Association between smoking and deaths due to colorectal malignant carcinoma: a national population-based case–control study in China

Background:

This study explored the association between smoking and colorectal malignant carcinoma (CRC) in the Chinese population at the national level for the first time.

Methods:

In the China Nationwide Retrospective Mortality Survey conducted during 1989–1991, 12 942 CRC cases among 1 136 336 all-cause deaths aged ⩾30 years were randomly assigned 25 884 control interviews from 325 255 surviving spouses of all-cause deaths across 103 urban and rural areas.

Results:

Compared with non-smokers, smoking significantly increased the risk of CRC-specific mortality by 9.8% (odds ratio (OR)=1.098, 95% confidence interval (CI)=1.046–1.153) adjusted for sex, age, and residence. There were significant dose–response relationships between smoking and CRC, such as smoking years, cigarettes smoked daily, and age at onset of smoking. Long-term heavy smokers aged ⩾50 years with ⩾30 smoking years and ⩾20 cigarettes daily had an excess risk of CRC deaths of 30.2% (OR=1.302, 95% CI=1.214–1.397). The strongest association between these smoking variables, such as long-term heavy smokers (OR=1.604, 95% CI=1.341–1.919), and CRC was observed among rural men.

Conclusions:

Quitting smoking at any time would likely be beneficial to CRC prevention. Long-term heavy smokers and rural men should be viewed as special targets for smoking prevention and cessation programs.China has become the largest consumer of tobacco in the world with an estimated 301 million current smokers (Li et al, 2011). The tobacco control situation in China is worrisome owing to the influences of a powerful tobacco industry with the competition between tobacco control organisations, and the tobacco industry is becoming increasingly fierce (Yang, 2013). As one of the most important smoking-related diseases, cancer is the second leading cause of deaths in the Chinese population. In developed countries, tobacco control accounted for almost all of the declines in smoking-related cancer mortality rates as seen during the past four decades (Cavalli, 2013).Colorectal malignant carcinoma (CRC) has become the third leading form of cancer incidence and the fifth leading cause of cancer mortality for Chinese people. CRC incidence and mortality rates have also increased at a faster pace than any other form of cancer in China, although the CRC incidence and mortality rates in China are still much lower compared with the rates in Western countries (Rozen et al, 2002). Furthermore, China has high prevalence of smoking, which has been recognised as one of the risk factors of CRC in Western countries (Chao et al, 2000; Botteri et al, 2008; Kenfield et al, 2008; Liang et al, 2009). However, the association between smoking and CRC in the Chinese population is unclear, with a positive association observed in the much more developed Hong Kong and Singapore Chinese (Ho et al, 2004; Tsong et al, 2007), but not in the more representative Shanghai Chinese (Chen et al, 1997; Ji et al, 2002).Therefore, for either tobacco control or CRC prevention, it is necessary to explore a possible association between smoking and CRC in China. The aim of the current study is to explore the evidence of an association between smoking and CRC deaths by using data of the China National Mortality Survey data set.     

The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication

Background:

Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care.

Methods:

Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil–lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months.

Findings:

Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272–576) days vs NLR⩾4, 257 (IQR 147–490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001).

Interpretation:

Neutrophil–lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients'' treatment response.Malignant pleural mesothelioma (MPM) remains a universally fatal neoplasm with a median life expectancy of 9–14 months following diagnosis (Yates et al, 1997; Chapman et al, 2009).In 2008, the National Institute for Health and Care Excellence (NICE) recommended the use of chemotherapy with pemetrexed and cisplatin for the palliative treatment of mesothelioma in England and Wales and this remains the first-line chemotherapy regimen of choice in patients with good performance status (Vogelzang et al, 2003; NICE (2008), HTA No. 135).With variable clinical responses to pemetrexed and cisplatin in MPM and common associated adverse effects (particularly nausea, fatigue and haematological toxicity) (Vogelzang et al, 2003), patient selection for treatment, individualised prognostic information at diagnosis and early disease response evaluation are important areas about which little is currently established.The most widely used method of chemotherapy response evaluation for MPM in a clinical trial setting is serial CT scanning, using the modified RECIST criteria (Nowak, 2005). Although the modified RECIST method has been shown to correlate with survival in patients receiving chemotherapy, it does not make a full assessment of the circumferential growth pattern of MPM, and high levels of interobserver variability have been reported (Armato et al, 2004; Byrne and Nowak, 2004). Volumetric assessment of CT may be superior to the modified RECIST (Guntulu et al, 2010), but both methods are labour intensive and probably not of universal applicability to clinical practice.Metabolic imaging with PET-CT using a composite output value incorporating ¹⁸FDG uptake and tumour volume (total glycolytic volume (TGV)), serum biomarkers including mesothelin and fibulin-3 and measures of systemic inflammation such as the NLR have all been the subject of preliminary research as markers of prognosis or treatment response in MPM (Francis et al, 2007; Grigoriu et al, 2008; Creaney et al, 2010; Kao et al, 2010; Nowak et al, 2010; Veit-Haibach et al, 2010; Pass et al, 2012; Creaney et al, 2014).The SWAMP trial was designed to systematically and prospectively examine the value of serum biomarkers, NLR and TGV measured by PET-CT, with correlation of markers to disease response, survival and quality of life.     

