Trastuzumab beyond progression in retrospective analyses: an issue of equal opportunities

Results of the Hermine study of trastuzumab beyond progression in breast cancer patients, published by Extra and colleagues in The Oncologist, are re-examined and an alternative explanation for the dismal postprogression survival time of patients stopping therapy is presented.We read with great interest the retrospective study published by Extra et al. [1] in The Oncologist and the accompanying editorial [2]. In particular, the analysis of patients continuing trastuzumab beyond disease progression was intriguing because of the inclusion of a control group of patients stopping trastuzumab at or just before disease progression. The authors correctly pointed out that the baseline prognostic profile of patients discontinuing trastuzumab was worse than that of patients in the continuation group. This introduced an obvious bias toward better clinical outcomes in patients continuing trastuzumab. However, we believe that the striking difference in the median survival times from the date of first progression (21.3 months versus 4.6 months) favoring patients continuing trastuzumab must have a more severe underlying bias. In a similar analysis that we published in The Oncologist in 2006, we could not find significant differences in clinical outcomes according to whether trastuzumab was continued or stopped in patients progressing during an initial trastuzumab-based regimen [3]. In particular, we observed that the median survival time from the date of first progression (henceforth, postprogression survival) for 40 patients continuing trastuzumab was 21.0 months, which is similar to that reported by Extra et al. [1]. However, 71 patients stopping trastuzumab and receiving additional anticancer therapy experienced a median postprogression survival interval of 18.7 months (Fig. 1). Notably, we identified two further groups of patients who did not continue trastuzumab beyond progression. Fourteen patients had experienced unacceptable trastuzumab-related toxicity leading to treatment discontinuation before progression. When disease progression occurred, they were not retreated with this monoclonal antibody. Another 21 patients experienced rapid progression during first-line trastuzumab-based therapy and were unable to receive additional anticancer therapy, but just supportive care. The median postprogression survival durations in the former and latter groups of patients were 7.8 months and 2.4 months, respectively (Fig. 1).Open in a separate windowFigure 1.Kaplan–Meier estimates of survival from the date of first progression in patients continuing trastuzumab beyond disease progression (black solid line), stopping trastuzumab and receiving additional anticancer therapy (black dashed line), stopping trastuzumab because of toxicity (grey solid line), and receiving only supportive care because of progression (grey dashed line).We excluded from our analysis these two groups of patients. In fact, a fair comparison of clinical outcomes to evaluate the hypothesis that continuing trastuzumab beyond progression is beneficial over no continuation requires that patients in the “control” group have “equal therapeutic opportunities” to patients in the “experimental” group. For patients experiencing prohibitive toxicity with trastuzumab or eligible for supportive care only, continuing trastuzumab beyond progression and, probably, receiving optimal anticancer treatment were not suitable therapeutic opportunities. Indeed, the clinical outcome of these patients was dismal, as described above.We noted that “stopping trastuzumab” was the only requirement described in patients in the control group of the Hermine study. We, therefore, went back to our original dataset and reanalyzed data using this same definition. All 106 patients stopping trastuzumab were compared with patients continuing trastuzumab beyond disease progression (Fig. 2). Survival from the date of first progression for patients continuing trastuzumab beyond disease progression was about 10 months longer than for those stopping trastuzumab (21.0 months versus 10.6 months; p = .03).Open in a separate windowFigure 2.Kaplan–Meier estimates of survival from the date of first progression in patients continuing trastuzumab beyond disease progression (solid line) or stopping trastuzumab (dashed line) (see text for details for the comparison group).We subsequently analyzed a comparison population including only those patients who could not receive trastuzumab because of prior toxicity or rapid disease progression (35 patients) (Fig. 3). In this case, patients stopping trastuzumab had a median postprogression survival duration of 3.7 months (p < .01), a finding that is remarkably similar to what was reported by Extra et al. [1]. We, therefore, argue that the dismal median postprogression survival time reported for the Hermine study (4.6 months) may not be a result of stopping trastuzumab. A more likely explanation is that a proportion of patients stopping trastuzumab could not go on to receive optimal anticancer therapy.Open in a separate windowFigure 3.Kaplan–Meier estimates of survival from the date of first progression in patients continuing trastuzumab beyond disease progression (solid line) or stopping trastuzumab (dashed line) (see text for details of the comparison group).Based on these considerations, it would be interesting if Extra and colleagues could reanalyze their data by distinguishing patients stopping trastuzumab according to whether or not they had “equal opportunities” to patients continuing trastuzumab beyond progression.Editor''s note: Dr. Extra was invited to reply but declined comment.     

