Current landscape of immunotherapy in the treatment of solid tumours, with future opportunities and challenges.

Immunotherapy has emerged as a new standard of care, showing survival benefit for solid tumours in multiple disease sites and indications. The survival improvements seen in diseases that were highly resistant to traditional therapies, with a poor prognosis, are unprecedented. Although the benefits observed in clinical trials are undeniable, not all patients derive those benefits, leading to emerging combination strategies and an ongoing quest for biomarker selection. Here, we summarize the current evidence for immunotherapy in the treatment of solid tumours, and we discuss emerging strategies at the forefront of research. We discuss future challenges that will be encountered as experience and knowledge continue to expand in this rapidly emerging field.

Expression of DNA damage response proteins in cervical cancer patients treated with radical chemoradiotherapy.

OBJECTIVE: The management of locally advanced cervical cancer has improved significantly with the advent of cisplatin-based chemoradiotherapy (CRT) as the primary treatment regimen. Nevertheless, a significant proportion of patients fail to respond or relapse on this treatment and have a very poor prognosis. Our goal was to determine the prognostic value of a panel of proteins involved in detection and repair of DNA damage. METHODS: We performed fluorescence immunohistochemistry, and used software analysis to assess expression of DNA damage response proteins ATM, DNA-PKcs, PARP-1, Ku70 and Ku86 in 117 pre-treatment specimens from patients with locally advanced cervical cancer. We compared expression to clinicopathologic correlates to determine prognostic significance. RESULTS: Five-year progression-free survival was significantly lower in the low expressors than in high expressors of ATM (35% vs. 58%, p=0.044) and PARP-1 (24% vs. 61%, p=0.003), and showed a trend to significance for DNA-PKcs (30% vs. 60%, p=0.050). Low expression of the same proteins also correlated significantly with lower overall survival. In multivariable analysis, adjusted for FIGO stage and tumor size, low ATM and PARP-1 expression was significantly associated with both poorer progression-free and overall survival. Pairwise analyses indicated that expression levels of these proteins were correlated. CONCLUSIONS: Expression of DNA damage response proteins in cervical cancer is associated with outcome in patients treated with CRT. Immunohistochemical analysis of these proteins may be useful in guiding treatment decisions in such patients.

Shame, guilt, and communication in lung cancer patients and their partners.

Lung cancer patients report the highest distress levels of all cancer groups. In addition to poor prognosis, the self-blame and stigma associated with smoking might partially account for that distress and prevent patients from requesting help and communicating with their partners. The present study used innovative methods to investigate potential links of shame and guilt in lung cancer recovery with distress and marital adjustment. A specific emphasis was an examination of the impact of shame on partner communication. Lung cancer patients (n = 8) and their partners (n = 8) completed questionnaires and interviews that were videotaped. We report descriptive statistics and Spearman correlations between shame and guilt, relationship talk, marital satisfaction, distress, and smoking status. We coded the interviews for nonverbal expressions of shame. Greater self-reported shame was associated with decreased relationship-talk frequency and marital satisfaction, and with increased depression and smoking behaviour. Nonverbal shame behaviour also correlated with higher depression and increased smoking behaviour. Guilt results were more mixed. More recent smoking behaviour also correlated with higher depression. At a time when lung cancer patients often do not request help for distress, possibly because of shame, our preliminary study suggests that shame can also disrupt important partner relationships and might prevent patients from disclosing to physicians their need for psychosocial intervention and might increase their social isolation. Even if patients cannot verbally disclose their distress, nonverbal cues could potentially give clinicians an opportunity to intervene.

Evaluation of immunohistochemical markers in non-small cell lung cancer by unsupervised hierarchical clustering analysis: a tissue microarray study of 284 cases and 18 markers.

