bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric salivary gland neoplasms: The M. D. Anderson Cancer Center experience
Authors: Huh W. W. , Bosworth C. , Hessel A. C. , Mahajan A. , Hughes D. P. , Herzog C. E.
Published: March 2020

20006

Background: Epithelial salivary gland neoplasms (ESGN) are uncommon tumors that mainly occur in adults, only 5 percent of ESGNs occur in children. Data regarding differences in clinical presentation and biologic behavior of these tumors between adult and pediatric patients remain unclear. There is less data concerning the role of radiation therapy in the treatment of ESGNs in pediatric patients. Methods: Retrospective review of medical records of patients presenting under age 18 years from January 1988 to August 2006. Results: 45 patients were evaluable. 26 patients were female. Median age at diagnosis was 14.7 years. Mucoepidermoid carcinoma (MEC) was seen in 22 cases (49%), acinic cell carcinoma 10 cases (22%), adenocystic carcinoma (ACC) 8 cases, and pleomorphic adenoma (PA) 5 cases. The parotid area was the most common involved site (25/45; 56%) with MEC and acinic cell noted in 80% of parotid cases. 76% of MEC cases (16/21) were grade 2 or 3 tumors. Initial complete resection was achieved in 20 ESGN cases, while the remaining cases required re-excision or adjuvant therapy. Thirteen patients received postoperative radiation. Median age was 15.8 years. Radiation therapy was used in 6 ACC cases, 4 MEC and 3 adenoid cystic. Primary site and first echelon nodes dose range was 54–64 Gy, and supraclavicular dose was 50 Gy in those in whom regional nodes were treated. Positive margin status and local invasion (perineural, lymphatic, or nodal) were the most common indications. Mean follow-up for 35 patients was 60.3 months (2–175 months). Nine patients were lost to follow- up, and one patient received therapy at another institution. Two patients died from progressive disease, and both had received radiation therapy. Conclusions: MEC is the most common ESGN in pediatrics, and the parotid is the most common involved site. Complete surgical resection remains the treatment of choice. Radiation therapy may be used as adjuvant therapy, but more study is required.

No significant financial relationships to disclose.
The incidence of pseudo-progression in a cohort of malignant glioma patients treated with chemo-radiation with temozolomide
Authors: Taal W. , Brandsma D. , de Bruin H. G. , Bromberg J. E. , Swaak-Kragten A. T. , Eijkenboom W. M. , van den Bent M. J.
Published: March 2020

2009

Background: Radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) is now the standard of care for newly diagnosed glioblastoma. The occurrence of pseudo-progression at the end of RT is an often-mentioned phenomenon, but the actual incidence is unknown. It is also unclear if this is only a radiological phenomenon or is accompanied by clinical signs and symptoms. We retrospectively assessed this phenomenon in a cohort of patients treated with chemo-irradiation with temozolomide (RT/TMZ). Methods: The pre- and post-chemo-radiotherapy brain CT’s and MRI’s from all patients treated with RT/TMZ for a malignant glioma in the Daniel den Hoed Cancer Center between 2000 and 2005 were reviewed. Treatment consisted of 60 Gy RT in 6 weeks combined with daily TMZ (75mg/m2/day), followed after 4 weeks by 6 cycles of TMZ (150–200 mg/m2/day 1–5 every 4 weeks). Scans were made prior to the start of RT, four weeks after the end of RT and thereafter every three months. Macdonald’s criteria were used to assess the response. In addition information was collected on clinical signs and symptoms, dexamethasone dose, histology, and survival. Results: Sixty-five patients were identified; 54 had been diagnosed with a GBM. Mean age was 48 years and 42 were male. In 23 patients the first follow-up scan 4 weeks after the end of RT showed progression as compared to the pre-RT imaging. This was accompanied by clinical deterioration in12 patients. All patients continued with adjuvant TMZ. In 12 of these 23 patients the MRI and clinical signs and symptoms stabilized or improved in the months thereafter. In 8 of these 12 patients a response was observed without additional treatment other than TMZ. In none of these cases changes in dexamethasone dose could explain the observed MRI changes. Conclusions: In up to 50% of high grade glioma patients treated with chemo-irradiation with TMZ and a progressive MRI lesion immediately after RT suffer from pseudo-progression; this was observed in 12 out of 65 patients. These data support the notion to continue TMZ in case of progressive lesions immediately after RT/TMZ. Studies on recurrent gliomas that accept patients with progressive lesions directly after chemo-radiation will lead to an overestimation of the results.

No significant financial relationships to disclose.
Dendritic cell vaccination in combination with TLR-7 agonist, imiquimod, following radio-chemotherapy for newly diagnosed glioblastoma
Authors: Liau L. M. , Prins R. M. , Odesa S. K. , Yang M. Y. , Lin M. S. , Khan-Farooqi H. , Soto H. , Lai A. , Bosch M. , Boynton A. , Cloughesy T. F.
Published: March 2020

