Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors.

Background: To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods: We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan-Meier method was used to estimate PFS and OS. Results: With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001. Conclusion: The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort.

Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor.

BACKGROUND: The emergence of a primitive neuroectodermal tumor (PNET) within a germ-cell tumor (GCT) is rare. We assess the prognosis and response to treatment. PATIENTS AND METHODS: Eighty-one patients were identified. Selected patients were treated with cyclophosphamide 1200 mg/m(2), doxorubicin 75 mg/m(2), and vincristine 2 mg i.v. alternating with ifosfamide 1.8 g/m(2) x 5 days plus etoposide 100 mg/m(2) x 5 days (CAV/IE). Ewing's sarcoma (EWS) translocation was assessed using a FISH-based method. RESULTS: Median follow-up was 41 months. Seventy-six patients had PNET in the primary tumor or in initial metastasis. Five harbored PNET only at relapse. Twenty-six of 76 underwent primary retroperitoneal lymph node dissection, 13 of whom had retroperitoneal PNET and four are dead of disease (DOD). Fifty of 76 were initially treated with GCT chemotherapy (n = 49) or CAV/IE (n = 1). Twenty-seven of these 50 underwent complete postchemotherapy resection of residual PNET and 17 are DOD. Ten patients received CAV/IE. Eight achieved an objective response, and five are currently alive. One of the 14 specimens examined carried the EWS translocation. CONCLUSIONS: PNET of GCT origin is associated with an adverse outcome. For low-volume disease, surgery is the optimal initial therapy. CAV/IE may have a role in patients with unresectable disease.

Outburst of Jupiter's synchrotron radiation after the impact of comet Shoemaker-Levy 9.

Jupiter's nonthermal microwave emission, as measured by a global network of 11 radio telescopes, increased dramatically during the Shoemaker-Levy 9 impacts. The increase was wavelength-dependent, varying from approximately 10 percent at 70 to 90 centimeters to approximately 45 percent at 6 and 36 centimeters. The radio spectrum hardened (flattened toward shorter wavelengths) considerably during the week of impacts and continued to harden afterward. After the week of cometary impacts, the flux density began to subside at all wavelengths and was still declining 3 months later. Very Large Array and Australia Telescope images of the brightness distribution showed the enhancement to be localized in longitude and concentrated near the magnetic equator. The evidence therefore suggests that the increase in flux density was caused by a change in the resident particle population, for example, through an energization or spatial redistribution of the emitting particles.

Commentary on "Prognostic effect of carcinoma in situ in muscle-invasive urothelial carcinoma patients receiving neoadjuvant chemotherapy."

BACKGROUND: Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes. MATERIALS AND METHODS: Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy. RESULTS: A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio = 4.08; 95% CI: 1.19-13.98; P = 0.025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = 0.055) and OS (104.5 vs. 152.3 months; P = 0.091) outcomes similar to those for the pCR patients. CONCLUSION: The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted.

Bone marrow colony-forming cells in mice with virus-induced lymphoid leukemia: relation to serum colony-stimulating activity and blood granulocytes.

Mice with advanced lymphoid leukemia have elevated peripheral blood granulocytes and elevated serum colony-stimulating activity, which promotes the in vitro growth of granulocyte and/or macrophage colonies. The number of bone marrow precursor cells of the in vitro granulocyte and/or macrophage colonies varied from normal to 10% of normal. The elevation of colony-stimulating activity correlated best with a combination of increased blood granulocytes and a deficiency of bone marrow precursor cells, which suggested that colony-stimulating activity is a leukopoietin that increases the efficiency and rate of production of granulocytes.

Effect of Corynebacterium parvum on the proliferative rate of granulocyte-macrophage progenitor cells and the toxicity of chemotherapy.

We have studied the interaction of Corynebacterium parvum and a variety of cell cycle-specific and cell cycle-nonspecific chemotherapeutic agents on granulocyte-macrophage progenitor cells [colony-forming units culture (CFU-c)] in C57BL/6 mice. In vitro tritiated thymidine suicide studies showed an increased rate of proliferation of bone marrow CFU-c 24 hr after C. parvum injection. In vivo toxicity of cell cycle-specific agents but not of cell cycle-nonspecific agents for bone marrow CFU-c was increased 24 hr after C. parvum injections. The increased numbers of CFU-c in the spleen, induced by C. parvum, were also sensitive to a cell cycle-specific agent for up to 7 days after C. parvum injection. The findings suggest differences in the kinetics of proliferation of splenic compared to bone marrow CFU-c. The relative time of administration of chemotherapy and immunostimulants such as C. parvum will have to be carefully considered in the design of clinical trials.

Altered toxicity of 5-fluorouracil following treatment with Corynebacterium parvum.

