What is stage II in high-grade primary gastric lymphoma? How to define the range of "localized disease"

We conducted a retrospective analysis to evaluate the Musshoff staging system for high-grade primary gastric lymphoma (HG-PGL), particularly in those patients with stages IE and IIE localized diseases. One hundred twenty-six patients presented with stage IE or IIE diseases were retrospectively reclassified on the basis of a pretreatment CT examination as to whether there was lymph node involvement. A positive M1 node (by AJCC staging system) on pretreatment CT scanning was associated with poor clinical outcome for localized stage I or II patients.     

Is the positive predictive value of high-grade cytology in predicting high-grade cervical disease falling due to HPV vaccination?

A fall in the positive predictive value (PPV) of cytological predictions of high-grade squamous intra-epithelial lesions (HSIL) or adenocarcinoma-in-situ (AIS) has been predicted in the post-HPV vaccination era due to the decrease in underlying prevalence of cervical lesions. Data was extracted from the Victorian Cervical Screening Registry including cervical cytology tests taken between 2000 and 2016 and any subsequent histology performed within 6 months of the cytology. PPV was calculated for each age group (<20, 20–24, 25–29, 30–34, 35–39, 40–49, 50–59, 60–69, 70+ years) and calendar year. The x2 (chi-square) test was used to identify significant trends in PPV over time in each age group in both the pre-vaccination (2000–2006) and the post-vaccination (2007–2016) periods. The overall PPV of HSIL/AIS cytology in predicting histologically confirmed high grade disease (HGD, HSIL/AIS+) was 75% and this was consistent across the different calendar years. When stratified by age group, there was a decreasing trend in the PPV in women aged <20 years (p_trend = 0.0006) and 20–24 years (p_trend = 0.0004) in the post-vaccination period but not in the pre-vaccination period (p_trend = 0.82 and p_trend = 0.73, respectively). No such decline in PPV was noted in either the pre-vaccination or the post-vaccination periods for any other age groups except the oldest women, aged 60–69 years and 70+ years. The decline in PPV of HSIL/AIS cytology in predicting HGD in age groups <20 and 20–24 years in the post-vaccination period could be an impact of the HPV vaccination.     

Genomics of pancreatic cancer: Does it make any improvement in diagnosis, prognosis and therapy?

Pancreatic cancer (PanC) is an extremely life-threatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well.     

Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup

Large randomised trials are mandatory when one wants to examine the effects of different aspects (such as the treatment modality) of a pathological condition on the overall outcome. This is especially true when studying a disease in which there is a multifactorial influence on progression and outcome such as osteosarcoma. Data on 570 patients with biopsy-proven primary central osteosarcoma of an extremity included in two consecutive studies of the European Osteosarcoma Intergroup (EOI) were analysed in order to evaluate if the histological subtype of the biopsy specimen correlated with the subtype of osteosarcoma represented in the resected specimen, if there was a relationship between the histological subtype and overall survival and if there was a relationship between the histological subtype and histological response to chemotherapy. High-grade osteosarcoma, as defined by established criteria, was subtyped as either conventional, chondroblastic, teleangiectatic, small cell, fibroblastic, osteoclast rich, anaplastic and sclerotic/osteoblastic well differentiated. A panel of experienced pathologists with a special interest in bone pathology was appointed to review the histological diagnosis and to assess the tumour response to chemotherapy on the resected specimen of each patient entered into the trials. Subtyping on the biopsy specimen proved to be highly representative for the subtype of the whole tumour. In 102 patients for which subtyping was performed on the biopsy and the resected specimens, there were only two discrepancies. Of the 568 patients for whom subtype was available, 404 (71%) were of the conventional type, 54 (10%) were chondroblastic, 53 (9%) had fibroblastic tumours and the remainder consisted of rare subtypes. A good response to preoperative chemotherapy was defined as 90% or more necrosis. The proportion of patients responding well to chemotherapy differed significantly between subtypes (Chi-square test statistics=11.44, P=0.01 on 3 degrees of freedom (d.f.)). In comparison with the conventional subtype, there was a higher proportion of good responders in the fibroblastic group and a lower proportion of good responders in the chondroblastic group. Good responders had a significantly better survival than patients who responded poorly to the pre-operative chemotherapy (logrank statistic=25.20, P<0.01 on 1 df). Survival did not differ significantly according to subtype (logrank statistic=2.72, P=0.44 on 3 df), although there was a suggestion that patients with chondroblastic tumours experienced a better long-term survival. This large set of prospectively-collected data provides important information on the relationship between pathological subtype, histological response and survival. Histological response has a known prognostic effect on survival, and we have shown that the rates of response differ by subtype. There is some evidence from this study that the specific histological subtypes, i.e. the chondroblastic subtype, experience better survival. However, despite this large multi-institutional study, we have insufficient numbers of non-conventional tumours to examine this unambiguously for these subsets.     