Anti-programmed cell death protein-1/ligand-1 therapy in different cancers

Immunologic checkpoint blockade with antibodies against the programmed cell death protein-1 (PD-1) or its ligand (PD-L1) is an effective method for reversing cancer immunosuppression and thereby promoting immune responses against several cancer types. Anti-PD-1 and anti-PD-L1 antibodies have resulted in long-term responses with minimal side effects in significant numbers of patients with melanoma, lung, kidney, bladder and triple-negative breast cancer, as well as in chemotherapy-refractory Hodgkin disease. There is already evidence from at least one randomised trial that anti-PD-1 therapy is superior to chemotherapy in the treatment of patients with metastatic melanoma, and two anti-PD-1 antibodies, pembrolizumab and nivolumab, have been approved by the US Food and Drug Administration for the treatment of patients previously treated for metastatic melanoma. It is anticipated that approvals by drug regulatory bodies will be forthcoming in several cancers in the next months.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 or its ligand (PD-1/L1) represent a paradigm shift in immunotherapy for cancer, as it focus on the disinhibition of native immune responses instead of the prior focus in activation of the immune system with tumour vaccines or recombinant cytokines. Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. CTLA-4 was the first negative regulatory checkpoint receptor to be clinically targeted. CTLA-4 is upregulated early during the T-cell activation and its expression dampens T cells by outcompeting CD28 in binding CD80 and CD86 (Linsley et al, 1994; Egen and Allison, 2002; Riley et al, 2002). Antibodies that block CTLA-4 enhance immune responses by activating effector T cells, but probably also by interacting with other immune cells such as regulatory T cells (Tregs), which exhibit immunosuppressive properties (Lenschow et al, 1996; Wing et al, 2008). The anti-CTLA-4 antibody ipilimumab (Yervoy; Bristol-Myers Squibb, Princeton, NJ, USA) showed a significant overall survival (OS) improvement in patients with advanced melanoma in two randomised phase III trials (Hodi et al, 2010; Robert et al, 2011), and was approved by the US Food and Drug Administration (FDA) and other drug regulatory bodies in 2011. The broad activation of the immune system and deregulation of an immunologic homoeostasis achieved by blocking CTLA-4 might be responsible for the development of inflammatory or autoimmune toxicities, reported in ∼15% of the patients (Robinson et al, 2004).In contrast, PD-1 appears to have a prominent role in modulating T-cell activity in peripheral tissues via interaction with its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). Programmed cell death protein-1 is an immune checkpoint receptor that prevents overstimulation of immune responses and contributes to the maintenance of immune tolerance to self-antigens (Freeman et al, 2000; Keir et al, 2006; Korman et al, 2006; Okazaki and Honjo, 2007). Upon antigen recognition, activated T cells express PD-1 on their surface and produce interferons that lead to the expression of PD-L1 in multiple tissues, including cancer (Ishida et al, 1992; Pardoll, 2012). Binding of PD-1 to its ligands limits effector T-cell activity, and therefore regulating detrimental immune responses and preventing autoimmunity (Topalian et al, 2012a). Programmed cell death protein-1 is not only induced on effector T cells but also on Tregs (Francisco et al, 2009), activated B cells and natural killer cells (Terme et al, 2011), suggesting its contribution to other important immune cell functions.Besides the interaction between CTLA-4 and PD-1 with their respective ligands, other costimulatory and inhibitory interactions regulate T-cell responses. Although not the focus of the current review, examples of promising inhibitors of immune checkpoint targets that are being pursued clinically using blocking antibodies include the lymphocyte-activation gene 3, the T-cell membrane protein 3 or the adenosine receptor A2aR.     

Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer

Background:

Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers.

Methods:

Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0–1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles.

Results:

Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84–567 days).

Conclusions:

Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose–response has its limitations.Poly(ADP-ribose) polymerase (PARP) inhibitors are an exciting development in anticancer therapy (Sonnenblick et al, 2015). The superfamily of PARP enzymes consists of 17 members, with PARPs 1–3 being activated by, and promoting the repair of, DNA breaks (Schreiber et al, 2006). The most abundant PARPs, PARP-1 and 2, play an essential role in the repair of DNA single-strand breaks (SSBs) via the base excision repair/single-strand break repair (BER/SSBR) pathway. Poly(ADP-ribose) polymerase inhibition results in accumulation of unrepaired SSBs, leading to collapsed replication forks and DNA double-strand breaks (DSBs). The Homologous Recombination repair (HRR) pathway, in which BRCA1 and BRCA2 are key elements, is essential to the efficient and error-free repair of such lesions (Helleday et al, 2007). Germline (g) mutations in either the BRCA1 or BRCA2 genes render individuals at high life-time risk of breast and ovarian cancer (Gudmundsdottir and Ashworth, 2006) and these subsequent cancers may have HRR deficiency (HRD). PARP inhibitors (PARPis) have been shown to selectively kill cells and xenografts with HRD by a process known as ‘synthetic lethality'' (Bryant et al, 2005; Farmer et al, 2005). ‘Synthetic lethality'' is the concept by which death results from the inactivation of two genes or pathways when inactivation of either gene or pathway alone is nonlethal (Kaelin, 2005). Subsequent early-phase clinical trials of PARPis have shown promising antitumour activity in BRCA-mutant cancers with acceptable toxicity profiles (Fong et al, 2009; Audeh et al, 2010; Tutt et al, 2010; Sandhu et al, 2013). In addition, PARPis, as single agents, may have a broader application in the treatment of cancers with HRD not directly due to gBRCA mutations. For example, ∼50% of high-grade serous ovarian cancers (HGSOCs) were shown in The Cancer Genome Atlas Network (TCGAN) molecular analysis to harbour HRD (The Cancer Genome Atlas Research Network, 2011). This HRD included somatic BRCA mutations (6–8%), and epigenetic silencing in genes not associated with BRCA but essential to HRR function, such as ATM, CHEK2, RAD51 and MRE11A. Similarly 55% of unselected HGSOCs were found to have HRD using a functional assay of HRR, and be sensitive to PARP inhibition (Mukhopadhyay et al, 2010). Induction of HRD in cancers by altering the tumour microenvironment through hypoxia (Chan et al, 2010) or by combining PARPis with agents that might downregulate HRR, such as VEGF inhibitors (Lui et al, 2014), might render HRR-competent cells sensitive to PARP inhibition. This concept, known as ‘contextual'' synthetic lethality, could broaden the application of this class of drugs in the treatment of cancer and is the rationale behind other ongoing clinical trials (www.clinicaltrials.gov).Rucaparib (CO-338; formally known as PF-01367338 and AG-014699) is a potent selective small-molecule inhibitor of both PARP-1 and PARP-2, with a respective Ki of 0.8 and 0.5 nM (Thomas et al, 2007). In addition, it has recently been shown to have activity against the tankyrases TANK1 and 2 otherwise known as PARP5A and PARP5B (Wahlberg et al, 2012). The free base compound AG-014447 (8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5- tetrahydro-azepino[5,4,3-cd]indol-6-1) is available in phosphate and camphorsulphonic acid salt forms. The phosphate salt (intravenous (i.v.) formulation) was named rucaparib by Clovis Oncology Inc. (Boulder, CO, USA), following their acquisition of the full rights to the agent in 2011. The oral camphorsulphonic acid salt formulation is known as rucaparib camsylate. For the purpose of this report the investigational agent will be termed i.v. and oral rucaparib. In preclinical models {"type":"entrez-nucleotide","attrs":{"text":"AG014699","term_id":"3649917","term_text":"AG014699"}}AG014699 (i.v. rucaparib compound) inhibits tumour growth in not only mutant BRCA1/2 models, but also in those with non-BRCA mutant-deficient HR, such as deficient XRCC3 and epigenetically silenced BRCA1 (Drew et al, 2011a). Phase 1 (in advanced solid tumours) and 2 (in melanoma) studies of i.v. rucaparib in combination with the oral DNA methylating agent temozolomide were completed in 2005 and 2008 respectively (Plummer et al, 2008, 2013). No rucaparib-related serious adverse effects were reported in the phase I trial and PARP inhibition of >90% in tumours and surrogate tissues following single i.v. doses were observed.This is the first study to investigate the antitumour effects of single-agent i.v. and oral rucaparib in patients with gBRCA mutant advanced breast and ovarian cancers. Employing a range of dosing schedules, the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles of rucaparib are assessed.     

Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network

Background:

Adjuvant trastuzumab with chemotherapy is standard treatment for HER2-positive breast cancer, defined as either HER2 IHC3+ or IHC2+ and FISH amplified. The aim of this study was to investigate the degree to which HER2 amplification in terms of HER2 gene copy numbers in HER2+IHC2+ cancers affected the outcome in a community setting.