Recent studies have demonstrated that systemic Corynebacterium parvum increases serum granulocyte-macrophage colony-stimulating factor and stimulates the proliferation of granulocyte-macrophage progenitor cells. It was hypothesized that more rapid cycling of granulocyte-macrophage progenitor cells would render the cells more sensitive to a cell cycle-specific chemotherapeutic agent. The colony-forming ability of bone marrow granulocyte-macrophage progenitor cells was assayed in vitro with soft agar cultures. C. parvum given before 5-fluorouracil in C57BL/6 mice increased the granulocyte-macrophage progenitor cell toxicity, the lymphopenic effect, and the lethality of 5-fluorouracil. When C. parvum was given after 5-fluorouracil, there was more rapid rebound of granulocyte counts to normal or supranormal levels.

Effect of Corynebacterium parvum on colony-stimulating factor and granulocyte-macrophage colony formation.

Because Corynebacterium parvum has tumor-inhibitory properties and stimulates granulocyte-macrophage production, it may have clinical value in combination with chemotherapy. The leukopoietic effect of killed suspensions of C. parvum was studied in mice using the technique of in vitro clonal culture of hematopoietic cells. After C. parvum injection, there was a prompt, sustained elevation of serum colony-stimulating factor followed by an increase in granulocyte-macrophage precursor cells in the spleen and increases in blood mononuclear and granulocyte cells. Colony-stimulating factor production is suggested as a major mechanism of stimulation of granulocyte-macrophage proliferation by C. parvum. Since rapidly proliferating hematopoietic cells may have increased sensititity to cytotoxic agents, the details of hematopoietic stimulation by C. parvum may be critical in the sequential timing of combined C. parvum and chemotherapy treatment to obtain maximal tumor inhibition and minimal hematopoietic toxicity.

Decreased liver and lung drug-metabolizing activity in mice treated with Corynebacterium parvum.

Injections of killed suspensions of Corynebacterium parvum (i.p.) in young male mice were followed by time- and dose-dependent decreases in the drug-metabolizing activity of liver microsomes and lung homogenates. In vitro assays with model substrates [aminopyrine, aniline, p-nitroanisole, and benzo(a)pyrene] were used to quantitate drug-metabolizing activity. It is likely that such decreases in mixed function oxidases activity will act to significantly alter the pharmacokinetics of concurrently or subsequently administered drugs. The results provide a possible mechanism to explain several previously reported immunochemotherapeutic interactions.

Expression of cyclooxygenase-2 (COX-2) in human invasive transitional cell carcinoma (TCC) of the urinary bladder.

Cyclooxygenase (COX)-inhibiting drugs have antitumor activity in canine and rodent models of urinary bladder cancer. Two isoenzymes of COX have been identified, COX-1 and COX-2. The purpose of this study was to characterize COX-1 and COX-2 expression in human invasive transitional cell carcinoma of the urinary bladder by immunohistochemistry and Western blot analysis. COX-2 was not expressed in normal urinary bladder samples but was detected in 25 of 29 (86%) invasive transitional cell carcinomas of the urinary bladder and in 6 of 8 (75%) cases of carcinoma in situ. These results indicate that COX-2 may play a role in bladder cancer in humans and support further study of COX-2 inhibitors as potential antitumor agents in human bladder cancer.

Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation.

The human AP endonuclease (Ape1 or ref-1) DNA base excision repair (BER) enzyme is a multifunctional protein that has an impact on a wide variety of important cellular functions including oxidative signaling, transcription factor regulation, and cell cycle control. It acts on mutagenic AP (baseless) sites in DNA as a critical member of the DNA BER repair pathway. Moreover, Ape1/ref-1 stimulates the DNA-binding activity of transcription factors (Fos-Jun, nuclear factor-kappaB, Myb, ATF/cyclic AMP-responsive element binding protein family, HIF-1alpha, HLF, PAX, and p53) through a redox mechanism and thus represents a novel component of signal transduction processes that regulate eukaryotic gene expression. Ape1/ref-1 has also been shown to be closely linked to apoptosis associated with thioredoxin, and altered levels of Ape1/ref-1 have been found in some cancers. In a pilot study, we have examined Ape1/ref-1 expression by immunohistochemistry in sections of germ cell tumors (GCTs) from 10 patients with testicular cancer of various histologies including seminomas, yolk sac tumors, and malignant teratomas. Ape1/ref-1 was expressed at relatively high levels in the tumor cells of nearly all sections. We hypothesized that elevated expression of Ape1/ref-1 is responsible in part for the resistance to therapeutic agents. To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN. Using an oligonucleotide cleavage assay and immunohistochemistry to assess Ape1/ref-1 repair activity and expression, respectively, we found that the repair activity and relative Ape1/ref-1 expression in GCT cell lines are directly related. NT2/D1 cells transduced with Ape1/ref-1 exhibited 2-fold higher AP endonuclease activity in the oligonucleotide cleavage assay, and this was reflected in a 2-3-fold increase in protection against bleomycin. Lesser protection was observed with gamma-irradiation. We conclude that: (a) Ape1/ref-1 is expressed at relatively high levels in some GCTs; (b) elevated expression of Ape1/ref-1 in testicular cancer cell lines results in resistance to certain therapeutic agents; and (c) Ape1/ref-1 expression in GCT cell lines determined by immunohistochemistry and repair activity assays parallels the level of protection from bleomycin. We further hypothesize that elevated Ape1/ref-1 levels observed in human testicular cancer may be related to their relative resistance to therapy and may serve as a diagnostic marker for refractory disease. To our knowledge, this is the first example of overexpressing Ape1/ref-1 in a mammalian system resulting in enhanced protection to DNA-damaging agents.