What is it like living with the diagnosis of cancer?

This article discusses in-depth interviews of 12 persons, who had been diagnosed for cancer from 6 months to 3 years earlier, concerning what it is like to live with the diagnosis of cancer. The persons interviewed were aged 43–70 years, and 11 of the 12 had received successful radical treatment; one patient was treated for symptoms, but with an uncertain future development. This investigation shows that the period of waiting from the first suspicion of cancer until diagnosis confirmation of the disease was a period of great stress, and that the following period until the commencement of treatment was also a very difficult one. The investigation also shows that there was no follow-up of individual patients concerning their need to talk about their difficult new life-situation brought about by the disease. Receiving the diagnosis of cancer was remembered as being a very dramatic experience for the informants. The informants were satisfied with the medical treatment they received, but they also feel that there should have been some kind of programme available to care for their psycho-social needs. In the rehabilitation phase, they feel that they were left to their own resources; during this period, they felt physically and mentally drained, and they did not have the knowledge to tackle their new and difficult life-situation. The threat of new cancer cells being discovered is always with patients. Attending the check-ups is also described as a period of stress.     

Evaluation of pirarubicin–cisplatin chemotherapy in the treatment for refractory and recurrent high-grade osteosarcoma: experience of a single institute

The purpose of this study was to investigate the feasibility and efficacy of pirarubicin (THP)-cisplatin (DDP) chemotherapy for refractory and recurrent high-grade osteosarcoma. Between 2008 and 2010, 23 patients with refractory and recurrent high-grade osteosarcoma were included in this analysis. THP was given at a dose of 50 mg/m(2) i.v. d1 and DDP 100-120 mg/m(2) i.v. d2-3 every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. Tumor response was usually evaluated every two chemotherapy cycles by CT/MRI scan. The primary end point was overall response rate, secondary endpoint including progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities. A total of 68 cycles were given, median 2 per patient (range 2-7). Overall response rate was 13% and disease control rate was 34.5%, with 3 partial responses and 5 stable diseases. Median time to progression and overall survival time were 2 (95%CI 2-11) and 10 months (95%CI 6-23), respectively. Major severe toxicities were grade 3 or 4 leucopenia occurred 12 times (17.7%) in total cycles; Mild toxicities included grade 1 or 2 nausea and vomiting (80.9%), leucopenia (61.8%), fatigue (50.0%), and alopecia (79.4%). THP-DDP regimen chemotherapy represents an active and well-tolerated treatment for Chinese refractory and recurrent high-grade osteosarcoma patients. Further assessment is necessary to confirm the safety and efficacy of this treatment.     

Does stage at diagnosis explain the difference in survival after breast cancer in Denmark and Sweden?

Breast cancer survival differs 9 percentage points between the neighbouring countries of Denmark and Sweden. The authors' aim was to analyse whether this was caused by early detection in Sweden. The extent of disease and outcome was compared in two population-based breast cancer cohorts in 1983-1989. Breast cancer management was decentralized in Denmark without mammography screening whereas treatment in Sweden was centralized and the population partly screened. Ten- and 15-year relative survival was 15% and 6% higher in Sweden (p<0.001) with corresponding differences in crude and disease-specific survival. Stage distribution was significantly more favourable in the Swedish cohort. In multivariate analysis age, tumour size, extent of axillary surgery, and spread affected survival; however, the impact of region persisted (p<0.001). Reanalysis without screening-detected patients only slightly affected the impact of region. It was concluded that early detection had significant impact on survival but other regional differences might be of importance.     

Is frozen-section diagnosis a reliable guide in surgical treatment of stage I endometrial carcinoma?

Frozen-section diagnoses and paraffin-section diagnoses were compared in 154 patients in stage I endometrial adenocarcinoma. In 134 (87%) of the 154 patients (p < 0.001), a corresponding depth of myometrial invasion was found, and in 132 (85.7%) patients the same tumor grade was established (p < 0.001). Frozen-section diagnosis of stage I endometrial adenocarcinoma is reliable for estimation of the extent of disease and accurately identifies patients who require surgical staging.     

Celebrities and screening: a measurable impact on high-grade cervical neoplasia diagnosis from the ‘Jade Goody effect' in the UK

Background:

The celebrity Jade Goody''s cervical cancer diagnosis was associated with increased UK cervical screening attendance. We wanted to establish if there was an increase in high-grade (HG) cervical neoplasia diagnoses, and if so, what the characteristics of the women with HG disease were.

Methods:

We analysed prospective data on 3233 consecutive colposcopy referrals in North East London, UK, from 01 April 2005 to 30 June 2010. Characteristics and outcomes of pre- and post-Goody cohorts were compared.