2021

Background: Standard therapy for glioblastoma, which includes surgery followed by radiation and concurrent chemotherapy, creates a low tumor burden environment that could be ideal for immunotherapeutic approaches. We conducted a Phase I study to assess the safety and immunologic responses of tumor lysate-pulsed dendritic cell (DC) therapy plus topical imiquimod, in combination with standard radio-chemotherapy. Methods: Thirteen patients with newly diagnosed glioblastoma were immunized using autologous tumor lysate-pulsed DC. Each patient initially received 3 immunizations at 2-week intervals, following completion of a 6-week course of radio- chemotherapy. Four patients received 1 million DC, 4 received 5 million, and 5 received 10 million DC per immunization. Patients without tumor progression subsequently received booster vaccinations combined with topical administration of the TLR-7 agonist imiquimod. Immunologic responses to tumor antigens were monitored by HLA-restricted tetramer staining, CTL assays, and quantitation of T-regulatory cells. Clinical tumor growth was monitored by brain MRI scans every 2 months, and the primary clinical endpoint was 2-year survival. Results: All immunizations were well tolerated, with only mild side effects attributable to the DC vaccination and imiquimod adjuvant. Increased levels of CD8+ T cells reactive against tumor antigens, (e.g., gp100, TRP-2, her-2, survivin, and CMV antigens), were detected in 5 patients. Median PFS and OS have not been reached in this trial. To date, 6 of the 13 patients have progressed, and 4 of those have died. The median PFS to date is 18.1 mos. and median OS is 33.8 mos. This compares favorably with controls from the published literature, with a median PFS of 6.9 mos and OS of 14.6 mos. Conclusions: This study demonstrates the safety and clinical/immunologic effects of an autologous tumor lysate-pulsed DC vaccine for patients with newly diagnosed glioblastoma. The adjunctive use of the TLR-7 agonist imiquimod with DC vaccination appears to be non-toxic, and deserves further study. We demonstrate that this active immunotherapy strategy can generate antigen-specific immunologic responses in brain tumor patients following standard radio-chemotherapy.

No significant financial relationships to disclose.
Comparing cerebral blood volume and vascular permeability measurements with tumor volume measurements following anti-angiogenesis therapy in recurrent gliomas
Authors: Narayana A. , Chheang S. , Knopp E. , Peccerelli N. , Babb J. , Johnson G. , Gruber M. , Allen J. , Zagzag D. , Law M.
Published: March 2020

2030

Background: Dynamic susceptibility contrast-enhanced MRI (DSC MRI) is emerging as an important adjunctive biomarker to assess the effectiveness of anti-angiogenic therapies in the treatment of brain tumors. The purpose of our study is to compare changes in relative cerebral blood volume (rCBV) and in perfusion-permeability index (KTrans) with those of tumor volume measurements (T1c, T2/Flair) in predicting tumor therapeutic response in recurrent high-grade gliomas treated with bevacizumab, an anti-VEGF monoclonal antibody. Methods: 11 patients were treated with one to four cycles of bevacizumab and CPT-11. Their histological diagnoses were: glioblastoma multiforme (n=7), anaplastic astrocytoma (n=2), anaplastic oligodendroglioma (n=1), and diffuse pontine glioma (n=1). All patients had baseline DSC MRI scans prior to the administration of bevacizumab and were followed clinically and radiographically with both conventional and DSC MRI. Mixed model regression was used to compare the pre-treatment and post-treatment levels of each response measure. Results: There were statistically significant reductions in both actual rCBV measurements and T1c enhancement following treatment with bevacizumab and CPT-11. The pretreatment rCBV and T1c rates of change (as determined per 100 days) correlated significantly with time (p values are 0.0229 and 0.0014, respectively), while only the post treatment rCBV demonstrated significant rate of change (p value = 0.0001), suggesting that rCBV may reflect the effects of bevacizumab better than tumor volume. However, when the changes in rate from pre- to post-treatment status were considered, both rCBV and T1c demonstrated significance (p= 0.0001, 0.0157, respectively). There was a trend towards females having higher mean levels of KTrans than males at the same time point relative to treatment onset, but the result was not statistically significant (p=0.072). Conclusions: rCBV as measured from DSC MRI can be used as a surrogate biomarker to determine therapeutic response to bevacizumab. This may influence the neurosurgical risk/benefit equation as well as alter the aggressiveness of the post-operative adjuvant therapy in patients with recurrent gliomas.

No significant financial relationships to disclose.
Treatment of gliomatosis cerebri with temozolomide: A retrospective study of the AINO (Italian Association for Neuro- Oncology)
Authors: Soffietti R. , Rudà R. , Laguzzi E. , Buttolo L. , Pace A. , Carapella C. , Riva M. , Salvati M. , Silvani A. , Caroli M.
Published: March 2020

2033

Background: The optimal management for patients with primary gliomatosis cerebri is unknown, and some recent studies suggest that temozolomide could be useful as an upfront treatment. Methods: Between 1999 and 2005, 46 patients with biopsy proven gliomatosis cerebri were treated with temozolomide either upfront or at progression after prior radiotherapy/chemotherapy. Histological diagnoses were as follows: glioblastoma in 3 patients, malignant glioma in 8, anaplastic astrocytoma in 8, gemistocytic astrocytoma in 2, astrocytoma in 13, anaplastic oligodendroglioma in 1, anaplastic oligoastrocytoma in 1, oligoastrocytoma in 1, oligodendroglioma in 4, glial proliferation consistent with GC in 5. Median age was 49 years (range 14–70), with 20 males and 26 females and a median KPS at diagnosis of 80 (range 50–90). Twenty-three out of 46 (50%) pre-treatment MRI demonstrated some degree of contrast enhancement. Twenty-three of 46 patients were treated upfront, while 23 had received prior radiation therapy or nitrosourea-based chemotherapy. All patients received temozolomide 200 mg/m2 die for 5 days every 4 weeks until progression or unacceptable toxicity. Response was evaluated, according to Macdonald criteria, on T1-weighted with Gadolinium and FLAIR images. Results: Two patients (4%) showed a CR of the contrast enhancing area, 2 patients (4%) a PR, 5 (11%) a minor response, 18 (39%) a SD and 19 (42%) a PD. Overall response rate (CR + PR + “minor response”) was 19%, while a clinical benefit was observed in 13/46 patients (28%). Median TTP was 9 months (range 1–27), and median survival 14 months (range 3–123). PFS at 6 months was 57%, at 12 months 35%. Oligodendroglial tumours showed a 38% response rate and a TTP of 11 months. Response rate was higher among patients treated at progression compared to those treated upfront (13% versus 26%). Grade III-IV haematological toxicity was mild. Conclusions: Temozolomide has some activity in primary GC (19% response rate), and is well tolerated. A significant neurological improvement can be observed in patients with either response or stable disease on MRI. To improve the efficacy of temozolomide in the upfront setting (in order to delay a large field RT), a phase II study with a dose-dense regimen is ongoing.