Methods:

Case records of 311 consecutive patients with early breast cancer presenting between 1st January 2005 and 31st December 2008 were reviewed. Progression-free survival and overall survival were calculated with the Kaplan–Meier method using STATA 13.

Results:

Among 3+ cases (n=230) 163 received T vs 67 no-T. Among 2+ cases (n=81) 59 received T vs 22 no-T. Among 59 IHC2+-treated cases n=28 had an average of >12, n=13 had >6 to <12, and n=18 had >2 to <6 HER2 gene copies, respectively. The time of progression and overall survival of high and low copy number patients was similar and better than the intermediate copy number and the untreated cohorts.

Conclusions:

High HER2 copy number (>12) appears to be associated with consistently better response compared with patients with intermediate HER2 copy numbers (6–12). In light of emerging data of patients showing insensivity to trastuzumab therapy, we propose that the HER2 gene copy number value should be included as an additional indicator for stratifying both the management and the follow-up of breast cancer patients.Trastuzumab is a humanised monoclonal antibody directed at the human epidermal growth factor receptor 2 (HER2), which is overexpressed in ∼15% of newly diagnosed invasive breast cancers (HER2+) (Slamon et al, 1987). Adjuvant trastuzumab, in conjunction with chemotherapy, is now the standard of care for these patients, following the significantly improved outcomes demonstrated in several large multinational clinical trials. (Piccart-Gebhart et al, 2005, Romond et al, 2005, Slamon et al, 2006, Joensuu et al, 2006). A similar magnitude of benefit has been confirmed in a ‘community'' setting in a UK Cancer network (Webster et al, 2012).Accurate diagnosis of HER2+ cancers is important to maximise the benefit of targeted therapy. All breast cancers should now be tested for HER2 expression and two methods are used. Firstly, immunohistochemistry detects HER2 protein expression on the cell membrane, and is described on a scale of 0–3 based on the Hercept Test Score (Dowsett et al, 2003). Thus, scores 0 and 1+ are considered negative, and score 3+, meaning that >30% of invasive tumour cells demonstrate uniform intense membrane staining, considered to be positive. An equivocal result represented by score 2+, requires further tests for confirming the presence or absence of HER2 gene amplification and this is achieved using the second method, in situ hybridisation or most commonly fluorescent in situ hybridisation (FISH). The most recent guidelines produced by the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) (Wolff et al, 2007) define a FISH result of more than six copies of the HER2 gene per nucleus, or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2 as a positive result. A ratio of HER2/CEP17 >2.0 was required to enter the large adjuvant trastuzumab trials, and was approved by the US FDA.Despite the undoubted benefits of trastuzumab relapses do still occur and clearly not all patients derive the same benefit from treatment. HER2 gene amplification in those cancers considered HER2+ is variable and raises the question—does the degree of HER2 amplification influence outcome?To answer this question, researchers have looked to the data sets of the original landmark adjuvant studies. For example, a retrospective analysis of the HERA trial dataset (Dowsett et al, 2009) investigated whether IHC status (2+ vs 3+), the degree of FISH amplification or polysomy of chromosome 17 affected clinical outcome and the conclusion was that there was no evidence for reduced benefit for adjuvant trastuzumab in IHC2+FISH+ cases.This study is a follow on to the previously published South East Wales Network experience (Webster et al, 2012), and our aim was to examine, again in a ‘community'' setting, whether the degree of HER2 positivity affected the outcome of adjuvant treatment.     

Quetiapine Sustained Release in Treatment of Delirium Induced by Cerebral Metastasis

While haloperidol represents the first-line treatment of delirium, some studies have shown that atypical antipsychotics could be used as an efficacious treatment in delirium management. This article reports a case of a delirious patient, treated effectively and quickly with Quetiapine sustained release with negligible side effects.Key Words: Delirium, Quetiapine, Cognitive impairment, Confusional state, Agitation

‘If the patient is delirious, does not recognize his friends and cannot hear or understand, this is a mortal symptom.’Hippocrates

Delirium, also known as acute confusional state or encephalopathy, is a common syndrome that affects about 10-30% of hospitalized patients [1]. Delirious patients have a high risk of mortality and morbidity, thus increasing the costs to society. According to the Diagnostic and Statistical Manual for Mental Disorders (ed. 4, text revision; DSM-IV-TR) by the American Psychiatric Association [2], delirium is a ‘disturbance of consciousness […] with reduced ability to focus, sustain or shift attention’, and with an acute onset and a fluctuating course. Cognitive impairments, agitation, disorders of thought and of perceptions are common phenomena in delirious patients.Pathogenesis of delirium is related with a reduction of cholinergic neurotransmission, with a hyperactivity of dopamine and norepinephrine neural pathways, and with changes in serotonin and γ-aminobutyric neurotransmission [3, 4].Although the use of haloperidol is the gold standard in delirium treatment, in recent studies many authors [5,6,7,8] have discussed the possibility of the use of atypical antipsychotics in delirium management. A systematic review of efficacy and safety of atypical antipsychotics showed that haloperidol was the first-line treatment, although atypical antipsychotics could be preferred to reduce extrapyramidal side effects [9]. There are some data on the use of Risperidone and Olanzapine in the treatment of delirium [1, 5, 7, 10, 11] while other atypical antipsychotics have limited data [1]. Some authors reported the efficacy of Quetiapine in delirium, indicating an improvement in delirious symptoms [6, 12, 13, 14, 15]. This case report evidences the efficacy and the safety of 300 mg of Quetiapine sustained release (SR) in the treatment of delirium.     

Editor's choice: Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials

Purpose

To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM).

Methods

A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM.

Results

A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis.