Late relapse of testicular cancer.

PURPOSE: This study analyzed a large group of patients with testicular germ cell cancer in complete remission, who relapsed more than 2 years after completion of treatment. PATIENTS AND METHODS: A review of all patients treated at Indiana University Medical Center from 1979 through 1992 for late relapse was conducted. Eighty-one patients were treated for late relapse of testicular cancer. Forty-seven patients relapsed more than 5 years after successful management of their initial disease. RESULTS: At initial diagnosis, 35 patients had clinical stage I, 18 stage II, and 28 stage III disease. Twenty-three of 35 stage I, all 18 stage II, and all 28 stage III patients were treated by chemotherapy before their late relapse. The median follow-up duration of patients post-management of late relapse was 4.8 years. Twenty-one patients (25.9%) are continuously disease-free. Nineteen of these 21 patients had surgical resection of carcinoma or teratoma as a component of their therapy. Of sixty-five patients treated for late relapse by chemotherapy, 17 (26.2%) had a complete response, but only two have been continuously disease-free with chemotherapy alone. These two never received prior chemotherapy. CONCLUSION: Late relapse of testis cancer is more common than previously thought. Surgery is the preferred mode of therapy. Chemotherapy has only modest success in this entity, in contrast to the excellent results in de novo germ cell tumors. Patients treated for testicular germ cell cancer need annual follow-up evaluations throughout their life due to the possibility of late relapse.

Identification of clinical stage A nonseminomatous testis cancer patients at extremely low risk for metastatic disease: a combined approach using quantitive immunohistochemical, histopathologic, and radiologic assessment.

PURPOSE: To evaluate previously determined predictors of metastasis in low-stage testis cancer in a consecutive group of clinical stage A patients. PATIENTS AND METHODS: Ninety-one consecutive clinical stage A nonseminomatous germ cell tumor (NSGCT) patients who underwent primary nerve-sparing retroperitoneal lymph node dissection (NSRPLND) had orchiectomy specimens and computed tomographic (CT) scans evaluated blindly in a quantitative fashion. These scores were then correlated with pathologic stage using previously determined paradigms. RESULTS: Using volume of embryonal carcinoma in the orchiectomy specimen, lymph node diameters in the primary landing zones and MIB-1 staining of the orchiectomy specimen, 41 patients were classified as low risk for metastasis. Forty of these 41 had pathologic stage A disease at RPLND. CONCLUSION: These parameters can identify a low-risk group of patients for metastasis who can be rationally offered surveillance.

Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma--predominant testis cancer.

PURPOSE: To determine the incidence of metastatic disease and usage of chemotherapy (adjuvant or metastatic) after primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) I embryonal carcinoma (EC)-predominant testicular cancer. EC predominance was defined as the presence of EC at a level greater than that of any other histologic diagnosis. PATIENTS AND METHODS: All CS I patients with nonseminomatous germ cell tumors who underwent RPLND at Indiana University from 1990 to 1995 were reviewed retrospectively. RESULTS: Two-year follow-up was available for 292 of 320 patients. EC-predominant disease was found in 125 (42.8%) of 292. Eighty-five (68.0%) of 125 patients with EC-predominant disease had pathologic stage (PS) I, and 18 (21.2%) of this group of 85 relapsed. A significantly lower PS I relapse rate of 3% was found for patients who had non-EC-predominant disease (P <.0001). PS II disease was more frequent in patients with EC predominance, as 40 (32.0%) of 125 had retroperitoneal metastases, compared with 26 (15.6%) of 167 patients with a non-EC-predominant histologic diagnosis (P =.0024). Chemotherapy was administered to 48 (38.4%) of the 125 patients with CS I EC-predominant disease after RPLND. This included 25 CS I patients with PS II disease who received adjuvant chemotherapy in addition to 23 patients who subsequently required chemotherapy for relapse after RPLND. Ten (66. 6%) of 15 PS II EC-predominant patients were cured by surgery alone. Currently, all 125 EC-predominant patients are disease-free. CONCLUSION: Patients with CS I EC-predominant disease are at a relatively high risk for metastatic disease.