This study has investigated a panel of immunomarkers in non-small cell lung carcinoma (NSCLC). Unsupervised hierarchical clustering analysis was used to investigate the possibility of identifying different subgroups in NSCLC based on their molecular expression profile rather than morphological features. A tissue microarray consisting of 284 cases of NSCLC was constructed. Immunohistochemistry was used to detect the presence of 18 biomarkers including synaptophysin, chromogranin, bombesin, NSE, GFI1, ASH-1, p53, p63, p21, p27, E2F-1, cyclin D1, Bcl-2, TTF-1, CEA, HER2/neu, cytokeratin 5/6, and pancytokeratin. Univariate analysis of all 18 markers for prognostic significance was performed. Immunohistochemical scoring data for NSCLC were analysed by unsupervised hierarchical clustering analysis. Kaplan-Meier survival curves were plotted for the different cluster groups of lung tumours identified by this method. Analysis of the three different World Health Organization (WHO) subtypes (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) of NSCLC individually showed that different markers were significant in different subtypes. For example, p53 and p63 were significant for squamous cell carcinoma (p = 0.007 and p = 0.03, respectively), whereas cyclin D1 and HER2/neu were significant prognostic markers for adenocarcinoma (p = 0.025 and p = 0.015, respectively). These markers were not significant prognostic predictors for NSCLC as a group. Hierarchical clustering analysis of NSCLC produced four separate cluster groups, although the vast majority of cases were found in two cluster groups, one dominated by squamous cell carcinoma and the other by adenocarcinoma. The clinical outcomes of cases from the four cluster groups were not significantly different. Prognostic indicators vary between different morphological subtypes of NSCLC. Unsupervised hierarchical clustering analysis, based on an extended immunoprofile, identifies two main cluster groups corresponding to adenocarcinoma and squamous cell carcinoma; cases of large cell carcinomas are assigned to one of these two groups based on their molecular phenotype.

Is specimen mammography beneficial?

HYPOTHESIS: Specimen mammography is not beneficial in the management or outcome of patients undergoing image-guided needle-localized breast biopsies. DESIGN: A retrospective study of consecutive patients who underwent needle/dye-localized breast biopsies between January 1, 1993, and December 31, 1995. SETTING: National Cancer Institute (Bethesda, Md)-designated comprehensive cancer center. PATIENTS: One hundred sixty-four patients underwent 165 needle/dye-localized breast biopsies for suspicious mammographic abnormalities. RESULTS: In only 3 (1.8%) of 165 patients did the patient clearly benefit from specimen mammography. In no patient was a malignant neoplasm missed. The mean time for the specimen mammogram was 20 minutes, adding an additional 55 hours of operating room time. Specimen mammography cost an additional $60,522 and was incorrect in 41 (24.8%) of 165 patients. CONCLUSION: Specimen mammography added little to patient care, as only 3 (1.8%) of 165 patients benefited from the information.

The molecular basis and clinical management of ataxia telangiectasia.

The unique combination of phenotypic manifestations seen in ataxia telangiectasia (AT) has intrigued neurologists, oncologists, radiation biologists and immunologists for several decades. Initially, the primary care givers of AT patients are often pediatricians but neurologists will inevitably become involved in their care. Over the last few years great strides have been made in understanding the genetic basis of this disease but useful therapeutic interventions are still not available. In this article, we review the clinical features and the current understanding of the pathophysiology of the syndrome. In addition, we address issues related to genetic counseling, prenatal diagnosis, screening and implications for AT heterozygotes.

Mediastinal germ cell tumor in a child with precocious puberty and Klinefelter syndrome.

An 8-year-old boy presented with precocious puberty and a mediastinal mass. A computer search showed that this rare presentation is most common with germ cell tumor of the mediastinum in children with Klinefelter syndrome. The tumor was completely resected after preoperative chemotherapy, and the patient is well 2 years after the operation. In patients with Klinefelter syndrome, germ cell tumors are 50 times more common than in patients without Klinefelter syndrome, usually contain nonseminomatous elements, present at an earlier age, and are seldom testicular in location.

Biodistribution of 111In- and 90Y-labeled DOTA and maleimidocysteineamido-DOTA conjugated to chimeric anticarcinoembryonic antigen antibody in xenograft-bearing nude mice: comparison of stable and chemically labile linker systems.