No significant financial relationships to disclose.
Single fraction radiosurgery of epidural spinal cord compression: Tumor control and neurologic outcome
Authors: Ryu S. , Rock J. , Jain R. , Ellika S. , Jin J. , Anderson J.
Published: March 2020

2041

Purpose: Spine radiosurgery improves the pain and quality of life in spine metastasis. Phase II study was performed to determine the clinical efficacy of radiosurgery for malignant epidural spinal cord compression. Method: Total 67 patients with 93 lesions of epidural spinal cord compression at the solitary spine level were accrued. All patients had pathology-proven malignancy and had epidural tumor seen on MRI or CT scan. For radiosurgery, grossly visible tumor including the involved spine was treated with single fraction radiosurgery dose of 14–20 Gy. Spinal cord dose constraint was 10 Gy to 10% partial volume of the cord. Followup included neurological exam and imaging studies every 2 months. Endpoints were radiographic tumor control and neurological outcome. Median followup time was 8 months (2–30 months). Results: Objective radiographic tumor response was seen in 82% of patients. At 2 months, complete response was in seen 27%, partial response in 30%, and minimal response in 23%, Epidural tumor progressed in 6% at or the adjacent spine level. Thecal sac patency (= decompression effect) seen on T2-weighted MR image was improved in 82% of the lesions. There was average 68% volumetric reduction of tumor at the level of most severe cord compression. This tumor reduction opened the thecal sac patency to average 75% following radiosurgery, compared to 45% before radisourgery (p<0.05). Majority of patients with neurological deficit prior to radiosurgery were ambulatory with an improved neurological function or remained clinically stable. There was one case of likely long-term radiation-induced myelopathy 13 months after radiosurgery. Conclusion: Single fraction radiosurgery achieves significant tumor response and decompressive effect of spinal cord compression. Even minimal tumor response relieves the spinal cord compression and potential neurologic improvement. Spine radiosurgery can be a viable treatment option for spinal cord compression.

No significant financial relationships to disclose.
A phase II trial of temozolomide and vinorelbine for patients with recurrent brain metastases
Authors: Iwamoto F. M. , Omuro A. M. , Raizer J. J. , Nolan C. P. , Hormigo A. , Lassman A. B. , Gavrilovic I. T. , Abrey L. E.
Published: March 2020

2050

Background: Temozolomide has shown modest efficacy in the treatment of recurrent brain metastases. We designed a regimen combining temozolomide with vinorelbine, a lipophilic agent that crosses the blood-brain barrier, trying to improve efficacy. Methods: This is a phase II trial with 28-day cycles using temozolomide (150 mg/m2, days 1–7 and 15–21) and vinorelbine on days 1 and 8. We previously reported a phase I trial that established an MTD of 30 mg/m2 of vinorelbine in this combination, but the dose was decreased to 25 mg/m2 in this phase II trial. The phase II component was planned as a two-stage clinical trial. Since two or more responses were observed after the 20 initial patients, 15 more assessable patients were required. This design had a 91% probability to detect a true response rate of 20% or more. The primary endpoint was objective radiographic response. Secondary endpoints include OS, PFS and toxicity. Patients = 18 years old with KPS = 60, adequate organ function and progressive or recurrent brain metastases were eligible. Results: Thirty-six patients (13 men, 23 women) with a median age of 56 years (range, 38–76) and median KPS of 80 were enrolled. The primary tumor sites were lung (n=19), breast (n=11), colon (n=2), bladder (n=1), endometrium (n=1), head/neck (n=1) and kidney (n=1). Prior therapies included whole-brain radiation therapy (81%), chemotherapy (97%), radiosurgery (42%) and brain metastasis resection (47%). Objective radiographic response was 7% (1 CR and 1 minor response); 4 patients had SD and 23 PD. Three patients withdrew consent and did not undergo follow-up scans, 2 patients did not receive the planned treatment and 2 patients recently began treatment and have not been assessed. The median follow-up was 12.3 weeks and 72% of patients have died. Median PFS and OS were 8.3 weeks and 5 months, respectively. Grade 3/4 toxicities were mainly hematological and 3 patients were removed from the study due to myelosuppression. Conclusions: In this heavily pretreated population of patients with brain metastases, adding vinorelbine to temozolomide does not seem to improve response rates as compared to temozolomide alone. Single-agent temozolomide also has a more favorable toxicity profile.

[Table: see text]
The use of in-vitro drug resistance levels as a predictor of outcome in soft tissue sarcoma
Authors: Schleicher L. , Hesdorffer M. , Taub R.
Published: March 2020

20510

Background: We have assayed in-vitro drug resistance and immunohistochemical staining for drug resistance markers (MDR-1, MRP) in patients with metastatic soft tissue sarcoma patients. We looked at resistance to Cisplatin, Doxorubicin, and Ifosphamide, prior to beginning chemotherapy. The aim of this study was to investigate the validity of in-vitro drug resistance testing as a predictor of outcome. Methods: Viable tumor samples obtained at time of recurrence or metastasis from 13 patients with metastatic soft tissue sarcoma were tested by a semiquantitative 12 hour tritiated-thymidine uptake cell-proliferation assay (EDR test, Oncotech Inc., Tusin, California) for resistance to the chemotherapy drugs cisplatin, doxorubicin, and ifosphamide. The mean drug resistance level for these three drugs was plotted against survival in months, both from time of metastasis and time of initiation of chemotherapy. Mean resistance was also correlated with positive staining for either MDR-1 or MRP. Results: There was no relationship found between the mean drug resistance and survival, either from time of metastasis (correlation coefficient -0.0596) or time of initiation of chemotherapy (correlation coefficient - 0.1864). There was no correlation between mean drug resistance and; 1) presence of MDR-1 staining (correlation coefficient -0.1269), 2) presence of MRP staining (correlation coefficient -0.2175), 3) presence of either staining for MDR-1 or MRP (correlation coefficient -0.2636). Conclusions: 1) In-vitro drug resistance is not predictive of outcome in patients with soft tissue sarcoma. 2) There is no correlation between the mean drug resistance and positive staining for either MDR-1 or MRP.