Conclusion

Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials.The term “leptomeningeal metastasis” (LM), also known as neoplastic meningitis, refers to involvement of the cerebrospinal fluid (CSF) and leptomeninges (pia and arachnoid) by any solid tumor or hematologic malignancy. When caused by systemic cancer, LM is often called carcinomatous meningitis or meningeal carcinomatosis and is reported in 4%–15% of patients with cancer.^1–13 Lymphomatous or leukemic meningitis occurs in 5%–15% of patients with lymphoma or leukemia.^1–13 LM is the third most common metastatic complication affecting the central nervous system (CNS) after brain metastases and epidural spinal cord compression, with 7000–9000 new cases diagnosed annually in the United States.^1–13 In decreasing order, the most common sources of systemic cancer metastatic to the leptomeninges are breast, lung, melanoma, aggressive non-Hodgkin'' lymphoma, and acute lymphocytic leukemia.Leptomeningeal metastasis usually (>70%) presents in the setting of active systemic disease but can present after a disease-free interval (20%) and even be the first manifestation of cancer (5%).^1–13 A diagnosis of LM must be considered in patients with cancer and neurologic symptoms.^1–13 Neurologic dysfunction most commonly involves one or more segments of the neuraxis, including cerebral hemispheres, cranial nerves, spinal cord, or spinal roots. Because any site in the CNS may be involved, clinical manifestations of LM overlap significantly with those of parenchymal brain metastases, treatment-related toxicities, metabolic disturbances, and, rarely, neurologic paraneoplastic syndromes.Clinical manifestations that strongly suggest the diagnosis of LM include cauda equina symptoms or signs, communicating hydrocephalus, and cranial neuropathies. Early in the disease, neurologic involvement can be subtle, such as an isolated diplopia or radicular pain.^1–13 In some patients, cerebral hemisphere symptoms such as altered mental status or seizures may predominate. Neuroimaging (ie, MRI of brain or spine) may suggest LM based upon focal or diffuse enhancement of the leptomeninges, nerve roots, or ependymal surface and, in the context of a patient with cancer and low likelihood of infectious meningitis, may be diagnostic of LM. Brain parenchymal metastases from nonhematologic cancers coexist in 38%–83% of LM patients.^14–18 The reported rates of negative CNS imaging in patients with LM range from 30% to 70%, thus normal CNS imaging does not exclude a diagnosis of LM. CSF analysis is crucial to diagnosing LM, as in nearly all patients some abnormality of CSF opening pressure, protein, glucose, or cell count will be apparent.^5,9,19 The finding of tumor cells in CSF establishes a definitive diagnosis of LM (excluding patients within 2 wk of a CNS tumor resection), but a single CSF analysis has a high false negative rate (nearly 50%) for positive cytology even when multiple large volume (>10 mL) samples are sent for cytologic examination and prompt processing methods are utilized.⁵ Repeated CSF analysis when initially negative increases the chances of finding malignant cells to 80% or more. CSF tumor marker concentrations are of unproven value, with the exception of nonseminomatous germ cell tumors.^20,21 In patients with hematologic cancers, CSF flow cytometry is more sensitive than CSF cytology and additionally requires a comparatively smaller volume of CSF (<2 mL) for analysis. The most specific ancillary study results (ie, positive cytology, abnormal flow cytometry [in hematologic cancers], and abnormal neuroimaging) can be negative or inconclusive in LM. The diagnosis of probable LM is made in patients with cancer when neurologic symptoms are suggestive for LM, associated with nonspecific CSF abnormalities and negative or inconclusive MRI studies.Two particular challenges arise in the treatment of LM: (i) deciding whether to treat and (ii) if LM-directed treatment is considered, deciding how to treat (radiotherapy, surgical intervention, systemic or intra-CSF chemotherapy).^{1–13,22–27} The optimal patients for treatment include those with low tumor burden as reflected by functional independence and lack of major neurologic deficits, no evidence of bulky CNS disease by neuroimaging, absence of CSF flow block by radioisotope imaging, expected survival >3 months, and limited extraneural metastatic disease.^28,29 CNS imaging studies commonly recommended prior to treatment are neuraxis MRI and, in patients considered for treatment with intra-CSF chemotherapy, a radioisotope CSF flow study; the latter is recommended in guidelines but infrequently utilized.^30,31 Flow studies assist in determining whether intra-CSF chemotherapy will distribute homogeneously throughout the CSF. If CSF is compartmentalized or flow impaired, therapeutic concentrations of chemotherapy may not reach all sites of disease and may be associated with increased risk of treatment-related neurotoxicity.^30,31 If intra-CSF chemotherapy treatment is believed warranted, a decision is made whether to treat by lumbar administration (intrathecal) or via a surgically implanted subgaleal reservoir and intraventricular catheter (ie, an Ommaya, Sophysa, or Rickham reservoir system).³²The role of surgical intervention in LM is largely limited to placement of a ventriculoperitoneal shunt in patients with symptomatic hydrocephalus, implantation of an intraventricular catheter and subgaleal reservoir for administration of cytotoxic drugs, or, very occasionally, obtaining a meningeal biopsy for pathological confirmation of LM.^1–13,22 Radiotherapy is used in the treatment of LM^1–14 to palliate symptoms, such as cauda equine syndrome and cranial neuropathies, to decrease coexistent bulky disease and correct regional areas of impaired CSF flow when patients are treated with intra-CSF chemotherapy. Common regimens are 20–30 Gy in 5–10 fractions to whole brain or to a partial spine field. Whole-neuraxis irradiation is often avoided in the treatment of LM from solid tumors, because it is associated with significant bone marrow toxicity and has not been shown to offer a therapeutic advantage.High-dose systemic chemotherapy with methotrexate (MTX) and cytarabine may result in cytotoxic CSF concentrations, theoretically obviating the need for intra-CSF chemotherapy.^25–27 However, the majority of systemic chemotherapy and many targeted chemotherapies, such as imatinib, lapatinib, rituximab, and trastuzumab, do not penetrate the intact blood–brain barrier in adequate concentrations—thus, the CNS including CSF may become a “sanctuary site” with such treatments. However, systemic chemotherapy has a role in the treatment of LM as an adjunct treatment of extraneural disease and possibly bulky subarachnoid disease.^{1–13,25–27} Importantly, intra-CSF chemotherapy commonly used in the treatment of LM is based upon limited studies with small numbers of patients and it has never been clearly established as an effective treatment for LM in a prospective randomized trial.^32–38     

A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets,which circumvents the need for tumor establishment in mice