Results:

Goody''s diagnosis was associated with an increased incidence of colposcopy referrals in all subsequent annual quarters (incidence rate ratio (IRR) 1.3–1.9, P<0.002–P<0.0005) and increased HG disease diagnoses in the fourth quarter 2008/2009 (IRR 1.3, P=0.05) and first quarter 2009/2010 (IRR 1.3, P=0.07). We observed 1.90-fold (CI: 1.06–3.39), 2.06 (CI: 1.13–3.76) and 2.13-fold (CI: 1.07–4.25) respective increases in the odds of HG disease women being screening-naive in the first and second quarter 2009/2010, and the first quarter 2010/2011 (P<0.04, P<0.02 and P<0.04, respectively). There was a 2.23-fold increase in the odds of screening-naive HG disease women being symptomatic post-Goody''s diagnosis (P=0.023). The age distributions of the pre- and post-Goody cohorts did not differ in any study group.

Conclusion:

Continued publicity about celebrities'' diagnoses might encourage screening in at-risk populations.     

Is Age Still the Deciding Factor? Commentary on “The Effect of Age on Delay in Diagnosis and Stage of Breast Cancer” by Partridge et al.

The study by Partridge et al., published in this edition of The Oncologist, is examined.Young breast cancer patients face multiple different challenges when diagnosed and when undergoing treatment for breast cancer than do postmenopausal patients. Very young breast cancer patients, especially those aged <35 years, have been described in multiple reports to have a worse prognosis [1–3]. Additionally, because women are not routinely recommended to consider initiating screening mammography until their 40s or 50s, a younger woman is more likely to develop a cancer at an advanced stage and to be diagnosed because of the onset of symptoms. There remains concern that a delay in diagnosis of breast cancer in a younger woman is one of the contributing factors to these worse outcomes in young breast cancer patients.It was estimated by the American Cancer Society that ∼5% of cases of breast cancer will be diagnosed each year in women aged <40 years [4]. Several case series have demonstrated worse outcomes in younger breast cancer patients. Nixon et al. [1] reported on 107 patients aged <35 years with either stage I or stage II breast cancer and compared them with their older counterparts. The younger patients were found to have a statistically significant greater recurrence risk and risk for developing distant metastatic disease. Kroman et al. [3] reported that younger women who had node-negative cancers or tumors <2 cm were significantly more likely to die from their cancer if they did not receive systemic adjuvant therapy. However, this effect was mitigated if they received cytotoxic therapy. Race may also play a factor in the diagnosis of breast cancer in young women. Black women have a twofold higher chance of being diagnosed at <35 years of age than white females. In addition, black women have higher presenting stages and higher mortality rates from breast cancer in the U.S. than white women [5, 6].When looking at the underlying biology of younger women with breast cancer, the majority of reports show a higher rate of hormone receptor–negative tumors [1–3] than in postmenopausal breast cancer patients. When evaluating very low-risk disease, such as node-negative tumors that are ≤1 cm, age was identified as an independent risk factor for the recurrence-free survival interval. This was more significant in women with human epidermal growth factor receptor (HER)-2⁺ and hormone receptor–positive tumors and was not demonstrated to be significant in patients with triple-negative tumors [7]. Additionally, Anders et al. [8] used microarray data from 784 women with early-stage breast cancers, again demonstrating lower percentages of hormone receptor positivity and higher grade tumors. There were 367 gene sets found to significantly differentiate the tumors arising in younger women from those in older women. Examples of gene sets that were differentiated by age included those encoding epidermal growth factor receptor and mammalian target of rapamycin as well as BRCA1, among many others [8]. This information was particularly intriguing and hypothesis generating regarding combination therapy that could take advantage of such pathways in younger breast cancer patients. Therefore, the question remains, is it truly the age of the patient herself that is the underlying cause of this described worse prognosis or is age just a surrogate marker for more aggressive tumor subtypes that occur more frequently in younger patients?Another confounding factor in this debate is the question surrounding a delay in diagnosis. There have been conflicting reports on whether or not a delay in diagnosis and a delay from the time of first symptom to the time of treatment initiation influence breast cancer prognosis. One large systematic review demonstrated that delays of 3–6 months from the time of diagnosis to the time of initiation of treatment were associated with a statistically significant lower 5-year survival rate [9]. However, it was noted that, in the included studies that did account for stage, a delay was not associated with a worse overall survival outcome. Younger patients who had not previously been designated to be high risk and had not undergone earlier screening would be expected to present with more advanced stages of disease than postmenopausal women whose cancer was diagnosed on screening mammography. In the most recent screening mammography recommendations by the U.S. Prevention Services Task Force, mammogram recommendations were changed to start after age 49, to increase the interval between screenings, and to individualize the decision for women in their 40s [10]. This change was a result of the lack of available randomized data showing a lower mortality rate with screening in this age group, although recently Hellquist et al. [11] used data collected from the Swedish mammography screening program to evaluate their experience with screening women aged 40–49 years and showed a relative risk for mortality for those who underwent screening of 0.71, which was statistically significant, and estimated that 1,252 women needed to be screened to save one life. There currently are no recommendations for screening mammography in women aged <40 years unless they have been identified to be at high risk for developing breast cancer, such as women with a hereditary predisposition to develop breast cancer, such as patients with BRCA1 or BRCA2 mutations. Therefore, as routine strategies for screening are currently evaluating women aged >40 years, except in special populations, younger women who develop breast cancer are more likely to present with clinical symptoms.In the current retrospective study by Partridge et al. [12], the authors use the National Comprehensive Cancer Center Network database to evaluate 21,818 women with breast cancer, stages I–IV, of whom 2,445 were aged ≤40 years. The purpose of the study was to evaluate if age alone was considered an independent risk factor for a delay from the time of the first symptom to the time that the woman sought treatment and was initially diagnosed with breast cancer. This study therefore asks a slightly different question: does age factor into actually seeking evaluation and undergoing diagnostic procedures? Additionally, the authors evaluated other socioeconomic factors such as race, education, employment status, and type of initial sign or symptom. When evaluating age as a factor in delay to breast cancer diagnosis, age ≤40 years old was initially found to be associated with a >60-day delay in diagnosis—odds ratio (OR), 1.52; 95% confidence interval (CI), 1.39–1.67; p < .0001. However, when the multivariate model was adjusted for the initial sign or symptom, there was no longer a statistically significant difference. Also in multivariate modeling, those women who had an initial sign or symptom had a significantly greater association with a >60-day delay in diagnosis (OR, 3.31; 95% CI, 3.08–3.56). Women with screening-detected tumors were more likely to be diagnosed with an earlier stage of breast cancer (64% of women diagnosed using screening were diagnosed with stage I tumors, compared with 28% of women who presented with an initial sign or symptom).This was a very well-conducted study using a very detailed database that spans several cancer centers throughout the U.S. The study has the expected limitations of a retrospective database study, including recall bias and the lack of information regarding previous screenings and whether or not patients had been identified as having a high risk for developing breast cancer. Also, women who were included had been referred to or sought treatment at a large comprehensive cancer center and may not reflect presentation patterns elsewhere. It would be interesting to note if there is any difference in time to delay not by age but by tumor biology. If a tumor has a more aggressive growth pattern, such as triple receptor–negative or HER-2⁺ tumor, will that influence more substantially the time to diagnosis? For this analysis, the authors did not include tumor receptor information in their modeling. Given the understanding of these inherent limitations, the study does provide insight as to whether or not age is a barrier to seeking treatment and being diagnosed with breast cancer.The failure of age to be consistently associated with a delay in diagnosis of breast cancer in this study when controlling for stage of disease leads back to the original concern: is it age or is it biology? If a delay does not appear to be the significant factor for young breast cancer patients and thus not likely to be the underlying cause of worse outcomes, the underlying biology of the disease that commonly presents in younger women should continue to be the main target. It will also be important to identify those women diagnosed at a young age with less biologically aggressive tumors who should be spared systemic therapy. In order to improve our therapies as well as to improve patient outcomes, we need to continue to develop strategies for identifying women at higher risk for developing breast cancer, for improving knowledge on the importance of family history, for improving genetic risk assessment, for identifying known and yet to be identified hereditary cancer syndromes, and, finally, for personalizing screening, prevention, and treatment strategies.See the accompanying article on pages 775–782 of this issue.     