No significant financial relationships to disclose.
Contrast-enhanced ultrasonography (CEUS) in retroperitoneal liposarcomas
Authors: Brandi M. , Badalamenti G. , Sorrentino F. , Vizzini L. , Incorvaia L. , Rinaldi G. , Sanfilippo M. , Gebbia N. , Intrivici C. , Caruso G.
Published: March 2020

20514

Background: CEUS with second-generation contrast agents has been proposed to monitor tumor response to imatinib in patients with metastatic GIST. There are no data in patients with other sarcomas. Our aim was to assess the value of CEUS as a marker of tumor response in retroperitoneal liposarcoma, in addition to its ability to render the baseline malignancy grade of the disease. Methods: CEUS was performed after a SonoVue injection (Bracco, Milano, Italia). SonoVue is a suspension of microbubbles of exafluoride sulphure gas (average diameter 3 μm) with a phospholipidic shell. A low mechanical index (MI<0.09) was used in order to minimize microbubbles rupture. Ultrasound device systems (Philips ATL HDI 5000, Bothel, Washington) with a broandband probe (2–5 Mhz) and specific contrast agent algorithms (Pulse Inversion Harmonic Imaging) were used. The use of this algorithm allowed a real time imaging of all vascular phases (arterial, portal and late). All patients underwent CT scan, PET tomography and routine blood examinations. Ten patients with retroperitoneal liposarcomas were enrolled in this study (5 high grade, 3 intermediate grade, 2 low grade). Results: Five males and five females with metastatic or relapsed disease were enrolled. Median age was 57 years (range 40–70). All underwent chemotherapy with Ifosfamide and Doxorubicin. In all patients there was a clear correlation between contrast enhancement and grading: in low-grade patients there was no contrast enhancement, while the highest level of enhancement was seen in undifferentiated sarcomas. With regard to tumor response to chemotherapy, only 4 patients were evaluable. One patient had a PR and 3 patients had PD. In the 3 patients with PD CEUS showed contrast enhancement, PET was uptaking, but CT scan did not detect any change. In the patient with a PR, strong decrease of tumor perfusion on CEUS and uptaking on PET was seen, again with no change on CT scan. Conclusions: These preliminary observations suggest that CEUS may be more useful than CT scan on assessing tumor response in retroperitoneal sarcomas, and may predict the baseline malignancy grade. Data on a larger number of patients will be presented.

No significant financial relationships to disclose.
Endosialin/TEM1: Cellular localization and prevalence in soft-tissue tumors and carcinomas
Authors: Rouleau C. , Weber W. , Bagley R. , Morgenbesser S. D. , Kataoka S. , Honma N. , Hasegawa K. , Ishida I. , Thurberg B. L. , Teicher B. A.
Published: March 2020

20520

Background: Tumors grow more slowly in endosialin/TEM1 KO mice compared to WT, suggesting that host endosialin/TEM1-positive stroma promotes malignancy (Nanda, PNAS, 2006). Methods: We surveyed 92 human clinical samples by IHC (52 epithelial tumors, 40 sarcomas) to measure the extent of endosialin/TEM1 expression and assess cellular localization. Expression was also studied in primary cell cultures and 49 cancer lines. Results: 46/52 adenocarcinomas and carcinomas (88.5%) expressed endosialin/TEM1 mainly in pericytes (7/7 bladder, 7/11 breast, 5/5 colon, 7/8 ovarian, 7/7 renal, 2/2 liver, 4/5 lung, and 7/7 gastric). In some tumors, endosialin/TEM1 was present in pericytes and in fibroblasts (2/7 bladder, 4/11 breast, 5/5 colon, 5/8 ovarian, 2/7 renal, 2/2 liver, 1/5 lung and 7/7 gastric cancers). 32/40 sarcomas (80%) expressed endosialin/TEM1 mainly in pericytes (10/11 synovial sarcomas, 9/10 malignant fibrous histiocytomas, 3/5 Ewing's sarcomas, 3/5 angiosarcomas, 3/4 rhabdomyosarcomas, 2/2 pleiomorphic sarcomas, 1/1 Kaposi's sarcoma, 0/1 leiomyosarcoma and 1/1 liposarcoma). Synovial sarcomas displayed intense fibroblast staining. Endosialin/TEM1 was expressed by sarcoma cells in a few samples. In culture, we previously showed expression in human fibroblasts, endothelial precursor cells, pericytes and mesenchymal stem cells (MSC). We now report that endosialin/TEM1 mRNA is present in MSC during osteogenic and adipogenic differentiation. In 49 human tumor lines, expression was restricted to sarcoma cells (7/15 sarcoma, 0/5 melanoma, 0/2 neuroblastoma, 0/4 breast, 0/1 ovarian, 0/3 prostate, 0/1 renal, 0/1 liver, 0/3 pancreatic, 0/6 colorectal and 0/8 hematopoietic cancer lines). Conclusions: Endosialin/TEM1 is frequently expressed in clinical cancer (85% of 92 samples), both in epithelial and mesenchymal tumors. Cellular expression is mesenchymal in clinical samples and in culture. In tissues, endosialin/TEM1 is present in pericytes and fibroblasts, with some expression in sarcoma cells. The importance of endosialin/TEM1-positive stroma in experimental animals and prevalence in patient samples warrant further investigation. Endosialin/TEM1 may be a useful therapeutic target.