Myeloid-derived suppressor cells (MDSCs) exhibit potent immunosuppressive activities in cancer. MDSCs infiltrate tumors and strongly inhibit cancer-specific cytotoxic T cells. Their mechanism of differentiation and identification of MDSC-specific therapeutic targets are major areas of interest. We have devised a highly efficient and rapid method to produce very large numbers of melanoma-infiltrating MDSCs ex vivo without inducing tumors in mice. These MDSCs were used to study their differentiation, immunosuppressive activities and were compared to non-neoplastic counterparts and conventional dendritic cells using unbiased systems biology approaches. Differentially activated/deactivated pathways caused by cell type differences and by the melanoma tumor environment were identified. MDSCs increased the expression of trafficking receptors to sites of inflammation, endocytosis, changed lipid metabolism, and up-regulated detoxification pathways such as the expression of P450 reductase. These studies uncovered more than 60 potential novel therapeutic targets. As a proof of principle, we demonstrate that P450 reductase is the target of pro-drugs such as Paclitaxel, which depletes MDSCs following chemotherapy in animal models of melanoma and in human patients. Conversely, P450 reductase protects MDSCs against the cytotoxic actions of other chemotherapy drugs such as Irinotecan, which is ineffective for the treatment of melanoma.Myeloid-derived suppressor cells (MDSCs) have been recognized as major contributors to tumor-induced immunosuppression. Tumor-infiltrating MDSCs strongly inhibit cytotoxic T cells, and their expansion favors tumor progression and metastasis [1, 2]. Counteracting MDSC activities strongly enhances anti-cancer treatments and prolongs survival. Specific MDSC elimination by chemotherapy significantly contributes to anti-tumor efficacy [3-5]. Interestingly, conventional dendritic cells (DCs) remain unaffected by some of these chemotherapy treatments and the mechanisms underlying selective MDSC susceptibility to these drugs are currently unknown. The availability of large numbers of tumor-infiltrating MDSCs would significantly improve research in their biology and functions, and facilitate anti-MDSC drug discovery.MDSCs in mice comprise a heterogeneous population of immature CD11b^high Gr-1⁺ myeloid cells [6]. However, their discrimination from other myeloid cells such as immature DCs, M2 macrophages, monocytes and neutrophils remains somewhat ambiguous. Nevertheless, mouse MDSCs are classified into monocytic (M) and granulocytic (G) subsets, which differ in Ly6C-Ly6G expression profiles. M-MDSCs are Ly6C^high Ly6G^−/low while G-MDSCs are Ly6C^int/low Ly6G^high. Both subsets suppress immune responses through several pathways, including L-arginine depletion through arginase-1 (arg-1) and inducible nitric oxide synthase (iNOS) activity, increased generation of reactive oxygen species (ROS) and production of immunosuppressive cytokines such as TGF-β [7, 8].For their study, MDSCs are isolated from the spleen or directly of tumors from a large number of tumor-bearing mice [9-11]. However, spleen MDSCs are phenotypically and functionally different from tumor-infiltrating MDSCs [11, 12]. Moreover, isolated intra-tumor MDSCs are usually contaminated with other myeloid cells, do not proliferate well ex vivo, lack plasticity of differentiation and are prone to apoptosis [9, 13, 14]. In addition, low MDSC numbers are obtained from within tumors [12, 15]. Ex vivo MDSC production systems have been developed, which rely on incubation of bone marrow (BM) cells with high concentrations of recombinant GM-CSF, alone or in combination with other cytokines, and sometimes supplemented with cancer cell-derived conditioning medium. Nevertheless, these methods achieve MDSC differentiation efficiencies of around 30%-40% of total cells [13, 14]. In practical terms, none of these methods have yet replaced the purification of MDSCs directly from tumors of cancer-bearing mice. Therefore, high-throughput and drug discovery studies with isolated intra-tumor MDSCs are certainly a challenge.     

Impact of body composition on clinical outcomes in metastatic renal cell cancer

The study of Steffens et al. investigating the influence of body composition on outcomes in metastatic renal cell cancer patients, published in this issue of The Oncologist, is reviewed.Systemic therapy for metastatic renal cell cancer (mRCC) currently revolves around inhibition of angiogenesis through the vascular endothelial growth factor (VEGF) pathway or the mammalian target of rapamycin (mTOR) pathway. Unfortunately, there are no validated predictive factors that can accurately determine whether a patient will benefit from treatment with molecularly targeted agents. However, many groups have identified prognostic factors that provide insight into a patient''s overall disease outcome independent of treatment [1]. These prognostic factors have been incorporated into multivariate models that stratify patients into poor, intermediate, and favorable risk groups. Commonly used models include the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria [2, 3], derived in the immunotherapy era, and the Heng criteria [4], derived from patients treated with novel anti-VEGF therapies (Open in a separate windowAbbreviations: KPS, Karnofsky performance status; LDH, lactate dehydrogenase; LLN, lower limit of normal; mOS, median overall survival; MSKCC, Memorial Sloan-Kettering Cancer Center; ULN, upper limit of normal.Obesity is an established risk factor for developing RCC [5–8], and several studies suggested, perhaps counterintuitively, that a high body mass index (BMI) confers a survival advantage to patients undergoing nephrectomy [9, 10]. In the particular setting of mRCC and targeted therapy, the prognostic impact of obesity and body mass is not clear.Potential mechanisms by which obesity could influence clinical outcomes include alterations in pharmocokinetics and drug concentrations as well as the presence of associated comorbidities such as diabetes and cardiovascular disease [11]. Obesity induces a “state of inflammation,” which results in elevations in tumor necrosis factor, interleukin (IL)-1β, IL-6, IL-1 receptor antagonist, and C-reactive protein [12]. Adipocytes produce multiple angiogenic factors such as VEGF and leptin [13]. Obesity can also activate the phosphoinositide 3-kinase–Akt–mTOR pathway via reactive oxygen species [14] and hyperinsulinemia/insulin like growth factor [15]. Several groups (16] found that a high BMI was independently associated with a longer overall survival (OS) time (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.49–0.91; p = .01) after adjusting for the Heng criteria in 475 mRCC patients treated with antiangiogenic therapy. Furthermore, patients with a normal BMI or low body surface area (BSA) had a shorter time to progression (TTP) and OS time than the obese group. However, BMI and BSA are relatively crude measurements of body composition.

Table 2.

