Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.

BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Bacille Calmette-Guerin disease following Bacille Calmette-Guerin vaccination of an HIV-infected health-care worker.

We present a case of Bacille Calmette-Guerin (BCG) lymphadenitis following immunization of a health-care worker with risk factors for HIV but undiagnosed infection. This case highlights the potential risks of BCG and clearly demonstrates the need to consider HIV testing in all patients prior to BCG vaccination.

Evidence of a parathyroid hormone-independent chronic effect of estrogen on renal phosphate handling and sodium-dependent phosphate cotransporter type IIa expression.

The effects of estrogen on phosphate metabolism are not well understood. To better define the chronic effects of estrogen on phosphate balance and on renal phosphate handling, the following groups were examined: A. young male and female rats, age- and weight-matched (age 8-10 weeks, 1 (st) study), and B. ovariectomized female rats (OVX), 22 weeks old, ovariectomized aged-matched rats receiving estrogen replacement (15 micromol x 3/week) for 14 weeks (OVX+E), control female rats (intact ovaries), and male rats, both age matched to OVX and OVX+E (2 (nd) Study). In younger females (1 (st) study), plasma phosphate was lower, whereas the urinary excretion of phosphate was higher than in males. In adult intact females and in OVX+E urinary excretion of phosphate was higher than in males and OVX (2 (nd) Study). In these rats, a significant correlation between plasma phosphate and estrogen level was found. Sodium-dependent phosphate cotransporter (NaPiIIa) mRNA expression and protein abundance were higher in the renal cortex of younger male rats than in age- and weight-matched females. In adult rats, NaPiIIa mRNA and protein abundance were higher in OVX than in OVX+E, and in mature males as compared with age-matched females. These differences were not related to the parathyroid hormone (PTH) levels. Chronic estrogen administration was also associated with increased plasma calcium level and urinary calcium excretion. These results suggest that chronic estrogen treatment is associated with an inhibitory, PTH-independent effect on the expression of NaPiIIa in the kidney, leading to sex-related differences in phosphate balance.

Validation of novel imaging methodologies for use as cancer clinical trial end-points.

The success or failure of a clinical trial, of any phase, depends critically on the choice of an appropriate primary end-point. In the setting of phases II and III cancer clinical trials, imaging end-points have historically, and continue presently to play a major role in determining therapeutic efficacy. The primary goal of this paper is to discuss the validation of imaging-based markers as end-points for phase II clinical trials of cancer therapy. Specifically, we outline the issues that must be considered, and the criteria that would need to be satisfied, for an imaging end-point to supplement or potentially replace RECIST- defined tumour status as a phase II clinical trial end-point. The key criteria proposed to judge the utility of a new end-point primarily relate to its ability to accurately and reproducibly predict the eventual phase III end-point for treatment effect, which is usually assessed by a difference between two arms on progression free or overall survival, both at the patient and more importantly at the trial level. As will be demonstrated, the level of evidence required to formally and fully validate a new imaging marker as an appropriate end-point for phase II trials is substantial. In many cases, this level of evidence will only become available by conducting a series of coordinated prospectively designed multicentre clinical trials culminating in a formal meta-analysis. We also include a discussion of situations where flexibility may be required, relative to the ideal rigorous evaluation, to accommodate inevitable real-world feasibility constraints.

Lessons learned from independent central review.