[Table: see text]
Multivisceral resections of gastrointestinal stromal tumors
Authors: Zhou Y. , Du C. , Fu H. , Zhao G. , Shi Y.
Published: March 2020

20523

Background: Gastrointestinal stromal tumors (GISTs) with positive kit staining, although rare, are the most common mesenchymal neoplasms affecting the gastrointestinal tract. We present our experience in the treatment of disease involving adjacent organs with multivisceral resections. Methods: The clinicopathologic records of twenty-two patients with multivisceral resection, among 170 patients suffered from GISTs treated in our hospital from 1994 to 2005, were retrospectively reviewed. Nine primary tumors originated from the stomach, 4 from the small intestine, 6 from the colorectum, 1 from abdominal cavity, and 2 from the retroperitoneal area. Meanwhile complete follow-up records were available in 15 patients with median 5-year follow-up. Results: The patients included 9 men and 13 women, from 36 to 77 year old. The largest tumor diameter ranged from 2 to 20 cm. The types of multivisceral operation comprised splenectomy (n=8), coloectomy (n=6), nephrectomy (n=5), partial hepatectomy (n=1), duodenectomy (n=1), oophorectomy (n=1), pancreatectomy (n=1), and adrenalectomy (n=1). None of lymph node metastatsis was found in 7 patients with lymph node dissection with gastric GISTs (n=5) or small intestinal GISTs (n=2). The involved organs confirmed by the pathologic diagnosis included kidney (n=2), spleen (n=2), pancreas (n=2), mesentery (n=1), and omentum (n=1). There was no perioperative mortality in this series. Among follow up patients, 9 were alive and 5 were died from the tumor recurrence or metastasis. Among them, one person with gastrectomy, pancreatectomy, adrenalectomy is still alive under 2 year follow-up by imatinib mesylate therapy postoperatively. Conclusions: Complete surgical resection with a negative gross margin by en bloc resection of the involved organs remains the standard treatment for non-metastatic GISTs. Imatinib mesylate represents a major breakthrough in the treatment of advanced GISTs and is the first effective systemic therapy for the disease.

No significant financial relationships to disclose.
Clinico-pathologic pattern of gastrointestinal stromal tumors (GIST) in southern India: A single-institution experience
Authors: Lamba M. , Mukherjee G. , Saini K. , Ramachandra C. , Rao C. , Kumar R. , Bapsy P. , Babu K. , Attili S. , Batra U.
Published: March 2020

20531

Background: There have been major advances in understanding the behavioral pattern, pharmacological intervention, and clinical response of GIST; yet Indian data in this regard is sparse. This study analyses the clinico-pathologic features in 36 patients (21 male, 15 female) of GIST seen at our institution. Methods: GIST was defined as a mesenchymal spindle or epithelioid cell lesion arising in the GI tract with CD117 immuno-reactivity. Retrospective data from January 03 to March 06 was analyzed for age, tumor site, morphology, immuno- reactivity, prognostic factors, response to treatment (by RECIST), and recurrence or metastasis. All patients had surgery; those with residual, recurrent, or metastatic disease got imatinib till tumor progression. Results: GIST presented at a mean age of 48.2 yrs (SD 6.4, range 34–65). The mean tumor size was 13.9 cm (range 2–42). The most common site was the small intestine (ileum 8, jejunum 7, duodenum 4). 24 patients (66.7%) had localized disease at baseline. Of these, 14 had local recurrence after surgery, and were given imatinib. 5 of them are in complete remission, 4 had partial response (PR), 3 patients died, and 2 had stable disease. Most patients with recurrent GIST had a mitotic rate of >10/50hpf. 8 patients developed metastasis, and received imatinib. Of these, 2 got a PR, 3 had progressive disease and died, and 3 had stable disease. 12 patients (33.3%) had metastasis at baseline (to liver and abdominal cavity), and underwent debulking. Of these, 6 patients with stable disease are on treatment with imatinib, 3 died and 3 were lost to follow-up. Conclusions: Average age of presentation was less than in Western reports. The commonest site was the small intestine as opposed to stomach in western literature. Mitotic rate was a better prognostic factor than gross tumor size. GIST with a mixed cell morphology showed aggressive behavior. Imatinib mesylate is useful in the post-operative management of GIST.

[Table: see text]

No significant financial relationships to disclose.
Single center phase II trial analysing the role of imatinib/hydroxyurea in patients (pts) with pretreated non-progressive glioblastoma (GBM) as maintenance treatment
Authors: Dresemann G. , Hosius C. , Nikolova Z. , Letvak L.
Published: March 2020