Retrospective studies evaluating the impact of body composition on outcome in metastatic renal cell carcinoma patients treated with antiangiogenic therapiesOpen in a separate windowAbbreviations: BMI, body mass index; BSA, body surface area; CI, confidence interval; DLT, dose-limiting toxicity; HR, hazard ratio; NA, not available; OS, overall survival.In the article that accompanies this commentary, Steffens et al. [17] evaluate the prognostic potential of four measures of body composition in 116 mRCC patients: BMI (kg/m²), BSA (m²), visceral fat area (VFA, in mm²), and superficial fat area (SFA, in mm²). Obesity was defined as a BMI ≥30 kg/m² based on current World Health Organization standards or a BSA above the European average for men (1.98 m²) and women (1.74 m²) [18, 19]. Baseline VFA and SFA were calculated based on baseline computed tomography (CT) scans using the methods of Yoshizumi et al. [20]. Given the paucity of normative data on VFA and SFA, the threshold for obesity was arbitrarily defined as a value above the median observed in the patient cohort. Obesity was present in 19.8% of patients based on BMI and in 62.9% of patients based on BSA. On multivariate Cox regression analysis, including histological subtype and MSKCC status, there was no significant association between the progression-free survival and OS and elevated BMI and BSA, the traditional definitions of obesity. However, elevated VFA and SFA were both independently associated with a longer progression-free survival and OS time (VFA: HR, 2.97; 95% CI, 1.36–6.47; p = .006; SFA: HR, 3.41; 95% CI, 1.61–7.25; p = .001).This is in stark contrast to the results of Ladoire et al. [21], who evaluated the prognostic impact of BMI, SFA, and VFA in French patients with mRCC. The same definition of obesity was used as in the German cohort (BMI >30 kg/m², SFA above the median, VFA above the median using the methods of Yoshizumi et al. [20]). The French cohort had mean baseline SFA and VFA similar to those of the German group, but more patients had a poor performance status (20 of 113 with a Karnofsky performance status score <80). On multivariate analysis, including the MSKCC group, high VFA was associated with a significantly shorter TTP and OS time (HR, 6.26; 95% CI, 2.29–17.08; p < .001) in patients treated with antiangiogenic drugs (n = 59), but not in patients treated with cytokines. BMI and SFA were not prognostic. Ladoire et al. [21] suggested that high VFA was a predictive factor because it was associated with worse outcomes for patients treated with antiangiogenic therapy but not cytokines.Another potentially important aspect of body composition is sarcopenia, or skeletal muscle wasting. In a single-institution study of patients with advanced lung and gastrointestinal malignancies, the concurrent presence of sarcopenia and obesity was associated with a worse OS outcome (HR, 4.2; 95% CI, 2.4–7.2; p .0001) than in nonsarcopenic obese patients [22]. The impact of sarcopenia on long-term outcomes in mRCC patients is unknown. Limited data are available from a subset of mRCC patients who participated in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a randomized trial of sorafenib compared with placebo after failure of standard therapy [23]. Sarcopenia was present in 72% of patients with a BMI <25 kg/m² and in 34% of patients with a BMI > 25 kg/m² [24]. Treatment with sorafenib led to a significant loss of skeletal muscle at 12 months (8.0% decrease; p < .01), compared with placebo. The skeletal muscle loss was postulated to be a result of the downstream effects of mTOR inhibition from sorafenib based on preclinical models [25]. Dose-limiting toxicities were most common in sarcopenic underweight patients (BMI <25 kg/m²) and least common in patients who were not sarcopenic and/or had a BMI >25 kg/m² [26]. Despite the small sample size, these data suggest that sarcopenia exacerbates sorafenib-induced toxicities. Sorafenib, in turn, exacerbates skeletal muscle loss, creating a vicious circle in this setting, leading to worse clinical outcomes.It is also worth mentioning that the better prognosis in obese patients observed by Choueiri et al. [16] and Steffens et al. [17] may be related to better tolerability of targeted agents that are dosed independently of body weight. However, intuitively, a major concern with obese patients is underdosing.The routine use of CT to assess therapeutic response provides an unparalleled opportunity to precisely quantify body composition. Superior outcomes were associated with elevated BMI and BSA in the study of Choueiri et al. [16] and with elevated SFA or VFA in the study of Steffens et al. [17]; conversely, poorer outcomes were linked with elevated VFA in the study of Ladoire et al. [21]. This may be a result of an imbalance in prognostic factors that were not controlled for and/or an unknown interaction or effect modifier more prevalent in one study than in another. Both Ladoire et al. [21] and Steffens et al. [17] performed their respective multivariate analyses controlling for the MSKCC criteria, which were validated in clinical trial patients in the immunotherapy era [2, 3]. Given the widely disparate results, the prognostic value of body composition (BMI, BSA, SFA, VFA, and sarcopenia) should be evaluated in a larger patient population to validate threshold values for SFA, VFA, and sarcopenia. Such studies will help determine whether body composition provides further refinement of the current prognostic models and pave the way for better prognostication.Editor''s Note: See the accompanying article, “Does obesity influence the prognosis of metastatic renal cell carcinoma in patients treated with vascular endothelial growth factor-targeted therapy?” by S. Steffens, V. Grünwald, K.I. Ringe, et al., on pages 1565–1571 of this issue.     

A Tale of Two Histiocytic Disorders

Histiocytosis, including the coexistence of Langerhans'' cell histiocytosis and Erdheim-Chester disease, is discussed.Histiocytosis is a group of rare disorders of unknown etiology characterized by proliferation and accumulation of histiocytes [1]. Histiocytosis is subclassified as Langerhans cell histiocytosis (LCH) and non-LCH. Non-LCH includes Rosai-Dorfman disease, Erdheim-Chester disease (ECD), interdigitating dendritic cell sarcoma, and histiocytic sarcomas [2]. Both LCH and ECD are caused by accumulation and proliferation of histiocytic cells, but each entity has distinct clinical and pathological features, although rarely both diseases can coexist [3, 4]. LCH is associated with accumulation of dendritic cells and typically presents in children, but less often in adults, with an incidence of nine cases per million per year. ECD is a disease of adults, which is associated with xanthogranulomatous infiltration of foamy macrophages. Only about 500 cases have been reported in the literature to date [3, 5]. It remains unclear whether LCH and ECD are neoplastic or reactive, but in many patients they behave like neoplasms. Advances in genome sequencing technologies led to the identification of BRAF V600E mutations in 57% (35 of 61) of patients with LCH and 54% (13 of 24) of patients with ECD [6, 7].Both LCH and ECD can vary in clinical presentation and prognosis depending on the extent of disease and organ involvement [8]. Therapeutic options include surgery, radiation, vinblastine, prednisone, 6-mercaptopurine, cladribine, and cytarabine for LCH and corticosteroids, vinca alkaloids, anthracyclines, cladribine, interferon-α, anakinra, imatinib, and, most recently, infliximab for ECD [3, 5, 8–18]. Whereas the treatment of LCH has been defined based on the results of prospective studies, including randomized trials, ECD is currently treated on the basis of information from published case series, mostly from Europe and North America [8–21].Yin et al. [22] are to be commended for presenting a patient with simultaneous LCH (Hand-Schuller-Christian disease) and ECD and their subsequent retrospective review of an additional 54 patients with LCH and six patients with ECD treated in a single tertiary referral center in China. The coexistence of these two entities is consistent with other previously published reports [4]. The patient presented by Yin et al. [22] had a relatively typical disease course over several years (currently 14 years from diagnosis), with symptoms including central diabetes insipidus, hyperprolactinemia, bone involvement, exophthalmus, and underactive thyroid. The patient had a favorable response to external-beam radiation therapy and systemic therapy with interferon-α. In their analysis of the 54 patients with LCH (eosinophilic granuloma, n = 49; Hand-Schuller-Christian disease, n = 5) and six patients with ECD, they [22] demonstrated that all 35 patients with unifocal eosinophilic granuloma were cured with surgery, and all patients with multifocal eosinophilic granuloma, Hand-Schuller-Christian disease, or ECD were alive, except for one woman who died from unspecified toxicity of chemotherapy.As mentioned, there is some agreement on how LCH should be managed; however, the treatment of patients with ECD remains empiric, based on evidence from case reports and case series [8–21]. The rarity of this entity makes the feasibility of conducting a prospective trial challenging [5]. Traditionally, patients with ECD were deemed to have a poor prognosis, and most patients succumbed to the disease within 3 years. In contrast, our experience suggests that, given the newer therapeutic options, including, but not limited to, interferon-α, imatinib, anakinra, and infliximab, patients can do well for a long period of time [8, 9, 12–14, 16, 17, 23]. These observations are consistent with the experience of Yin et al. [22], and it is also known that interferon-α is associated with a longer survival time than in historical controls [8]. The individual prognosis depends on the degree of organ involvement, infiltration of the central nervous system (CNS) or infiltration of critical visceral organs, and treatment, which can affect outcome [8]. A recent retrospective analysis of 53 patients treated in western European countries and Israel demonstrated 1-year and 5-year survival rates of 96% and 68%, respectively, which is in line with our experience [8, 9, 12]. Factors selected on multivariate analysis that predicted a poor survival outcome included CNS involvement and not being treated with interferon-α [8]. There is no systemic therapy that has been approved by regulatory agencies, and the available treatments are deemed to be not curative; however, they can lead to disease regression accompanied by symptom improvement and, at least for interferon, perhaps even to a longer survival duration. Despite the absence of randomized trials, our treatment options have nevertheless expanded substantially within the last several years. Interferon-α is often used as a frontline therapy for ECD [5, 8, 12]. Unfortunately, patients with ECD can have a poor tolerance to classic doses of interferon-α, such as three million units s.c. three times per week, although doses of one million units s.c. three times per week are usually well tolerated and, in our experience, are effective in about half the patients treated [12]. Interferon-α can be replaced by its pegylated form, which is more costly but has a more convenient weekly dosing schedule [14].Anecdotal reports have also demonstrated therapeutic responses with the BCR-ABL, KIT, and platelet-derived growth factor receptor tyrosine kinase inhibitor imatinib [9, 13, 24–26]. It has been hypothesized that imatinib can inhibit CD34⁺ peripheral blood progenitor cells from differentiating into histiocytes; however, beyond that the mechanistic explanation for the activity of imatinib remains unclear [27]. Because natural interleukin-1 receptor antagonist synthesis is induced after stimulation by interferon-α, anakinra, a recombinant human interleukin-1 receptor antagonist approved for rheumatoid arthritis in Europe and the U.S., was anecdotally tested in ECD patients, with encouraging results reported by several investigators [15, 18]. Anakinra mimics the function of a natural inhibitor of interleukin-1 receptor and is well tolerated, with immunosuppression and injection site tenderness being among its very few side effects. Therefore, anakinra can be a reasonable alternative for patients who cannot tolerate interferon-α or who are at risk for suffering deleterious side effects from interferon. The latest potential addition to the therapeutic armamentarium for ECD is the tumor necrosis factor (TNF)-α antibody infliximab [17]. In ECD patients, TNF-α is deemed to regulate the recruitment of histiocytes, and thus, its blockade can lead to disease control. To date, two patients with severe cardiovascular complications of ECD were treated with infliximab in a single institution setting and both showed improvement, with resolution of pericardial effusion and increased cardiac function [17].Recently, BRAF V600E mutations were found in 57% (35 of 61) and 38% (11 of 29) of patients with LCH and in 54% (13 of 24) of patients with ECD [6, 7, 28]. This mutation predicts a positive response to BRAF kinase inhibitors in patients with advanced melanoma [29, 30]. Recently, we showed that a patient with hairy cell leukemia and a BRAF mutation achieved a remarkable response after only 3 weeks of the BRAF inhibitor vemurafenib [31]. However, treatment of patients with LCH and ECD with BRAF mutations has not been reported.Despite many therapeutic advances, LCH and ECD remain difficult to eradicate. The arrival of new genotyping technologies, such as next-generation sequencing, has the potential to further explicate the molecular background of these disorders. Furthermore, the heterogeneity of these diseases may have biologic and therapeutic implications. It is known that LCH and ECD can coexist, and Yin et al. [22] reported simultaneously occurring Hand-Schuller-Christian disease and ECD. Furthermore, they also described potentially important clinical characteristics to differentiate these entities. Diabetes insipidus and pituitary stalk thickening point to Hand-Schuller-Christian disease; however, diabetes insipidus can also be found in ECD and osteosclerosis may also support an ECD diagnosis. The advent of advanced molecular technologies may help determine if specific molecular aberrations can differentiate these entities and predict therapeutic response.     

