Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer.

BACKGROUND: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. RESULTS: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first-line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. CONCLUSION: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.

Assessment of Upfront Selection Criteria to Prioritise Patients for Breath-hold Left-sided Breast Radiotherapy.

AIMS: Deep inspiratory breath-hold (DIBH) techniques for left breast and chest wall radiotherapy can reduce cardiac dose. We investigated the use of 'upfront selection' criteria for DIBH based on tumour bed position and whether cardiac shielding was used. MATERIALS AND METHODS: Four methods of selecting patients for DIBH were assessed retrospectively in a cohort of left breast and chest wall treatments. These were: (1) free breathing scan on all patients, selecting DIBH treatment for those with a predicted mean heart dose ≥3 Gy; (2) selective DIBH for those with maximum heart depth (MHD) on free breathing scan ≥1 cm; (3) use of an 'upfront selection process' using tumour bed position as initial selection and measurement of MHD on those not selected upfront; (4) DIBH on all. The methods were assessed on predicted mean heart dose, proportion needing two scans, sensitivity, specificity and the positive and negative predictive values. These were compared with method (1) as the gold standard. RESULTS: In total 134 cases were analysed. The predicted mean heart dose in free breathing was ≥3 Gy in 28 (20.9%). Therefore, applying method (1), 28/134 (20.9%) would be selected for DIBH treatment. Applying method (2), 66/134 (49.2%) would be selected for DIBH treatment, all requiring two scans. Of these, 40/66 (60.6%) would receive < 3 Gy in free breathing so are over-selected; 2/68 (2.9%) would have received >3 Gy in free breathing so failed to be selected. Selection using method (3) was similar to method (2), but only five patients required two planning scans; 61/134 (45.5%) cases would be selected for DIBH upfront and 5/134 (3.7%) after initial free breathing scan; 42/66 (63.6%) of those selected for DIBH treatment would receive <3 Gy in free breathing and 4/68 not selected (6%) would receive >3 Gy in free breathing. For methods (2) and (3) most patients not selected for DIBH would have had a mean heart dose of ≤3 Gy (64/68, 90%). Using method (3), 86% (95% confidence interval 67-96%) of patients with a mean heart dose >3 Gy would be selected for DIBH treatment. The estimated mean and standard error for the area under the receiver operator characteristic curve for MHD as a predictor for mean heart dose was 0.85 (0.03). CONCLUSION: This study supports the use of proposed an 'upfront selection process' as a means of selecting patients for treatment with DIBH and avoiding two radiotherapy planning scans. Calculation of MHD can be used as a surrogate for mean heart dose in the selection of cases for DIBH.

Adequacy of diagnostic tests and surgical management of symptomatic invasive lobular carcinoma of the breast.

INTRODUCTION: Invasive lobular carcinoma (ILC) presents diagnostic and therapeutic challenges as it produces subtle radiological changes. It has been suggested that it is not suitable for breast conserving surgery (BCS). The aim of this study was to ascertain the diagnostic adequacy of modern mammography and ultrasonography in the context of a fast track symptomatic diagnostic clinic in the UK. It also sought to compare the mastectomy, re-excision and BCS rates for ILC with those for invasive ductal carcinoma (IDC). METHODS: A retrospective analysis of prospectively collected data was carried out on all new symptomatic cancers presenting to the one-stop diagnostic clinic of a single breast unit between 1998 and 2007. RESULTS: Compared with IDC, ILC was significantly larger at presentation (46mm vs 25mm), needed re-excision after BCS more often (38.8% vs 22.3%) and required mastectomy more frequently (58.8% vs 40.8%). Although mammography performs poorly in diagnosing ILC compared with IDC, when combined with ultrasonography, sensitivity of the combined imaging was not significantly different between these two histological types. CONCLUSIONS: Provided ultrasonography is performed, standard radiological imaging is adequate for initial diagnosis of symptomatically presenting ILC but some additional preoperative workup should clearly be employed to reduce the higher number of reoperations for this histological type.

Sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with breast cancer: Are the current false negative rates acceptable?

The advent of sentinel lymph node biopsy has revolutionised surgical management of axillary nodal disease in patients with breast cancer. Patients undergoing neo-adjuvant chemotherapy for large breast primary tumours may experience complete pathological response on a previously positive sentinel node whilst not eliminating the tumour from the other lymph nodes. Results from 2 large prospective cohort studies investigating sentinel lymph node biopsy after neo-adjuvant chemotherapy demonstrate a combined false negative rate of 12.6-14.2% and identification rate of 80-89% with the minimal acceptable false negative rate and identification rate being set at 10% and 90%, respectively. A false negative rate of 14% would have been classified as unacceptable when compared to the figures obtained by the pioneers of sentinel lymph node biopsy which was 5% or less.

NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE100C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Neoadjuvant chemotherapy and primary-first approach for rectal cancer with synchronous liver metastases.