2055

Background: In GBM the highest malignant brain tumor with a median survival of about 15 months dysregulated signalling of platelet derived growth factor receptors (PDGF-Rs) is implicated in pathogenesis. I/HU showed impressive efficacy and tolerability in patients (pts) with recurrent progressing GBM. In 30 pilot pts with recurrent GBM the progression free survival (PFS) at 6 and 24 months (m) was 32% and 16% respectively. Disease stabilisation (SD) in 37% was an important result. SD for more than 2 years was possible. In GBM a short period of SD after primary or relapse treatment is typical. In this phase II study the efficacy of I/HU as maintenance treatment in pts with GBM in stage of SD was analysed. Methods: From December 2003 up to June 2005 30 GBM pts with documented SD for more than 6 weeks following prior treatment, including surgery, radiotherapy and at least one chemotherapeutic regimen were included,. No enzyme-inducing anticonvulsive drugs were allowed. I dose was 600 mg od, HU dose was 1000 mg (500 mg bid) as continuous oral treatment, pts were followed up by blood cell count weekly and magnetic resonance imaging every 6 weeks. Results: All 30 pts were eligible for safety and for 6, 12 and 18 m PFS and overall survival (OS); 25 pts were male, 5 pts female, median age was 44 years (32 to 71), 24 pts had primary (de novo) and 6 pts secondary GBM. All 30 pts had prior radiotherapy, 21 pts had prior temozolomide and 9 pts non- temozolomide containing regimens. 8 pts were free from relapse, 17 pts after first and 5 pts after second relapse. The median observation time is 28 m. 6, 12 and 18 m PFS was 60% (18/30), 40% (12/30) and 30% (9/30) respectively. 6, 12 and 18 m OS is 90% (27/30), 67% (20/30) and 53% (16/30) so far. PFS for more than 24 m occurred in 3/6 pts with secondary and in 2/24 pts with primary GBM. Toxicity was low (anemia grade 3: 2 pt; grade 2: 4 pts; leucocytopenia grade 3:2 pts; grade 2: 7 pts; thrombocytopenia grade 2: 4 pts), HU dose was reduced in 8 pts, I dose in 1 pt and G-CSF was given in 8 pts, no treatment related death occurred. Conclusion: I (600 mg/d)/ HU (1000 mg/d) was well tolerated in this study. Long-term disease stabilisation was possible - especially in pts with secondary GBM. Confirmation in further investigation is required.

[Table: see text]
A phase II trial of thalidomide (Thal) and procarbazine (Pro) in adults with recurrent or progressive malignant gliomas (MG)
Authors: Lesser G. J. , Stieber V. , Case D. , Enevold G. , Rosdhal R. , Tatter S. , Ellis T. , McMullen K. , Shaw E.
Published: March 2020

2067

Background: Thal and Pro are among the few agents with demonstrated activity against MG. A two-stage, phase II trial was initiated within the WFURB to establish the response rate of combination Thal-Pro in patients (pts) with recurrent or progressive MG. Methods: Eligibility included pt age = 18 with measurable tumor on contrast enhanced brain scans; KPS = 60; normal liver, kidney and hematologic function; and treatment with = 2 prior regimens. Pts were required to participate in the S.T.E.P.S. Program and mandated to comply with agreed upon measures to avoid conception. Protocol therapy included Pro 250mg/m2/d x 5d q 28days and Thal 200mg/day continuously. Intrapatient dose escalation of Thal was attempted (increase by 100mg/day weekly as tolerated) to a maximum of 800mg/day. All pts received daily pyridoxine(100mg), warfarin(1mg) and stool softeners/laxatives. MRI/CT scans were performed prior to each odd cycle (every 8 weeks) to assess response based upon changes in the products of the largest bidimensional tumor diameters. Quality of life questionnaires including the FACT-Br were performed at baseline and prior to each odd cycle in all treated pts. Results: 18 pts (11 male) were enrolled (median age 50, range 27–63). One pt refused any therapy and is excluded from the analysis. The 17 treated pts received 36 cycles (median 2) of therapy. The median maximum Thal dose achieved was 400mg (range 200–800). No complete or partial responses were seen; 1 pt (6%) experienced stable disease, 14 (82%) progressed as best response and 2 (12%) were not evaluable for response. Median time to progression was 2.1 months (95% CI, 1.5–2.5). 14 pts have died; median survival was 7.6 months (95% CI, 3.5–9.4). Grade 3/4 drug related toxicity was minimal. Conclusions: Despite modest individual response rates in multiple prior phase II and III trials, the combination of Pro and Thal demonstrated no efficacy in this trial and this combination is unworthy of further investigation in pts with MG. Supported by NCI 1 U10 CA81851 and Celgene.

No significant financial relationships to disclose.
Clinical outcome of glioblastoma multiforme patients with long-term survival
Authors: Yoon H. , Hottinger A. F. , DeAngelis L. M. , Lassman A. B. , Abrey L. E.
Published: March 2020

2069

Background: Glioblastoma multiforme (GBM) patients generally have a dismal prognosis with average survival of one year. Long-term survival of 3 years or more is rare and the clinical outcome of these patients has been poorly studied. Methods: Retrospective review of patients surviving 3 years or longer following diagnosis of GBM at our institution between 1985 and 2003. Clinical characteristics and long-term outcome were reviewed. Pathology was confirmed at our institution for all patients. Results: 39 long-term survivors of GBM were identified. Median age at diagnosis was 47 years (range: 14 - 69 years). Fifteen patients (pts) were older than 55 at time of diagnosis, and 5 were over 60. Presenting symptoms were headaches (56%), seizures (28%), hemiparesis (12%), aphasia (17%) or confusion (5%). Median KPS at diagnosis was 90 (range: 50–100). One patient (4%) underwent biopsy and X patients each (48%) underwent complete resection and incomplete resections. All patients received focal radiation therapy (RT) with a median dose of 5940 cGy (range: 4500 - 6120 cGy); 7 received concurrent temozolomide. Adjuvant chemotherapy in 35 pts consisted of temozolomide (54%), BCNU (38%), intra-arterial cisplatin (4%), or PCV (4%). Estimated median survival was 6.16 years (range: 3.1 - 18.2). After initial treatment, 11 pts had continuous clinical and radiographic remission, 28 relapsed, and 12 died. Median KPS at last follow-up was 70 (range 40 - 100). However, 19 pts (49%) developed delayed treatment-related complications at a median of 2.7 years (range: 1 -12 years) from initial diagnosis. Six (15%) developed RT necrosis (none of whom received concurrent temozolomide), 12 (31%) developed a subcortical dementia with associated leukoencephalopathy, and 9 (23%) developed strokes thought to be related to prior treatment. Conclusions: Long-term GBM survivors remain rare but occur in all age groups. These patients have a high risk of developing clinically significant long-term complications of their treatment.