Independent central review (ICR) is advocated by regulatory authorities as a means of independent verification of clinical trial end-points dependent on medical imaging, when the data from the trials may be submitted for licensing applications [Food and Drug Administration. United States food and drug administration guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Rockville, MD: US Department of Health and Human Services; 2007; Committee for Medicinal Products for Human Use. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) guideline on the evaluation of anticancer medicinal products in man. London, UK: European Medicines Agency; 2006; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-492 (oxaliplatin). Rockville, MD: US Department of Health and Human Services; 2002; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-923 (sorafenib tosylate). Rockville, MD: US Department of Health and Human Services; 2005; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-065 (ixabepilone). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-059 (lapatinib ditosylate). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Biologics Evaluation and Research. Approval package for BLA numbers 97-0260 and BLA Number 97-0244 (rituximab). Rockville, MD: US Department of Health and Human Services; 1997; United States Food and Drug Administration. FDA clinical review of BLA 98-0369 (Herceptin((R)) trastuzumab (rhuMAb HER2)). FDA Center for Biologics Evaluation and Research; 1998; United States Food and Drug Administration. FDA Briefing Document Oncology Drugs Advisory Committee meeting NDA 21801 (satraplatin). Rockville, MD: US Department of Health and Human Services; 2007; Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. JCO 2007(November):5210-7]. In addition, clinical trial sponsors have used ICR in Phase I-II studies to assist in critical pathway decisions including in-licensing of compounds [Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. JCO 2007(November):5180-6; Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. JCO 2007(August):3407-14; Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. JCO 2007(June):2171-7; Ghassan KA, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. JCO 2006(September):4293-300; Boué F, Gabarre J, GaBarre J, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. JCO 2006(September):4123-8; Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. JCO 2006(July):3354-60; Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. JCO 2006(June):2502-12; Jaffer AA, Lee FC, Singh DA, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. JCO 2006(February):663-7; Bouché O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Fédération Francophone de Cancérologie Digestive Group Study-FFCD 9803. JCO 2004(November):4319-28]. This article will focus on the definition and purpose of ICR and the issues and lessons learned in the ICR setting primarily in Phase II and III oncology studies. This will include a discussion on discordance between local and central interpretations, consequences of ICR, reader discordance during the ICR, operational considerations and the need for specific imaging requirements as part of the study protocol.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

BACKGROUND: Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. FUTURE WORK: A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

Recommendations for the assessment of progression in randomised cancer treatment trials.

Progression-free survival (PFS) is an increasingly important end-point in cancer drug development. However, several concerns exist regarding the use of PFS as a basis to compare treatments. Unlike survival, the exact time of progression is unknown, so progression times might be over-estimated (or under-estimated) and, consequently, bias may be introduced when comparing treatments. In addition, the assessment of progression is subject to measurement variability which may introduce error or bias. Ideally trials with PFS as the primary end-point should be randomised and, when feasible, double-blinded. All patients eligible for study should be evaluable for the primary end-point and thus, in general, have measurable disease at baseline. Appropriate definitions should be provided in the protocol and data collected on the case-report forms, if patients with only non-measurable disease are eligible and/or clinical, or symptomatic progression are to be considered progression events for analysis. Protocol defined assessments of disease burden should be obtained at intervals that are symmetrical between arms. Independent review of imaging may be of value in randomised phase II trials and phase III trials as an auditing tool to detect possible bias.

Sensitivity of renal cell carcinoma to aminoflavone: role of CYP1A1.

PURPOSE: The aminoflavone analogue (AF) exhibits antitumor activity in vitro, particularly against neoplastic cells of renal origin. We identified cellular correlates of responsiveness to AF in continuous human tumor renal cell carcinoma lines and in tumor cell isolates, termed renal carcinoma cell strains, from patients with clear cell and papillary renal neoplasms. MATERIALS AND METHODS: In vitro antiproliferative activity of AF was evaluated using the sulforhodamine B protein dye assay. In vivo antitumor activity of the drug was determined in mice bearing xenografts. Covalent binding of AF/metabolite(s) was assessed following exposure of cells to AF for 16 hours. CYP1A1 and CYP1B1 mRNA and apoptosis were quantitated by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: AF produced total growth inhibition in vitro in 3 of 6 human tumor renal cell lines at concentrations of 90 to 400 nM. In vivo treatment of mice bearing xenografts of the Caki-1 renal cell carcinoma, sensitive to AF in vitro, resulted in significant antitumor activity, including tumor-free survivors. Studies in 13 renal cell strains isolated from patients with clear cell (9) or papillary (4) renal cell carcinoma indicated that 3 of 4 papillary strains were sensitive to AF compared with 2 of 9 clear cell strains. AF sensitive renal cell lines and strains exhibited induction of CYP1A1 and CYP1B1 gene expression, increased covalent binding of AF metabolite(s) and apoptosis. CONCLUSIONS: AF has noteworthy antitumor activity against certain human tumor renal cell lines in vitro and in vivo, which correlates with drug metabolism to covalently binding metabolites after CYP1A1 and CYP1B1 gene expression. We hypothesize that it leads to apoptosis induction. AF sensitive renal cell strains are predominantly of the papillary histological type. These results are limited by the small numbers of cell lines and cell strains but they are suggestive of the need for further testing in larger collections of cell strains.

Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10(-7.5) M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10(-4) M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity.

Therapeutic studies.

This article discusses the problems in basic design, conduct, and interpretation associated with phases I, II, and III of the cancer clinical trials and explains the various statistical solutions to these problems. The fundamental problem common to all three trials is achieving a correct and precise answer to the question posed to inform future testing and treatment while protecting trial patients from receiving treatment that has demonstrated excessive toxicity or lack of clinical efficacy. This shared problem gives rise to statistical designs with basic similarities across the three trial types.

p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest.

The p53-inducible gene 3 (PIG3) was recently identified in a screen for genes induced by p53 before the onset of apoptosis. PIG3 shares significant homology with oxidoreductases from several species. In this study, PIG3-specific antibodies were used to analyze cellular PIG3 protein levels under control and genotoxic stress conditions. PIG3 protein was localized to the cytoplasm and induced in primary, non-transformed, and transformed cell cultures after exposure to genotoxic agents. The induction of PIG3 was p53-dependent and occurred with delayed kinetics as compared with other p53 downstream targets, such as p21 and MDM2. Using a p53-inducible cell model system, in which p53-mediated growth arrest is reversible, we found that PIG3 levels were increased during p53-mediated growth arrest. Interestingly, elevated levels of PIG3 were maintained in cells that resumed cycling in the absence of ectopic p53 expression, suggesting that PIG3 is a long-lived reporter, which may be useful for detecting transient activation of p53.

New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.

Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

Murine immune response to Neisseria meningitidis group C capsular polysaccharide: analysis of monoclonal antibodies generated in response to a thymus-independent antigen and a thymus-dependent toxoid conjugate vaccine.

Antibody (Ab) responses to polysaccharides (PSs) such as Neisseria meningitidis group C PS (MCPS) are characterized as being thymus independent (TI) and are restricted with regard to clonotype and isotype expression. PS conjugated to proteins, e.g., MCPS coupled to tetanus toxoid (MCPS-TT), elicits a thymus-dependent (TD) response. In order to understand the influence of the form of a vaccine (TI versus TD) on the Ab repertoire, we generated monoclonal antibody (MAb) panels from mice immunized and boosted with MCPS or MCPS-TT in different ways. The panels of MAbs were examined for isotype, fine specificity, affinity, and V(H) gene family usage. The use of MCPS-TT resulted in a shift in the isotype from immunoglobulin M (IgM) and IgG3 elicited in response to the MCPS to primarily IgG1. This isotype shift was accompanied by a change in the fine specificity of the response to the conjugate compared to that of PS. New fine specificities and increased affinity were observed in response to the TD antigen (Ag). Dot blot and Northern analyses of MCPS MAbs revealed that V(H) gene family usage is dominated by V(H)J558, used by 23 of 39 MAbs. V(H)3609 was seen in three MAbs of restricted fine specificity. V(H)Q52, V(H)7183, and V(H)VGAM3-8 were seen in more than one MAb across these panels, while V(H)10 and V(H)X24 were detected only once in response to the TI-2 Ag. All MAbs in the panels utilized kappa light chains, and all functional J(kappa) genes were expressed.