Cytopathological and chemico‐physical analyses of smears of mucosa surrounding oral piercing

Oral Diseases (2010) 16 , 160–166 Objective: The aim of this comparative study was to analyze cytopathologically and chemico‐physically the mucosa surrounding oral piercing to correlate results with adverse tissue signs. Materials and methods: The tongue superficial mucosa of 15 young subjects (control group) and the superficial mucosa surrounding oral piercing of 15 young subjects (test group, TG) were smeared on slides, Papanicolaou stained and analyzed under the optical microscope. Some smears were prepared for (back‐scattered) scanning electron microscope (SEM) and X‐ray microanalysis to study piercing fragments. Results: Smears of TG displayed a variable extent of bacterial cytolysis of epithelial cells, fungi, hyperkeratosis, parakeratosis, granulocyte infiltration, calcium formations and bacterial flora; the four last statistically significant (P < 0.05). Foreign bodies surrounded by keratinocytes were detected under both light and SEM. X‐ray microanalyses highlighted piercing alloy aggression, ion release and an inverse gradient of ion concentration inside keratinocytes. Conclusions: The pathological findings in smears correlated with adverse effects of oral piercing. Ion release may be related to direct toxic effects and belated reactions because of metal sensitization. A strict regulation of piercing is warranted.     

Olfaction in dentistry

Oral Diseases (2010) 16 , 221–232 Practitioners of oral medicine frequently encounter patients with complaints of taste disturbance. While some such complaints represent pathological processes specific to the gustatory system, per se, this is rarely the case. Unless taste‐bud mediated qualities such as sweet, sour, bitter, salty, umami, chalky, or metallic are involved, ‘taste’ dysfunction inevitably reflects damage to the sense of smell. Such ‘taste’ sensations as chicken, chocolate, coffee, raspberry, steak sauce, pizza, and hamburger are dependent upon stimulation of the olfactory receptors via the nasopharynx during deglutition. In this paper, we briefly review the anatomy, physiology, and pathophysiology of the olfactory system, along with means for clinically assessing its function. The prevalence, etiology, and nature of olfactory disorders commonly encountered in the dental clinic are addressed, along with approaches to therapy and patient management.     

Virulence of major periodontal pathogens and lack of humoral immune protection in a rat model of periodontal disease

Oral Diseases (2010) 16 , 686–695 Objective: This study was designed to test the hypothesis that periodontal pathogens Tannerella forsythia and Porphyromonas gingivalis are synergistic in terms of virulence potential using a model of mixed‐microbial infection in rats. Materials and methods: Three groups of rats were infected orally with either T. forsythia or P. gingivalis in mono‐bacterial infections or as mixed‐microbial infections for 12 weeks and a sham‐infected group were used as a control. This study examined bacterial infection, inflammation, immunity, and alveolar bone loss changes with disease progression. Results: Tannerella forsythia and P. gingivalis genomic DNA was detected in microbial samples from infected rats by PCR indicating their colonization in the rat oral cavity. Primary infection induced significantly high IgG, IgG2b, IgG1, and IgG2a antibody levels indicating activation of mixed Th1 and Th2 immune responses. Rats infected with the mixed‐microbial consortium exhibited significantly increased palatal horizontal and interproximal alveolar bone loss. Histological examinations indicated significant hyperplasia of the gingival epithelium with moderate inflammatory infiltration and apical migration of junctional epithelium. The results observed differ compared to uninfected controls. Conclusion: Our results indicated that T. forsythia and P. gingivalis exhibit virulence, but not virulence synergy, resulting in the immuno‐inflammatory responses and lack of humoral immune protection during periodontitis in rats.     

Factors influencing the regional haemodynamic responses to methanandamide and anandamide in conscious rats

Background and purpose:

In vitro evidence suggests that metabolism of anandamide by cyclooxygenase-2 (COX-2) may be more important when the primary metabolic pathway [i.e. fatty acid amide hydrolase (FAAH)] is inhibited. Thus, the first aim of the present study was to assess the effects of COX-2 and/or FAAH inhibition, on the cardiovascular actions of anandamide. The second aim was to compare the effects of anandamide with those of the metabolically stable analogue (i.e. methanandamide) and investigate mechanisms involved in responses to the latter in conscious rats.

Experimental approach:

Rats were chronically instrumented for recording blood pressure, heart rate and renal, mesenteric and hindquarters vascular conductances in the freely moving state.

Key results:

Inhibition of FAAH with URB597 (cyclohexycarbamic acid 3′-carbamoyl-biphenyl-3-yl-ester) augmented the haemodynamic actions of anandamide, but there was no effect of COX-2 inhibition with parecoxib, either in the absence or the presence of URB597. Methanandamide caused CB₁ receptor-mediated renal and mesenteric vasoconstriction and evoked β₂-adrenoceptor-mediated hindquarters vasodilatation.