High grade osteosarcoma of the extremities metastatic to the lung: Long-term results in 323 patients treated combining surgery and chemotherapy, 1985–2005

BackgroundApproximately one-third of patients with localized osteosarcoma at presentation relapse as well as about three-fourths of the patients with metastases at diagnosis, about 90% of relapses are lung metastases. The role of lung metastasectomy remains to be determined.Patientsand methods: Three hundred and twenty three patients, 88 with resectable lung metastases at diagnosis and 235 with localized disease at presentation who relapsed with lung metastases were treated.ResultsA total of 498 lung surgeries and 607 thoracotomies were performed. The 5 year overall survival was 37%. Final outcome was significantly related to presence or absence of metastasis, time of first relapse and presence of local recurrences. According to stage of the disease, the rate of a 5 year event-free survival (EFS) was 36% for patients with localized disease who later relapsed and 9% for patients with resectable lung metastases at presentation (p < 0.0001). However, there were no differences in EFS between patients who underwent two or three thoracotomies and patients who had four or five thoracotomies (7.5 vs 18.7%, p = 0.29).ConclusionsIn patients with recurrent resectable pulmonary metastases from high grade osteosarcoma treated with adjuvant or neoadjuvant chemotherapy, thoracotomy should always be considered regardless the number of previous lung relapses and the number of secondary pulmonary lesions.