
implemented in accordance with the Essential Areas and Policies of the
Accreditation Council for Continuing Medical Education (ACCME). The
Postgraduate Institute for Medicine is accredited by the Accreditation
Council for Continuing Medical Education (ACCME) to provide continuing
medical education for physicians. See other CME entries in the "Tidbits"
section at the end of this column.
Workshop on Medical Application of Genetic and Evolutionary Computation
(MedGEC)
MEDGEC
will be held as part of the 2006 Genetic and Evolutionary Computation
Conference (GECCO-2006); July 8-12, 2006, Seattle, Washington, USA;
Organized by ACM
SIGEVO. Subjects will include (but are not limited to) applications of
GEC to: Medical imaging, Medical signal processing, Clinical diagnosis and
therapy, Data mining medical data and records, Clinical expert systems,
Modeling and simulation of medical processes. A dedicated workshop at GECCO
provides a much needed focus for medical related Applications of EC, not
only providing a clear definition of the state of the art, but also support
to practitioners for whom GEC might not be their main area of expertise or
experience. The Workshop has two main aims: (i) to provide delegates with
examples of the current state of the art of applications of GEC to medicine.
(ii) to provide a forum in which researchers can discuss and exchange ideas,
support and advise each other in theory and practice.
Docetaxel and Gemcitabine Combination
“Docetaxel and gemcitabine
combination in 133 advanced soft-tissue sarcomas: A retrospective analysis”.
The abstract of this article by J. O. Bay et al, which appeared in
International Journal of Cancer, 2006 Feb 22, reads as follows: “Advanced
soft-tissue sarcomas are usually resistant to cytotoxic agents such as
doxorubicin and ifosfamide. Antitumor activity has been observed for
gemcitabine and docetaxel combination. We conducted a retrospective study on
133 patients (58 males/75 females) with unresectable or metastatic
soft-tissue sarcoma. The median age at diagnosis was 51.7 (18-82), with 76
patients with leiomoyosarcoma and 57 patients with other histological
subtypes. The initial localizations were limb (44), uterine (32),
retroperitoneal (23) and organs or bone (34). Patients received 900 mg/m(2)
of gemcitabine (days 1 and 8) over 90 min plus 100 mg/m(2) of docetaxel (day
8), intravenously every 21 days. Gemcitabine/docetaxel combination was well
tolerated with an overall response of 18.4% and with no clear statistical
difference between leiomyosarcomas and other histological subtypes (24.2%
versus 10.4% (p = 0.06)). No difference was found between uterine
soft-tissue sarcomas versus others. The median overall survival was 12.1
months (1-28). Better overall survival was correlated with leiomyosarcoma (p
= 0.01) and with the quality of the response, even for patients with stable
disease (p < 10(-4)). No statistical difference was found for the initial
localization. Response to treatment and overall survival were better for
patients in World Health Organization (WHO) performance status
classification (PS) 0 at baseline versus patients in WHO PS-1, 2 or 3 (p =
0.023 and p < 10(-4), respectively). Gemcitabine/docetaxel combination was
tolerable and demonstrated better response and survival for leiomyosarcoma,
especially for patients in WHO PS-0 at baseline. For the other histological
subtypes, the response was not encouraging, but the survival for patients in
response or stable suggests further investigation.”
Rhabdomyosarcoma: New Windows of Opportunity
Rhabdomyosarcoma: New Windows of Opportunity, by Philip P.
Breitfeld and William H. Meyer, The Oncologist, Vol. 10, No. 7, pp. 518-527,
August 2005. From the abstract: “Rhabdomyosarcoma is a highly malignant,
small blue cell tumor characterized by muscle differentiation. With modern
treatment, more than 70% of children and adolescents with this disease are
cured. Adequate biopsy to obtain sufficient tissue for accurate diagnosis
and molecular characterization is critical. Patients must be assessed for
tumor extent; the Intergroup Rhabdomyosarcoma Study (IRS) clinical group and
Staging system is universally applied in North America. Multidisciplinary
therapy is necessary to maximize cure rates. Local control relies on
complete surgical excision when possible; those whose tumors are not
completely excised and those with alveolar histology tumors require local
irradiation to maximize local control. In North America, vincristine,
dactinomycin, and cyclophosphamide are the standard chemotherapy agents. The
IRS has used therapeutic window studies to confirm the predictive nature of
preclinical xenograft models and to identify several new single agents and
combinations of agents with activity in high-risk patient groups. Despite
these efforts, the outcome for these high-risk patients remains poor. The
next generation of Children’s Oncology Group studies will evaluate the
efficacy of topoisomerase-I inhibitors and dose-compression therapy
approaches. New advances in molecular characterization of tumors, including
gene-expression analysis, may identify new therapeutic targets that can be
exploited by expanded preclinical drug discovery efforts, and hold the
promise of revolutionizing risk-based therapies.