Clinical stage B non-seminomatous germ cell testis cancer: the Indiana University experience (1965-1989) using routine primary retroperitoneal lymph node dissection.

Between 1965 and 1989, 1180 patients at Indiana University, U.S.A., underwent retroperitoneal lymph node dissection (RPLND) for non-seminomatous germ cell (NSGC) testis cancer of whom 638 cases had primary RPLND. A subset of 174 cases were considered clinical stage B (or II) before surgery (retroperitoneal nodal metastases by clinical staging). Surgery revealed that 23% (n = 41) had pathological stage A disease (no cancerous nodes). This error rate in clinical staging has decreased somewhat with improved techniques, but remains approximately 20% over the last decade. The relapse rate in pathological stage A (n = 41) was 5% (n = 2), both of whom were cured by chemotherapy. The relapse rate in pathological stage B without postoperative adjuvant treatment (n = 54) was 35% (n = 19); 2 patients died. This indicates that 65% of pathological stage B cases were cured by RPLND alone. From 1979 to 1989, the 140 pathological stage B cases participated in a randomised prospective trial of post-RPLND adjuvant chemotherapy versus no postoperative treatment. Forty two per cent (n = 59) received postoperative platinum-based therapy (two cycles), and there has been no relapse after RPLND for stage B disease. While advances in chemotherapy for NSGC testis cancer have led to its application by several study groups to clinical stage B (or II) testis cancer (with surgery reserved only for those in partial remission), the equivalent cure rate with RPLND surgery with chemotherapy rescue reserved for those who relapse appears to have both cost and risk-benefit advantages.

Breast cancer and pregnancy.

A diagnosis of breast cancer during pregnancy or the postpartum period is an unfortunate occurrence. Hormonal factors appear to play an important role early on in the development of breast cancer; however, pregnancy itself does not clearly influence the outcome of an established breast cancer. Diagnosis can be challenging in a pregnant woman and delays in diagnosis are common. Treatment decisions must take into consideration not only toxicity to the mother, but short- and long-term consequences for the fetus as well. Other special considerations with pregnancy-associated breast cancer include the timing of delivery, the potential for nursing, and concerns for future fertility. In general, management of pregnancy associated breast cancer follows the same principals as in non-pregnant patients of similar age. With thoughtful application of available therapies, outcome can be optimized for both the mother and her child.

Clinical stage I nonseminoma: surgery versus surveillance.

The presentation of nonseminomatous germ cell tumor confined clinically to the testicle (clinical stage I) is associated with a 30% incidence of occult retroperitoneal metastases. For decades, the standard of care in these patients has been a retroperitoneal lymph node dissection (RPLND), both for staging purposes, and, in the pre-modern chemotherapy era, it was performed with curative intent. The improvements in combination chemotherapy during the past 20 years have resulted in the cure of most individuals with small volume recurrent disease, calling into question the continued need for RPLND. The strategy of surveillance and chemotherapy for the 30% who relapse has gained acceptance, and, with meticulous follow-up, can result in the same excellent cure rates seen in patients treated with the surgical option. Although primary chemotherapy has also been suggested as a treatment option, the majority of patients will receive that chemotherapy unnecessarily, and cure rates with this strategy will not surpass those for surveillance or RPLND. Prognostic factors have been developed that can successfully identify a group of patients who are at an extremely low risk of relapse, thus potentially sparing these individuals any additional therapy. However, attempts to define a very high risk population have been unsuccessful to date, and we await the development of newer biologic markers able to predict which patients are most likely to have occult retroperitoneal disease and therefore most likely to benefit from additional "adjuvant" therapy post-orchiectomy.

Breast cancer and aging.

While many of the basic principles of breast cancer management are the same for younger and older women, a number of breast cancer issues particularly important for elderly women have not been resolved. Many of these management questions need answers based on data that are better than that currently available. At what age should the clinician consider cessation of screening mammography? For which very elderly patients might tamoxifen alone be adequate treatment for primary operable breast cancer? How can we develop better guidelines for the selection and administration of cytotoxic chemotherapy in an elderly population? What is the appropriate systemic adjuvant therapy, if any, for the patient over the age of 70? These and other questions may be answered through the development of clinical trials directed specifically at the elderly population.