ERK plays the baddie (again)

It has been known for many years that elevated signaling by the ERK1/2 pathway is frequently associated with the growth and survival of many tumor cell types under a variety of normal and stressful conditions, including the response of cells to other cancer interventional therapeutic strategies e.g., references ^1–4. There is, however, a modest significant literature showing that enhanced ERK1/2 signaling can also cause tumor cell death e.g., references ^5–8. The role of ERK1/2 signaling is clearly complex, for example as shown by the Koumenis group where inhibition of radiation-induced ERK1/2 signaling caused radiosensitization, whereas inhibition of curcumin-hyper-stimulated ERK1/2 signaling reduced radiosensitivity.⁷ Presumably this Janus-faced behavior of the ERK1/2 pathway in terms of cell survival regulation will depend upon the tumor cell type, the intensity of ERK1/2 stimulation, and the molecular intervention/drug being used.     

Genomancy: predicting tumour response to cancer therapy based on the oracle of genetics

Cells are complex systems that regulate a multitude of biologic pathways involving a diverse array of molecules. Cancer can develop when these pathways become deregulated as a result of mutations in the genes coding for these proteins or of epigenetic changes that affect gene expression, or both^1,2. The diversity and interconnectedness of these pathways and their molecular components implies that a variety of mutations may lead to tumorigenic cellular deregulation^3–6. This variety, combined with the requirement to overcome multiple anticancer defence mechanisms⁷, contributes to the heterogeneous nature of cancer. Consequently, tumours with similar histology may vary in their underlying molecular circuitry^8–10, with resultant differences in biologic behaviour, manifested in proliferation rate, invasiveness, metastatic potential, and unfortunately, response to cytotoxic therapy. Thus, cancer can be thought of as a family of related tumour subtypes, highlighting the need for individualized prediction both of disease progression and of treatment response, based on the molecular characteristics of the tumour.     

Major Clinical Impact of Platinum-Based Chemotherapy in a Patient with a Borderline Ovarian Cancer

A patient with extensive and painful chest wall involvement from a metastatic borderline cancer of the ovary was treated with a carboplatin plus paclitaxel chemotherapy regimen. She achieved a rather dramatic improvement of pain control, a significant biochemical response with 75% reduction of the CA-125 antigen level, but only limited radiographic tumor regression. This experience emphasizes the potential clinical utility of platinum-based cytotoxic chemotherapy in the setting of symptomatic advanced borderline ovarian cancer.Key Words: Borderline ovarian cancer, Chemotherapy of ovarian cancer, CarboplatinEpithelial ovarian cancer is among the most chemotherapy sensitive solid tumors with anticipated major objective response rates of 70-80% to several primary platinum-based combination chemotherapy regimens [1]. Even in the setting of recurrent disease, patients who have not received chemotherapy for more than 18 to 24 months may be anticipated to achieve partial remission rates of more than 60% following reintroduction of this class of cytotoxic drugs [2,3,4]. Further, available data document the biological and clinical activity of a number of non-platinum-based strategies in both the recurrent and platinum-resistant settings, as well as the favorable impact of such treatment on overall survival [5,6,7,8].However, for one group of epithelial ovarian malignancies there remains uncertainty regarding the benefits associated with the administration of cytotoxic anti-neoplastic agents, including the platinum drugs.Most borderline ovarian cancers present at an early stage where surgical treatment alone is curative in the large majority of cases [9,10,11]. However, this malignancy can progress in a manner essentially identical to that observed with the higher-grade epithelial cancers involving this organ, despite the fact that patients with this condition generally exhibit a far more indolent natural history even when initially presenting at an advanced stage [10,11,12,13].Although limited evidence to the contrary exists [14], considerable published literature has questioned the clinical utility associated with the administration of chemotherapy to women with borderline ovarian cancers [14,15,16]. The essential argument is that the anticipated very low objective response rate and uncertain impact of anti-neoplastic drug treatment on survival leads to the suggestion that patients are unlikely to benefit from cytotoxic chemotherapy [14,15,16]. These conclusions are supported by data demonstrating the quite modest activity of current chemotherapy in low-grade serous ovarian cancer [17].A recently managed patient with extensive chest wall involvement from a metastatic borderline ovarian tumor challenges this negative perspective, at least as regards the potential favorable impact of cytotoxic chemotherapy in the provision of symptomatic relief and substantially influencing overall clinical management.     