Conclusions and implications:

No evidence for an involvement of COX-2 in the systemic cardiovascular actions of anandamide could be demonstrated. Vasoconstrictor actions of methanandamide were shown to involve CB₁ receptors, whereas no involvement of CB₁ receptors in such actions of anandamide has been shown. However, β₂-adrenoceptor-mediated hindquarters vasodilatation, independent of CB₁ receptors, observed here with methanandamide, has previously been seen with anandamide and differs from previous results with other synthetic cannabinoids for which the response was CB₁ receptor-dependent. Thus, mechanisms underlying the cardiovascular actions of endocannabinoids and synthetic analogues appear to be agonist-specific.     

Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type and W/Wv mice

Background and purpose:

W/W^v and wild-type murine bladders were studied to determine whether the W/W^v phenotype, which causes a reduction in, but not abolition of, tyrosine kinase activity, is a useful tool to study the function of bladder interstitial cells of Cajal (ICC).

Experimental approach:

Immunohistochemistry, tension recordings and microelectrode recordings of membrane potential were performed on wild-type and mutant bladders.

Key results:

Wild-type and W/W^v detrusors contained c-Kit- and vimentin-immunopositive cells in comparable quantities, distribution and morphology. Electrical field stimulation evoked tetrodotoxin-sensitive contractions in wild-type and W/W^v detrusor strips. Atropine reduced wild-type responses by 50% whereas a 25% reduction occurred in W/W^v strips. The atropine-insensitive component was blocked by pyridoxal-5-phosphate-6-azophenyl-2′,4′-disulphonic acid in both tissue types. Wild-type and W/W^v detrusors had similar resting membrane potentials of −48 mV. Spontaneous electrical activity in both tissue types comprised action potentials and unitary potentials. Action potentials were nifedipine-sensitive whereas unitary potentials were not. Excitatory junction potentials were evoked by single pulses in both tissues. These were reduced by atropine in wild-type tissues but not in W/W^v preparations. The atropine-insensitive component was abolished by pyridoxal-5-phosphate-6-azophenyl-2′,4′-disulphonic acid in both preparations.

Conclusions and implications:

Bladders from W/W^v mice contain c-Kit- and vimentin-immunopositive ICC. There are similarities in the electrical and contractile properties of W/W^v and wild-type detrusors. However, significant differences were found in the pharmacology of the responses to neurogenic stimulation with an apparent up-regulation of the purinergic component. These findings indicate that the W/W^v strain may not be the best model to study ICC function in the bladder.     

Effects of interferon-beta on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-beta treatment in patients with multiple sclerosis

Interferon-beta (IFN-beta) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-beta is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-beta on the expression of co-signaling pathways (CD28-CD80/CD86, CD154-CD40, ICOS-ICOSL, PD-1-PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-beta in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-beta, and in vivo in whole blood samples of 32 untreated and 24 IFN-beta treated MS patients, including 13 patients longitudinal. IFN-beta treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4+-T-cells in vitro and in vivo. IFN-beta treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-beta (P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-beta upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-beta in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-beta treatment at early timepoints during IFN-beta therapy.     

Intractable neurostenalgia of the ulnar nerve abolished by neurolysis 18 years after injury

A 39 year-old farmer sustained a closed rupture of the left brachial artery, which was successfully managed by emergency vein graft repair of the artery. Adjacent nerve trunks were seen to be intact, but stretched. Burning pain in the distribution of the ulnar nerve started at day seven postoperatively, and worsened over the ensuing years. There was no response to membrane stabilising drugs, amitryptiline, nor to regional sympatholytic or local anaesthetic blocks. Neurolysis of the ulnar nerve, which was densely adherent to the dilated vein graft, abolished his pain.     

A chemical-genetic strategy reveals distinct temporal requirements for SAD-1 kinase in neuronal polarization and synapse formation

Background

β-Amyloid precursor protein (APP) has been reported to play a role in the outgrowth of neurites from cultured neurons. Both cell-surface APP and its soluble, ectodomain cleavage product (APPs-α) have been implicated in regulating the length and branching of neurites in a variety of assays, but the mechanism by which APP performs this function is not understood.

Results

Here, we report that APP is required for proper neurite outgrowth in a cell autonomous manner, both in vitro and in vivo. Neurons that lack APP undergo elongation of their longest neurite. Deletion of APLP1 or APLP2, homologues of APP, likewise stimulates neurite lengthening. Intriguingly, wild-type neurons exposed to APPs-α, the principal cleavage product of APP, also undergo neurite elongation. However, APPs-α is unable to stimulate neurite elongation in the absence of cellular APP expression. The outgrowth-enhancing effects of both APPs-α and the deletion of APP are inhibited by blocking antibodies to Integrin β1 (Itgβ1). Moreover, full length APP interacts biochemically with Itgβ1, and APPs-α can interfere with this binding.

Conclusion

Our findings indicate that APPs-α regulates the function of APP in neurite outgrowth via the novel mechanism of competing with the binding of APP to Itgβ1.