No significant financial relationships to disclose.
Irinotecan and bevacizumab in progressive primary brain tumors: The Cleveland Clinic experience
Authors: Kang T. , Jin T. , Peereboom D.
Published: March 2020

2077

Background: High-grade gliomas are generally resistant to modern chemotherapy. In the case of glioblastoma multiforme, median overall survival has been less than 12 months and progression free survival of less than 4 months. For patients with recurrent GBMs, the 6 month progression free survival is 15–20%. The combination of irinotecan and bevacizumab is an active regimen in the treatment of this disease. Herein we report the experiences with this regimen at our institution with the objective of identifying a therapy with a better outcome than historical results. Methods: Single institutional, retrospective review of 27 patients with recurrent or progressive high grade gliomas treated at the Cleveland Clinic Brain Tumor Institute from 7/2005 through 10/2006. Patients had progressed on at least one prior chemotherapy. Patients with prior irinotecan or bevacizumab were excluded. Patients were analyzed on an intention-to-treat basis, and outcomes estimated by the Kaplan-Meier method. Results: The median age of the group was 46 years (range 5–69). The median number of prior therapies was 2 (range 1–10). Twenty of 27 patients have progressed (74%), and 11 of 27 patients have died (41%). Kaplan-Meier estimates for outcomes are summarized in the table . Progression-free survival at 6 months is 46 %, with median of 5.1 months. Overall survival at 6 months is 84%, with median of 12.6 months. In 7 patients, treatment was terminated early prior to progression. Significant toxicities include: one patient who developed hematuria, one patient with deep venous thrombosis and one patient who experienced intracranial hemorrhage. Conclusions: Our experience suggests that the combination of irinotecan and bevacizumab improves the 6-month progression-free survival when compared to historical figures. The rate of severe toxicities is consistent with prior reports and mandates careful selection of patients. Further randomized, phase 3 studies should be done to validate these results.

[Table: see text]

No significant financial relationships to disclose.
Role of slug in TGF-β1 mediated MMP-9 expression in human oral squamous cell cancer
Authors: Joseph M. J. , Ananthanarayanan V. , Diamond M. E. , Sun L. , Munshi H. G.
Published: March 2020

21000

Background: Oral squamous cell cancer (OSCC) causes significant morbidity and mortality as a result of loco-regional invasion and distant metastasis. Invasive OSCC tumors demonstrate increased expression of matrix metalloproteinases (MMPs), including MMP-9. TGF-β1, which promotes MMP-dependent invasion, is also frequently overexpressed in OSCC. Recent reports indicate that TGF-β1 can signal through Snail family of transcription factors, including Slug, which are key regulators of epithelial to mesenchymal transition. Methods: To examine the relationship between TGF-β1 and MMP-9 in human OSCC tumors, phospho-Smad2 and MMP-9 expression was quantified in an oral cancer tissue microarray, and then the relationship determined using Pearson correlation coefficient. To understand the role of Slug in TGF-β1-mediated MMP-9 expression, premalignant oral keratinocyte cell lines (OKF4 and OKF6) and malignant OSCC lines (SCC25 and UMSCC1) were treated with TGF-β1 (10 ng/ml) and analyzed for Slug and MMP-9 expression at the message and protein levels. The specific role of Slug was determined by transfecting OSCC cells with Slug specific siRNA or control siRNA, treating with TGF-β1 for 24h, and determining the effect on MMP-9 expression. Results: There was a statistically significant correlation between phospho-Smad2 and MMP- 9 expression in human OSCC samples, with a Pearson correlation coefficient of 0.4392 (p=0.0007). In vitro, treatment of premalignant and OSCC cells with TGF-β1 induced both Slug and MMP-9 expression at the message and protein level. Interestingly, transfection of Slug siRNA in OKF4 and OKF6 cells increased both basal and TGF-β1-mediated MMP-9 expression, while transfection of Slug siRNA in SCC25 and UMSCC1 cells decreased basal and TGF-β1-mediated MMP-9 expression. Conclusions: Overall, our data indicate that TGF-β1 may regulate MMP-9 expression in human oral squamous cell cancer. Additionally, our data indicate a role for Slug in TGF-β1-mediated MMP-9 expression in oral cancer cells. Future experiments will examine the mechanism by which Slug differentially regulates MMP-9 expression in premalignant and malignant OSCC cells.

No significant financial relationships to disclose.
A high serum level of YKL-40 in patients with cervical cancer is associated with short survival
Authors: Roslind A. , Palle C. , Johansen J. S. , Christensen I. J. , Nielsen H. J. , Price P. A. , Nielsen D. L. , Mosgaard B. J.
Published: March 2020