Biodistributions of two radiometal chelate conjugates of the human/murine chimeric anticarcinoembryonic antigen monoclonal antibody cT84.66 were obtained in nude mice bearing LS174T human colorectal carcinoma xenografts. Derivatives of the macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) were covalently attached to the antibody by a stable amide linkage and by a maleimidocysteineamido side chain (MC-DOTA) that has been shown to be chemically labile at physiological temperature and pH. Biodistributions of both 111In and 90Y labels were obtained in these studies. At common biodistribution time points, it was found that the 111In label had greater uptake in the liver than 90Y for both conjugates. No significant differences were found with respect to bone uptake of 90Y using either chelate. Blood curves were generally lower at comparable time points for MC-DOTA, indicative of faster clearance as compared to DOTA. Tumor uptake was high for both conjugates (57-68% ID/g at 48 h), with a longer tumor residence time in the case of the DOTA conjugate, probably a result of its longer blood circulation times. We conclude that bone uptake of 90Y would be minimal if either DOTA or MC-DOTA were used as the bifunctional chelator. This would imply preference for these macrocyclic ligands if radiation doses to the bone marrow would be considered to be dominated by skeletal uptakes. Alternatively, if bone marrow radiation dose is dominated by circulating antibody, the chemically labile linker system employed by the MC-DOTA conjugate offers the advantage of enhanced blood clearance.

Similar mutant frequencies observed between pairs of monozygotic twins.

The relative contribution of both genetic and environmental factors to spontaneous mutation frequency in humans is unknown. We have investigated the contribution of genetic factors to this phenomenon by determining the in vivo mutant frequency at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in circulating T-lymphocytes obtained from pairs of monozygotic twins. hprt mutant frequencies were determined three times over fourteen days in six sets of monozygotic male twins (mean age 30) taking part in a Russian Space Program inclined bed rest experiment. Blood samples were obtained prior to, during, and immediately following the experiment. Mononuclear cells were separated, frozen, and flown to Canada for analysis using the hprt T-lymphocyte clonal assay. There is no evidence within this data set to demonstrate that the period of inclined bed rest to simulate the effects of weightlessness had any effect on the observed mutant frequency. However, the average mutant frequency for the six sets of Russian twins was found to be three times higher than that of Western counterparts. More surprisingly, the spontaneous mutant frequency of monozygotic twins was found to be much more similar within pairs than between pairs of twins. These data suggest that the contribution of genetics in the determination of mutation frequency is substantial. However, whether high concordance within twin pairs reflects shared environmental experience as well as common genetic factors is not entirely clear. More data will be required to distinguish genetic from environmental factors and to determine the degree to which mutant frequency is genetically determined.

Influence of local treatment on the recurrence rate of ductal carcinoma in situ.

BACKGROUND: Screening mammography has resulted in a significant increase in the diagnosis of ductal carcinoma in situ (DCIS). The role of breast conservation therapy and the long-term recurrence rate are still controversial. This article compares mastectomy, wide excision alone, and wide excision with radiation as treatments for DCIS. STUDY DESIGN: One hundred twenty-four cases of DCIS were retrospectively reviewed and were found to be pure DCIS by a senior pathologist. The mean age at diagnosis was 60 years (range, 33 to 81). Originally, 101 patients (81 percent) presented with calcification on mammogram, and 23 (19 percent) presented with a palpable mass. Histologic data showed that 54 (44 percent) had noncomedo type lesions, 46 (37 percent) had comedo type, and 24 (19 percent) had unknown type DCIS. RESULTS: Four of the 124 patients had a recurrence during a mean follow-up period of 43 months. Recurrence is defined as any development of DCIS or invasive carcinoma in the ipsilateral breast. There was one (1.3 percent) recurrence in the 75 patients treated with mastectomy (an adenocarcinoma of the chest wall), which occurred at 59 months. Treatment was 5,750 cGy to the chest wall and the patient is free of disease 37 months postradiation. There were three (11 percent) recurrences at 14, 21, and 29 months, respectively, in the 28 patients treated with wide excision alone. All three recurrences were found by calcifications on mammogram and all patients had comedo type original lesions. Two recurrences were pure DCIS of the breast. Both patients were treated with mastectomy and are free of disease at 33 and five months, respectively. The third recurrence was an invasive colloid carcinoma of the breast. Treatment was a modified radical mastectomy; the patient is free of disease after 62 months. There were no recurrences in the 21 patients who were treated with wide excision and radiation. Average total dose of radiation was 5,835 cGy (range, 4,500 to 6,480). CONCLUSIONS: The results of this study indicate that both mastectomy and wide excision with radiation are associated with very low recurrence rates. Wide excision alone is associated with a higher recurrence rate. However, all recurrences were detected mammographically and all lesions were salvaged by mastectomy. Therefore, the ultimate local control and survival rates were similar for all three modalities.

Impact of adjunctive testing on the diagnosis and clinical course of patients with acute appendicitis.