AIM: Up to a quarter of patients with rectal cancer have synchronous liver metastases at the time of diagnosis. This is a predictor of poor outcome. There are no standardized guidelines for treatment. We reviewed the outcomes of our patients with synchronous rectal liver metastases treated with a curative intent by neoadjuvant chemotherapy with or without chemoradiotherapy followed by resection of the primary tumour and then liver metastases. METHOD: Between 2004 and 2012, patients who presented with rectal cancer and synchronous liver metastasis were treated with curative intent with peri-operative systemic chemotherapy as the first line of treatment. Responders to chemotherapy underwent resection of the primary tumour with or without preoperative chemoradiotherapy followed by hepatic resection. RESULTS: Fifty-three rectal cancer patients with 152 synchronous liver lesions were identified. After a median follow-up of 29.6 months, the median survival was 41.4 months. Overall survival was 59.0% at 3 years and 39.0% at 5 years. CONCLUSION: Rectal resection before hepatic resection combined with neoadjuvant chemotherapy is associated with promising clinical outcome. It allows downstaging of liver lesions and removal of the primary tumour before the progression of further micrometastases. Furthermore, patients who do not respond to chemotherapy can be identified and may avoid major surgical intervention.

Prognostic biomarkers in squamous cell carcinoma of the anus: a systematic review.

BACKGROUND: recent decades have seen combination chemoradiotherapy become the standard treatment for anal squamous cell carcinoma (SCC). However, the burden of this disease continues to rise, with only 10% of patients with metastatic disease surviving >2 years. Further insight into tumour characteristics and molecular biology may identify novel therapeutic targets. This systematic review examines current prognostic markers in SCC of the anus. METHODS: an extensive literature search was performed to identify studies reporting on biomarkers in anal cancer in the context of clinical outcome following treatment primarily with chemoradiotherapy. RESULTS: in all, 21 studies were included. A total of 29 biomarkers were studied belonging to 9 different functional classes. Of these biomarkers, 13 were found to have an association with outcome in at least one study. The tumour-suppressor genes p53 and p21 were the only markers shown to be of prognostic value in more than one study. CONCLUSIONS: an array of biomarkers have been identified that correlate with survival following chemoradiotherapy in anal cancer. However, investigators are yet to identify a biomarker that has the ability to consistently predict outcome in this disease. Further studies are needed to elucidate whether these candidate biomarkers demonstrate their optimum value when they serve as targets for new therapeutic strategies.

Treatment of primary rectal squamous cell carcinoma by primary chemoradiotherapy: should surgery still be considered a standard of care?

Rectal squamous cell carcinoma is a rare tumour accounting for only 0.25% of all rectal carcinomas, yet it carries a significant mortality and morbidity. Radical surgery has been advocated as the primary treatment modality with or without adjunctive therapies despite the proven benefits of primary chemoradiotherapy for squamous cell carcinoma (SCC) of the anus. This report describes 7 cases of rectal squamous cell carcinoma from a single institution over a four-year period, treated with primary chemoradiotherapy. All patients demonstrated significant tumour regression, and surgery to the primary tumour was avoided in all but one of these cases. Primary chemoradiotherapy can achieve excellent local control for rectal squamous cell carcinoma with surgery employed only for unresponsive or recurrent tumours.

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy.

We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approximately 5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11-12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21-q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3-q4 and 18p11.31 and gains of 6p25.1-p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2-11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival.

BACKGROUND: We present extended follow-up from a prospective randomised trial evaluating the role of neoadjuvant chemoendocrine therapy in the treatment of operable breast cancer. PATIENTS AND METHODS: 309 women were randomised to primary surgery followed by eight cycles of adjuvant mitoxantrone, methotrexate with tamoxifen (2MT) or 2MT with mitomycin-C (3MT) versus the same regimen for four cycles before followed by four cycles after surgery. For this analysis the median follow-up of patients was 112 months. RESULTS: After 10 years follow-up there is still no statistically significant difference in disease-free survival (DFS) (71% versus 71%) or overall survival (OS) (63% versus 70%) when comparing adjuvant versus neoadjuvant treatment, respectively. Of 144 evaluable patients in the neoadjuvant arm, 74 achieved a good clinical response and 70 patients achieved a poor clinical response. Good responders had a superior DFS (80% versus 64%, P=0.01) and OS (77% versus 63%, P=0.03) compared to poor responders. CONCLUSIONS: At 10 years, neoadjuvant and adjuvant treatment continue to have equivalent OS and DFS. Good clinical response to neoadjuvant chemotherapy is associated with superior DFS and OS. This supports the use of clinical response of primary breast cancer to neoadjuvant therapy as a surrogate marker of survival benefit.

Molecular profiling of breast cancer: clinical implications.

Breast cancers are routinely subcategorised on the basis of clinical stage, cellular morphology and immunohistochemical analysis of a small number of markers. The recent development of gene expression microarray and related technologies provides an opportunity to perform more detailed profiling of the disease. It is anticipated that the molecular classification arising from such studies will be more powerful than its pathological predecessor at confining treatment to those patients who are most likely to benefit. It is likely that this will result in a much less frequent use of adjuvant chemotherapy. Furthermore, of those who do receive it, a higher proportion will benefit. If adopted, this will offer considerable patient benefits in terms of reducing unnecessary toxicity and have major health economic implications.