21004

Background: YKL-40 is secreted by tumor cells, macrophages and neutrophils. The exact function of YKL-40 in cancer is unknown. It may be a growth, differentiation or survival factor and play a role in angiogenesis. High serum levels of YKL-40 are associated with a poor prognosis in a variety of solid and hematological malignancies. The aim of this study was to examine if serum YKL-40 is a prognostic biomarker in patients with cervical cancer. Methods: YKL-40 was determined by ELISA (Quidel, Santa Clara, CA) in pretreatment serum samples from 116 patients with cervical cancer (FIGO stage Ia (N=5), Ib (N=55), II (N=27), III (N=25) and IV (N=4); median age 50, range 27–87 years). The median follow-up time was 3.2 years (range 2.1–4.4 years). 18 patients had a recurrence and 28 patients died. Results: Serum YKL-40 was increased (p<0.001) in the patients with cervical cancer (median 76 μg/l, range 20–2310) compared to healthy women (43 μg/l, range 20–172). Serum YKL-40 was higher than the age-corrected 95th percentile of serum YKL-40 in healthy women in 35% of the patients. Patients with high serum YKL-40 had significantly shorter survival than patients with normal serum YKL- 40 (HR=3.1, 95% CI: 1.5–6.5, p=0.002, logrank test). Univariate Cox analysis of serum YKL-40 (log transformed and treated as a continuous covariate) showed significant association with overall survival (HR=2.3, 95% CI: 1.7–3.2, p<0.0001). Multivariate Cox analysis including stage, menopausal status and serum YKL-40 (log transformed and treated as a continuous covariate) showed that stage (stage II+III vs. I: HR=6.4, 95% CI: 1.8–22.5, p=0.004) and serum YKL-40 (HR=1.6, 95% CI: 1.1–2.4, p=0.02) were independent prognostic variables of overall survival. Univariate Cox analysis of serum YKL-40 (log transformed and treated as a continuous covariate) demonstrated a significant association with risk of recurrence (HR=1.7, 95% CI: 1.1–2.7, p=0.02). Conclusion: Serum YKL-40 is a prognostic biomarker of recurrence-free and overall survival in patients with cervical cancer.

No significant financial relationships to disclose.
BRCA1 and BRCA2 mutation carrier predictions using the BRCAPRO model in clinic-based minority families enrolled in the Breast Cancer Family Registry (B-CFR)
Authors: Huo D. , Senie R. T. , Terry M. B. , Daly M. B. , Buys S. S. , Olopade O. I.
Published: March 2020

21037

Background: BRCA mutation prediction models, such as BRCAPRO, are used in cancer risk clinics, but they were developed based on mutation rates and penetrance observed in individuals of Ashkenazi Jewish and European ancestry. Furthermore, in clinical counseling it is not always clear whether to test additional family members for BRCA mutations after the proband tests negative. The aim of this study is to evaluate the performance of the BRCAPRO model among clinic-based minority families and to evaluate the clinical utility of testing additional family members in high risk families. Methods: A total of 314 families with at least one member having been tested for BRCA mutations were enrolled through the B-CFR. Families of Ashkenazi Jewish ancestry were excluded. Using the BRCAPRO model with default penetrance and allele frequency for non-Ashkenazi Jewish populations, the predicted likelihood of carrying either a BRCA1 or BRCA2 mutations was generated. Sensitivity, specificity, and area under the receiver operating characteristic curves (AUC) were calculated. Results: There were 55 African American, 181 Hispanic, 42 Asian American and 36 other minority families. The AUC was 0.771 (95% confidence interval, CI: 0.720–0.816) for all minorities combined. At a predicted probability of 10%, the sensitivity for identifying mutation carriers was 65% and the specificity was 76%. The performance was marginally significantly better for Hispanic families than the other minority groups (p=0.07). In 228 families (73%), multiple individuals were tested for BRCA mutations. After taking into account the mutation status of family members, the performance of the BRCAPRO model was improved: the AUC increased to 0.862 (95% CI: 0.820–0.899) and the specificity at the 10% threshold increased to 83%, while the sensitivity remained the same. Conclusions: The data support the use of BRCAPRO in pretest prediction of BRCA1/2 mutations for minority families in high risk clinic settings. Mutation status of family members provides additional predictive value, which may help counselors decide whether to offer other family members the test when one member has already tested negative, given a positive family history of breast and ovarian cancer.

No significant financial relationships to disclose.
Progesterone receptor gene polymorphism (PROGINS) in 701 women from a mammographic breast cancer screening program (NMPOA) in Southern Brazil
Authors: Giacomazzi J. , Aguiar E. , Palmero E. I. , Kalakun L. , Schuler-Faccini L. , Duarte Filho D. , Bedin A. , Caleffi M. , Giugliani R. , Ashton-Prolla P.
Published: March 2020

21048

Background: Several genetic polymorphisms in hormone receptor genes have been associated with breast cancer (BC) risk. Among these, a 306 base-pair insertion of the Alu subfamily in intron 7 of the progesterone receptor (PR) gene, (PROGINS), has been associated with decreased BC risk in several populations. In Brazil, BC is a significant public health problem, due to its high incidence and mortality rates. In Porto Alegre, Brazil`s southernmost capital, a multidisciplinary Breast Cancer Prevention Project - the Nucleo Mama Porto Alegre Cohort (NMPOA) was started in 2004 and includes a mammographic screening program for women ages 40–69 years. Goal: Determine the allelic and genotypic frequencies of PROGINS in women undergoing annual BC screening and correlate its presence with mammography results and presence of additional BC risk factors (family history of BC, body mass index, estimated BC risk by the Gail model and age) at baseline and after 10 years. Methods: A sample of 701 women from the NMPOA BC screening program was consecutively enrolled in the study from November/2005 until March/2006. Clinical data, mammography results (as BIRADS categories) and BC risk information was obtained by chart review. PROGINS genotyping was performed by polymerase chain reaction (PCR). Results: Of the 701 patients studied, 504 (71,0%) were wild-type homozygous, 184 (26,2%) heterozygous and 13 (1,8%) homozygous for the PROGINS polymorphism. These genotypic frequencies are similar to those of other reports in different populations. Genotype was correlated with 5-year and vital BC risk estimates (Gail model), body mass index, family history of BC and mammography findings. A statistically significant association was found between the presence of PROGINS and a positive family history of BC (p< 0,05). Conclusions: The genotypic and allelic frequencies of the PROGINS polymorphism were not significantly different from those reported previously for other populations. Prospective clinical evaluation of the women followed in this program and correlation of genotype with clinical findings may be important to elucidate additional risks associated with the PROGINS polymorphism.

No significant financial relationships to disclose.