Cefixime Allows Greater Dose Escalation of Oral
Irinotecan: A Phase I Study in Pediatric Patients With Refractory Solid
Tumors
Irinotecan is active against a variety
of cancers. However, severe diarrhea limits its usefulness. The
investigators of this Phase I study sought to determine the
maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics
of oral irinotecan and to evaluate whether coadministration of cefixime (8
mg/kg/d beginning 5 days before irinotecan and continuing throughout the
course) ameliorates irinotecan-induced diarrhea. The intravenous formulation
of irinotecan was administered orally daily for 5 days for 2 consecutive
weeks (repeated every 21 days) to children with refractory solid tumors. In
separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d
without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. The
investigators found that without cefixime, diarrhea was dose limiting at
irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The
MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Thus, the
investigators believe that cefixime administered with oral irinotecan allows
for a greater dose escalation of irinotecan.
Long-term results of a multicenter SAKK trial on high-dose ifosfamide and
doxorubicin in advanced or metastatic gynecologic sarcomas
Dose intensive
chemotherapy has not been tested prospectively for the treatment of
gynecologic sarcomas. The investigators of this trial studied the antitumor
activity and toxicity of high-dose ifosfamide and doxorubicin, in the
context of a multidisciplinary strategy for the treatment of advanced and
metastatic, not pretreated, gynecologic sarcomas. Thirty-nine patients were
enrolled onto a phase I–II multicenter trial of ifosfamide, 10 g/m2 as a
continuous infusion over 5 days, plus doxorubicin intravenously, 25
mg/m2/day for 3 days with Mesna and granulocyte-colony-stimulating factor
every 21 days. Salvage therapy was allowed after chemotherapy. Among the 37
evaluable patients, the tumor was locally advanced (n = 11), with
concomitant distant metastases (n = 5) or with distant metastases only (n =
21). After a median of three (range 1–7) chemotherapy cycles, six patients
experienced a complete response and 12 a partial response for an overall
response rate of 49%. The response rate was higher in poorly differentiated
tumors (62%) compared with moderately well differentiated ones (18%), but
was not different according to histology subtypes. Eleven patients had
salvage therapy, either immediately following chemotherapy (n = 7) or at
time of progression (n = 4). With a median follow-up time of 5 years, the
median overall survival was 30.5 months. Hematological toxicity was as
expected neutropenia, thrombopenia and anemia grade 3 at 50%, 34% and 33% of
cycles respectively. No toxic death occurred. The investigators conclude
that: (1) high-dose ifosfamide plus doxorubicin is an active regimen for all
subtypes of gynecological sarcomas; (2) its toxicity is manageable in a
multicentric setting; and (3) the prolonged survival might be due to the
multidisciplinary strategy that was possible in one-third of the patients.
Identification of the Transcriptional Regulatory Sequences of Human Calponin
Promoter and Their Use in Targeting a Conditionally Replicating Herpes
Vector to Malignant Human Soft Tissue and Bone Tumors
The calponin gene, normally expressed in
mature smooth muscle cells, is aberrantly expressed in a variety of human
soft tissue and bone tumors. In this study, the investigators showed that
expression of the calponin gene in human soft tissue and bone tumor cells is
regulated at the transcriptional level by the sequence between positions
-260 and -219 upstream of the translation initiation site. The investigators
also constructed a novel conditionally replicating herpes simplex virus-1
vector (d12.CALP) in which the calponin promoter drives expression of ICP4,
a major trans-activating factor for viral genes, and tested this virus
vector as an experimental treatment for malignant human soft tissue and bone
tumors. In cell culture, this d12.CALP virus vector selectively killed
calponin-positive human synovial sarcoma, leiomyosarcoma, and osteosarcoma
cells. For in vivo studies, 10 animals harboring SK-LMS-1 human
leiomyosarcoma cells were randomly divided and treated twice on days 0 and 9
intraneoplastically with either d12.CALP or with medium alone. The viral
treatment group showed stable and significant inhibition of tumorigenicity
with apparent cure in four of five mice by day 35. In addition, in mice
harboring two SK-LMS-1 tumors, replication of d12.CALP was detected in a
nontreated tumor distant from the site of virus inoculation. Thus, the
investigators believe that these results indicate that replication-competent
virus vectors controlled by the calponin transcriptional regulatory sequence
may be a new therapeutic strategy for treatment of malignant human soft
tissue and bone tumors.