The biology of neoadjuvant chemotherapy for breast cancer.

Neoadjuvant/pre-surgical medical therapy of breast cancer provides a unique opportunity to derive biological information related to tumour response. Large clinical trials of neoadjuvant chemotherapy have established that pathological complete remission is an independent predictor of improved disease-free survival. Clinical response has been found to parallel substantial reductions in the proliferation of breast cancer cells. Increased apoptosis also occurs, but it is not closely associated with response. Numerous biological markers such as p53, bcl-2, oestrogen receptor (ER) and HER2 have been assessed for their possible role in chemoresistance/response, but the data are not clear at this stage. Continuing work using cDNA microarrays may yield new, more reliable indices of likely response and an improved insight into biological processes related to chemotherapeutic response.

Pattern of local recurrence after conservative surgery and radiotherapy for soft tissue sarcoma.

PURPOSE: Over the past three decades our centre has adopted a policy of conservative surgery followed by adjuvant radicaldose radiotherapy for medium-and high-grade soft tissue sarcomas. For all cases of local recurrence following this treatment we aimed to define the spatial relationship between sites of recurrence and the positions of the phase 1 and 2 radiotherapy volumes. PATIENTS: We identified 25 cases of local recurrence recorded on our soft tissue sarcoma database between 1986 and 1999 inclusive. We excluded patients with macroscopic residual disease following surgery. Most patients were treated with a phase I volume corresponding to the entire muscle compartment (50 Gy in 25 fractions over 5 weeks) and a phase II volume corresponding to the tumour bed (10 Gy in five fractions). Six of the patients were treated according to a hyperfractionated regimen. METHODS: For each case we reviewed the diagnostic imaging, planning radiographs and prescription sheets. We audited whether treatment had been given according to protocol and defined whether recurrence had arisen in the phase 1 volume, phase 2 volume or 'out of field'. RESULTS: Four (16%) patients recurred within the phase I volume, 17 (68%) recurred within the phase II volume and four (16%) outside the irradiated volume including one marginal recurrence. In six patients there had been deviation from our radiotherapy protocol (usually unavoidable) including all three true out of field recurrences. DISCUSSION: The majority of recurrences occur in the phase 2 volume. Prospective multi-centre data collection and, ideally, a prospective randomised trial are required to formulate an improved treatment policy with respect to radiotherapy margins and dose.

Management problems in oncology.

Man has evolved sophisticated defence mechanisms over millions of years to combat insertion of foreign DNA into his cells. However, gene therapy carries huge potential for the treatment of cancer. The challenge is therefore to translate our scientific knowledge into a clinical reality.

Treatment of HIV-associated invasive anal cancer with combined chemoradiation.

There is an increased frequency of invasive anal cancer in HIV-seropositive men. Early treatment strategies in this patient group employed reduced dosages of chemotherapy or radiotherapy alone to reduce toxicity. Since 1989 we have used combined modality treatment consisting of chemotherapy 5-fluorouracil (5-FU) and mitomycin C, and concomitant radical radiotherapy to the pelvis (38-51 Gy in 20-30 fractions), with most patients receiving a perineal boost (10-18 Gy). 12 homosexual HIV-positive men have been treated. The median CD4 count at diagnosis of anal cancer was 209 cells/microl (range: 29-380 cells/microl), 5 had prior AIDS defining diagnoses. No patients had metastatic disease. Complete remissions were obtained in 9/11 evaluable patients and in 1 further patient following surgery. 2 patients relapsed both within 6 months of diagnosis. At a median follow-up of 4.8 years (range: 0.4-10 years), 4 patients have died (2 from anal cancer, 1 from treatment-related consequences and 1 from opportunistic infection in remission). Actuarial 2-year survival is 60% (95% confidence interval (CI): 29-91%). Grade 3 haematological toxicity was recorded in 3 patients, grade 4 and 5 gastrointestinal toxicity in 1 patient each and grade 3 skin toxicity in 1 patient. Radical chemoradiation may be given safely at conventional doses in HIV-positive patients, with a high complete response rate.

An examination of needlestick injury rates, hepatitis B vaccination uptake and instruction on 'sharps' technique among medical students.

A 12-question survey designed to examine venepuncture techniques and instruction and uptake of hepatitis B vaccination was completed by 172 of the 275 medical students to whom it was distributed (a response rate of 62.5%). Seventy-five injuries were reported, at an average of 0.3 per student per year. Of the respondents, 63% resheathed needles after use, a practice frequently cited as a cause of needlestick injury. However, in this sample resheathing was not significantly associated with a higher or lower injury rate (chi 2 = 2.07, P > 0.1). Of the respondents from the most recent intake, only 20 out of 57 had completed a course of hepatitis B vaccinations prior to the commencement of venepuncture duties. There was almost universal ignorance concerning the correct course of action following 'sharps' injury. Recommendations are made concerning hepatitis B vaccination and teaching strategies for medical students.