Treatment of experimental avascular necrosis of the femoral head with hyperbaric oxygen in rats: histological evaluation of the femoral heads during the early phase of the reparative process.

The healing of vascular deprivation-induced necrosis of the femoral head of rats exposed to hyperbaric oxygen was compared with that in untreated rats. The amount of necrotic bone, extent of osteoneogenesis, degree of remodeling, and changes of the articular cartilage were histologically graded on a semiquantitative scale of 0 to 3+. On the 2nd, 7th, and 21st postoperative days, there were no differences between the two groups. Newly formed appositional and intramembranous bone was more abundant and remodeling was more advanced in the femoral heads of the hyperbaric oxygen-treated than untreated rats sacrificed on the 42nd postoperative day; also there was less necrotic debris in the femoral heads of the treated rats. There were no differences in the severity of the degenerative changes of the articular cartilage of the treated and untreated rats. Exposure of rats to hyperbaric oxygen does not preserve tissue viability after all arteries supplying the femoral head are severed. Yet, resulting in an increased oxygen tension of the tissues, it seems to provide the optimal settings for reparative processes. The results suggest that hyperoxygenation-mediated relief of ischemia enhances the fibroblastic, angioblastic, osteoblastic, and osteoclastic activities such that healing of the rats' necrotic femoral heads is expedited.

[Disturbance of osmotic equilibrium as a possible cause of invagination or protrusion of plasmalemma on the initial stage od phagocytosis]. / O vozmushchenii osmoticheskogo ravnovesiia kak veroiatnoi prichine invaginatsii, ili protruzii, plazmalemmy fagotsitov na nachal'noi stadii fagotsitoza.

Despite the importance of phagocytosis studying for purposes of physiology and medicine, a physical cause of the initial stage of phagosome generation still remains apparently unclear. The original mathematical theory (Rubinstein, 1998) allows to suggest that the disturbance of osmotic equilibrium, resulting from the interaction between lysosomal hydrolases and their specific substrates, may cause the initial stage of phagosome formation in all biochemically diverse cases of phagocytosis. The author developed this theory without a collaboration with biologists, except for several consultations. The purpose of this paper is to attract the biologists attention to the main ideas underlying this theory, and to learn to what degree these ideas may be reasonable from the viewpoints of biologists.

Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins.

PURPOSE: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment. METHODS: Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (<1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (> or =3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group. RESULTS: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. CONCLUSION: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.

Murine immune responses to Neisseria meningitidis group C capsular polysaccharide and a thymus-dependent toxoid conjugate vaccine.

The polysaccharide (PS) capsules of many pathogenic bacteria are poor immunogens in infants and young children as a result of the delayed response to PS antigens during ontogeny. The development of polysaccharide-protein conjugate vaccines for Haemophilus influenzae type b, which have proven to be efficacious in this age group, has led to active development by a number of investigators of conjugate vaccines for other diseases. We describe here the response of several mouse strains to the capsular PS of Neisseria meningitidis group C (MCPS) conjugated to tetanus toxoid (MCPS-TT) and the same response in BALB/c mice as a model of the immune consequences of conjugate vaccine immunization. The use of a conjugate vaccine results in a shift in the isotype elicited in response to the MCPS, from immunoglobulin M (IgM) and IgG3 to primarily IgG1. A response to MCPS-TT is seen even among mouse strains which respond poorly to MCPS itself, emphasizing the importance of a strain survey when choosing a mouse model for a vaccine. The marked increase in IgG1 antibody titer was accompanied by a large increase in bactericidal activity of sera from these animals. Animals primed with the conjugate vaccine demonstrated a booster response after secondary immunization with either the MCPS or the conjugate. The ability to produce a boosted IgG1 anti-MCPS response to the MCPS can be transferred to adoptive recipients by B cells alone from mice primed with MCPS-TT but not mice primed with MCPS alone. These data indicate that in BALB/c mice a single immunization with MCPS-TT is sufficient to induce a shift to IgG1 and generate a memory B-cell population that does not require T cells for boosting.