The diagnosis of acute appendicitis is usually made from the history and physical examination. Recently, abdominal ultrasonography (US), laparoscopy, computerized tomography (CT), and barium enema (BE) have been used in the preoperative evaluation of patients with presumed appendicitis in order to improve the diagnostic accuracy. However, the usefulness of these tests in verifying the diagnosis of appendicitis has not been established. We reviewed the medical records of 203 patients who underwent appendectomy. One hundred patients were surgically treated before 1984 (group I) and 103 patients underwent surgery after 1988 (group II). Patients in group II were more likely to have preoperative US, laparoscopy, CT, or BE (24 in group II versus 3 in group I, p < 0.05). When groups I and II were compared, the rates of perforation (27% versus 20%), normal appendectomy (8% versus 11%), and the interval between admission and operation (12.2 hours versus 10.7 hours) and length of hospitalization (5.0 days versus 5.1 days) were not significantly different. We concluded that although adjunctive testing may be beneficial in selected patients, its routine use in patients suspected of having appendicitis cannot be advocated at present.

Bias and variability in blood pressure measurement with ambulatory recorders.

This study sought to determine whether patient characteristics such as age, sex, blood pressure, and pulse pressure differently affect the accuracy of an oscillometric (SpaceLabs 90207) and a microphonic (TM2420 version 7) blood pressure monitor. Blood pressure recorded by two oscillometric and two microphonic ambulatory monitors was compared with simultaneous readings by two pairs of trained, blinded observers using random-zero sphygmomanometry. One hundred and eighteen subjects (53 men and 65 women, aged 17 to 94 years; systolic pressure, 89 to 211 mm Hg; diastolic, 44 to 116 mm Hg) were studied. There were no significant differences within each observer pair or between the two observer pairs as well as no correlation between interobserver differences and patient characteristics. The differences between the monitor and trained observers' readings were 2.8 +/- 9.9 mm Hg systolic and 3.9 +/- 6.8 mm Hg diastolic for the SpaceLabs and 5.0 +/- 5.2 mm Hg systolic and 3.4 +/- 6.1 mm Hg diastolic for the TM2420. Patient characteristics that predicted measurement error were defined by multiple regression. For oscillometry, systolic measurement error was highly correlated with systolic pressure, pulse pressure, and subject age. The diastolic error was significantly correlated with pulse pressure, diastolic pressure, and subject sex. For the oscillometric monitor, patient characteristics accounted for 36.6% of the variation of the systolic error and 34.7% of the variation of the diastolic error. For the microphonic monitor, only age correlated with diastolic error, and no significant correlations were seen with systolic error. Patient characteristics accounted for only 1.2% of the systolic and 8.9% of the diastolic error.(ABSTRACT TRUNCATED AT 250 WORDS)

Age and blood pressure measurement: experience with the TM2420 ambulatory blood pressure monitor and elderly people.

The accuracy of the TM-2420 ambulatory blood pressure monitor was assessed in elderly people. Ninety-four subjects (44 men and 50 women), aged 60-94 with systolic blood pressure (SBP) of 97-208 mmHg and diastolic blood pressure (DBP) of 45-109 mmHg, including 23 with isolated systolic hypertension, were studied in three centres. The monitor was compared simultaneously with pairs of observers using the Hawksley random zero sphygmomanometer. The standard deviation of the difference (SDD) between observers was 4.2 mmHg (SBP), 2.9 mmHg (DBP). The mean difference was 0.49 mmHg (SBP) and 0.27 mmHg (DBP). The SDD between the monitor and the average of the observers' readings was 6.7 mmHg (SBP), 5.5 mmHg (DBP); the mean differences were 4.4 mmHg (SBP) and 4.8 mmHg (DBP). There were no significant differences between the two versions of the monitor used (5 and 7) or between the three pairs of observers. The monitor was equally accurate in isolated systolic hypertension (SDD observers and monitor 6.2 mmHg for SBP, 3.9 mmHg for DBP, mean differences 4.3 mmHg for SBP, 4.5 mmHg for DBP). Twenty-four-hour ambulatory blood pressure monitoring was carried out in 129 subjects aged 60-79; 89% of the monitoring attempted were successful with error rates of < 10%. The mean error rate was 3.8%. The device was well tolerated with only 4.7% of the subjects not completing a monitoring.