The investigators of this study report that
while combined-modality treatment of high-risk, high-grade soft tissue
sarcomas of the extremity and body wall leads to significant toxicity, there
is evidence that aggressive chemotherapy with radiotherapy may be
beneficial. The researchers conducted a study involving patients at 31
institutions, which included 64 patients with high-grade soft tissue sarcoma
of at least 8 cm in diameter. The patients received three cycles of
neoadjuvant modified mesna, doxorubicin, ifosfamide and dacarbazine (MAID),
interdigitated radiotherapy and following resection, three postoperative
cycles of modified MAID. Three patients had fatal grade 5 toxicities, and
another 53 had grade 4 toxicities. Sixty-one patients underwent surgery. Of
these, 5 were amputations and 2 were considered treatment related. The
estimated rates of 3-year disease-free survival were 56.6%. For
distant-disease free and overall survival, the corresponding rates were
64.5% and 75.1%. In an accompanying editorial Dr. Peter Pisters of M.D.
Anderson Cancer Center concludes: (1) anthracycline-based pre- or
postoperative chemotherapy has short- and long-term toxicities; (2) more
chemotherapy is more toxic; (3) the clinical benefit from adjuvant
anthracycline-based chemotherapy—if it exists—is small, and the therapeutic
ratio is thus very small; and (4) new treatment approaches are desperately
needed.
Oncogenic Property of Acrogranin in Human Uterine Leiomyosarcoma: Direct
Evidence of Genetic Contribution in In vivo Tumorigenesis
To identify potential oncogenes that
contribute to the development of uterine leiomyosarcoma, the investigators
of this study conducted a cDNA microarray analysis between normal uterine
smooth muscle and uterine leiomyosarcoma. They found that acrogranin (also
named PCDGF or progranulin) is overexpressed in uterine leiomyosarcoma. With
immunohistochemical staining of 12 leiomyosarcoma cases, they verified
acrogranin expression in tumor cells. Furthermore, the intensity of
acrogranin expression correlated with high histologic grade and poor
prognosis. To directly analyze the oncogenic properties of acrogranin, they
established an immortalized uterine smooth muscle cell line by transfection
of human telomerase reverse transcriptase into primary culture. This cell
line retained the original characteristics of uterine smooth muscle cells.
Transfection of acrogranin into the immortalized uterine smooth muscle cells
resulted in colony formation in soft agar. Transfection of both acrogranin
and SV40 early region (SV40ER) into the immortalized uterine smooth muscle
cells resulted in an increased number of colonies and increased colony size
in soft agar versus transfection of SV40ER alone. The investigators showed
that only immortalized uterine smooth muscle cells expressing both
acrogranin and SV40ER are capable of tumor formation in nude mice. Thus, the
investigators conclude that acrogranin is overexpressed in uterine
leiomyosarcoma cells, particularly in high-grade cases, and forced
expression of acrogranin in immortalized uterine smooth muscle cells
contributes to malignant transformation, which suggest that acrogranin plays
an important role in the pathogenesis of uterine leiomyosarcoma.
Validation of an anti-sphingosine-1-phosphate antibody as a potential
therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor
lineages
San Diego State University researchers have
created an antibody that hinders the growth of tumors by preventing blood
vessel formation. As published in the March issue of Cancer Cell, a leading
oncology journal, the research team describes the antibody, Sphingomab™,
that can be used as a drug to reduce the size of tumors in experimental
animal models of human cancer. The antibody works as a molecular sponge by
soaking up sphingosine-1-phosphate (S1P), a molecule that has been proven to
stimulate the growth of new blood vessels. S1P has been identified as a
mediator of tumor cell proliferation and protector of tumor cells from
chemotherapy drugs. By neutralizing S1P, the Sphingomab antibody inhibits
the new blood vessel formation that tumors require to thrive, a process
called 'tumor angiogenesis.' The group's research tested the antibody in
mice tissue implanted with drug-resistant human breast, ovarian and lung
cancer cell lines, as well as a mouse skin cancer cell line. In ovarian
cancer models, two of five subjects displayed no tumors, and three subjects
had tumors with 68 percent less volume than those in the control group.
Tumors were reduced by about 60 percent in volume in lung and breast cancer
models. "This groundbreaking research provides new hope for therapeutic
treatments for forms of cancer that are resistant to current therapeutics,"
lead researcher Roger Sabbadini said. "The Sphingomab antibody is especially
powerful as it is shown to prevent tumors from a variety of cancers, as
opposed to being effective against only one type of cancer." Sabbadini will
present the team's findings at the annual conference for the American
Association of Cancer Researchers, April 1-5, in Washington D.C.
Tidbits
Chemotherapy-Induced Nausea and Vomiting: Addressing the Continuing
Problem of Delayed Nausea,
CME,
Presenters: Gary R. Morrow, Ph.D. MS,
and Jane T. Hickok, MD, MPH
Imaging X-rays Cause Cancer: A Call
to Action for Caregivers and Patients,
CME,
Author: Richard C. Semelka, MD
V3N2
ESUN Copyright © 2006 Liddy Shriver Sarcoma
Initiative.
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