New methods to control neuroblastoma growth

Downstream of growth factor receptors, signaling by the phosphoinositide 3 kinase (PI3K) pathway is known to play an important role in the growth and survival of many tumor types. The PI3K pathway simplistically comprises PI3K itself, followed by PDK-1, then AKT and finally glycogen synthase kinase 3 (GSK3).¹ PI3K/AKT signaling promotes increased GSK3 phosphorylation, that is associated with reduced GSK3 activity. There are two isoforms of GSK3, GSK3α and GSK3β, which have a high degree of sequence homology.² GSK3 plays a role not only in the regulation of glycogen synthase activity but in the expression of multiple other proteins that play a role in cancer biology, including cyclins and anti-apoptotic proteins.^3,4     

Priming BCL-2 to kill: the combination therapy of tamoxifen and ABT-199 in ER+ breast cancer

The B-cell lymphoma/leukemia 2 protein (BCL-2) may help many types of cancers to evade cell death. However, identifying exactly where this is the case is a challenge. ABT-199 is a small molecule that selectively inhibits BCL-2, which is currently in clinical trials in lymphoid malignancies. While inhibiting BCL-2 by itself can cause cell death in hematopoietic tumors, single-agent activity is harder to observe in solid tumors. Combining ABT-199 with tamoxifen, the standard endocrine therapy for estrogen receptor-positive breast cancers, 85% of which have BCL-2 expression, represents a new strategy to prime cancer cells for apoptosis and elicit better cancer cell death responses.Breast cancer is a heterogeneous disease with at least four categories according to its molecular markers and gene expression profiles [1]. Estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) are the hallmarks for the classification and they determine chemotherapy choices and clinical outcome. Anti-estrogen therapy with tamoxifen or aromatase inhibitors is a standard endocrine therapy in many clinical situations for ER⁺ tumors. Unfortunately, a significant fraction of patients with ER⁺ do not respond to such therapies or they relapse after the initial remission [2,3]. Looking for more effective treatments is an urgent need in breast cancer research. In Cancer Cell (the July 8 issue of 2013 [4]), Vaillant and colleagues addressed this issue with the newest member of the AbbVie (North Chicago, IL, USA) BCL-2 (B-cell lymphoma/leukemia 2 protein) inhibitor drug family, ABT-199.ABT-199 belongs to the anti-BCL-2 inhibitor family originally developed by Abbott, whose research-based pharmaceuticals operation is now AbbVie. ABT-737 and the orally bioavailable ABT-263 (navitoclax) are the other two closely related inhibitors. ABT-737 and ABT-263 inhibit BCL-xL and BCL-w as well as BCL-2. They have been extensively studied in in vitro cell-based or animal models and in primary patient samples [5,6]. Clinical application of ABT-263 has been limited, however, at least partially due to the thrombocytopenia caused by inhibition of BCL-xL in circulating platelets [7,8]. ABT-199 more selectively inhibits BCL-2 and has demonstrated little or no effect on platelets in vitro and in vivo[9-11].BCL-2 is one of the most important anti-apoptotic proteins in the BCL-2 family with regard to cancer. This family comprises both anti- and pro-apoptotic proteins to govern commitment to cell death via the mitochondrial-dependent apoptotic pathway. The most dominant BCL-2 dependence has been demonstrated in hematopoietic cancers such as lymphoma or leukemia [9]. However, recent analysis for 11,212 early-stage breast cancer cases has concluded that BCL-2 is a favorable prognostic marker for breast cancer across molecular subtypes and independent of adjuvant therapy [12]. The addition of BCL-2 into the model for a subset of cases improved survival prediction. Luminal breast cancer (mostly ER⁺ breast cancer as studied by Vaillant and colleagues) has the highest BCL-2 expression (83% compared with 50% for HER2⁺, 18.5% for basal-like, and 41.4% for marker-null subtypes). The high BCL-2 protein levels (by immunohistochemistry) suggest an opportunity to target these cancers with BCL-2 inhibitors.As shown in the article by Vaillant and colleagues [4] and a relevant article published by the same group [13], however, BCL-2 inhibitors alone do not yield breast tumor xenograft regression. This contrasts to single-agent applications for ABT-263 or ABT-199 in chronic lymphocytic leukemia, which can elicit notable responses even in chemo-refractory disease [9]. Vaillant and colleagues, using breast primary tumor xenografts in a nonobese diabetic/severe combined immunodeficient (IL2Rγc^−/−) mouse model, demonstrate that the combination of tamoxifen and ABT-737 or ABT-199 produced the largest reduction of tumor volumes and much longer survival outcome than tamoxifen or ABT drug alone. This is consistent with the finding in BCL-2⁺ basal-like breast cancer xenografts, in which the tumor burden was reduced only in the combination of ABT-737 and cytotoxic docetaxel [13]. A mechanism of the activity of ABT-199 is that the BCL-2 protein was primed with pro-apoptotic protein BIM, suggesting that ABT-199 was provoking release of BIM and initiation of apoptosis. In other studies, BCL-2 complexes with pro-apoptotic protein BIM have been shown to be important in determining cellular sensitivity to BCL-2 inhibition [14,15].Many chemotherapies kill cancer cells via the mitochondrial apoptotic pathway. The interplay of BCL-2 family proteins largely determines the fate of cancer cells. ABT-199 offers a great clinical opportunity because of its specificity to BCL-2 which enhances its tolerability as well as its unique mechanism of action directly at mitochondria. In combination therapy, BCL-2 inhibition, even when it does not cause outright cell death, can prime cancer cells so that they move closer to the threshold of commitment to apoptosis. In this position, cancer cells are thus rendered more sensitive to subsequent therapies, as with tamoxifen in the article by Vaillant and colleagues [4]. Thus, in ER⁺ breast cancer, the combination of ABT-199 with tamoxifen provides a new strategy to overcome the protective effects of BCL-2 and deliver efficacious therapies. In the coming years, it will be very interesting to see in which cancers analogous combinations of ABT-199 with standard therapies can be used to improve clinical outcome.