Laparoscopic versus open left lateral hepatic sectionectomy: A comparative study

Background

Laparoscopic liver surgery has been difficult to popularize. High volume liver centres have identified left lateral sectionectomy (LLS) as a procedure with potential for transformation into a primarily laparoscopic procedure where surgeons can safely gain proficiency.

Methods

Forty-four patients underwent either laparoscopic (LLLS) or open (OLLS) left lateral sectionectomy (of segments II/III) for focal lesions at Southampton General Hospital.

Results

OLLS and LLLS groups were matched for age, sex and tumour types resected. Median operative time in the LLLS group was 180 (40–340) min and 155 (110–330) min in the OLLS group (p = 0.885) with median intra-operative blood loss in the LLLS group 80 (25–800) ml versus a larger 470 (100–3000) ml; p = 0.002 for patients receiving OLLS. Post-operative stay was also shorter in the LLLS group (3.5 (1–6) days) compared to the OLLS group (7 (3–12) days; p < 0.001). Resection margin was not different in the two groups (11 (1.5–30) mm (LLLS) versus 12 (4–40) mm (OLLS); p = 1) and neither was the complication rate (13% for LLLS versus 25% for OLLS; p = 0.541). There were no conversions to open in the LLLS group and no deaths in either group at 90 days. Between the first and second 12 LLLS the median operative time fell from 240 (70–340) min to 120 (40–120) min; p = 0.005 as well as median post-operative hospital stay from 4.5 (2–6) days to 2 (1–4) days, p = 0.001.

Conclusion

LLLS is a viable alternative to OLLS with potential improvements in intra-operative blood loss and shorter hospital stay without adversely affecting successful resection or complication rates. Larger prospective studies are required to explore this new avenue in laparoscopic liver surgery.     

Immunomodulation with dendritic cells and donor lymphocyte infusion converge to induce graft vs neuroblastoma reactions without GVHD after allogeneic bone marrow transplantation

Background:

Mounting evidence points to the efficacy of donor lymphocyte infusion (DLI) and immunisation with tumour-pulsed dendritic cells (DC) in generating graft vs leukaemia reactions after allogeneic bone marrow transplantation (BMT). We assessed the efficacy of DLI and DC in generating potent graft vs neuroblastoma tumour (GVT) reactions following allogeneic BMT.

Methods:

Mice bearing congenic (H2K^a) Neuro-2a tumours were grafted with allogeneic (H2K^b) T-cell-depleted bone marrow cells. Tumour-pulsed donor DC (DC^Neuro2a) were inoculated (on day +7) in conjunction with donor (H2K^b) and haploidentical (H2K^a/b) lymphocytes.

Results:

Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice. Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DC^Neuro2a and lymphocytes devoid of graft vs host (GVH) activity (H2K^a/b). In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT.

Conclsions:

The GVHD is not a prerequisite to induce GVT reactivity after allogeneic BMT, but is rather detrimental to induction of anti-tumour immunity by DC-mediated immunomodulation. Simultaneous inoculation of tumour-pulsed donor DC and DLI synergise in stimulation of potent GVT reactions to the extent of eradication of established NB tumours.     

Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: a literature review

Increased understanding of the genetic aetiology of advanced non-small-cell lung cancer (aNSCLC) has facilitated personalised therapies that target specific molecular aberrations associated with the disease. Biopsy samples for mutation testing may be taken from primary or metastatic sites, depending on which sample is most accessible, and upon differing diagnostic practices between territories. However, the mutation status concordance between primary tumours and corresponding metastases is the subject of debate. This review aims to ascertain whether molecular diagnostic testing of either the primary or metastatic tumours is equally suitable to determine patient eligibility for targeted therapies. A literature search was performed to identify articles reporting studies of mutations in matched primary and metastatic aNSCLC tumour samples. Clinical results of mutation status concordance between matched primary and metastatic tumour samples from patients with aNSCLC were collated. Articles included in this review (N =26) all reported mutation status data from matched primary and metastatic tumour samples obtained from adult patients with aNSCLC. Generally, substantial concordance was observed between primary and metastatic tumours in terms of EGFR, KRAS, BRAF, p16 and p53 mutations. However, some level of discordance was seen in most studies; mutation testing methodologies appeared to play a key role in this, along with underlying tumour heterogeneity. Substantial concordance in mutation status observed between primary and metastatic tumour sites suggests that diagnostic testing of either tumour type may be suitable to determine a patient’s eligibility for personalised therapies. As with all diagnostic testing, highly sensitive and appropriately validated mutation analysis methodologies are desirable to ensure accuracy. Additional work is also required to define how much discordance is clinically significant given natural tumour heterogeneity. The ability of both primary and metastatic tumour sites to accurately reflect the tumour mutation status will allow more patients to receive therapies personalised to their disease.     

The impact of organisational external peer review on colorectal cancer treatment and survival in the Netherlands

Background:

Organisational external peer review was introduced in 1994 in the Netherlands to improve multidisciplinary cancer care. We examined the clinical impact of this programme on colorectal cancer care.

Methods:

Patients with primary colorectal cancer were included from 23 participating hospitals and 7 controls. Hospitals from the intervention group were dichotomised by their implementation proportion (IP) of the recommendations from each peer review (high IP vs low IP). Outcome measures were the introduction of new multidisciplinary therapies and survival.

Results:

In total, 45 705 patients were included (1990–2010). Patients from intervention hospitals more frequently received adjuvant chemotherapy for stage III colon cancer. T2–3/M0 rectal cancer patients from hospitals with a high IP had a higher chance of receiving preoperative radiotherapy (OR 1.31, 95% CI 1.11–1.55) compared with the controls and low IP group (OR 0.75, 95% CI 0.63–0.88). There were no differences in the use of preoperative chemoradiation for T4/M0 rectal cancer. Survival was slightly higher in colon cancer patients from intervention hospitals but unrelated to the phase of the programme in which the hospital was at the time of diagnosis.

Conclusions:

Some positive effects of external peer review on cancer care were found, but the results need to be interpreted cautiously due to the ambiguity of the outcomes and possible confounding factors.     

Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment

Background:

Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported.

Methods:

We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months.

Results:

Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR.

Conclusion:

The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.     

Occult cause of paraneoplastic acanthosis nigricans in a patient with known breast dcis: case and review

Paraneoplastic acanthosis nigricans (pan) is an infrequently encountered cutaneous manifestation of internal malignancy. Here, we describe a case of pan in the setting of a known breast ductal carcinoma in situ, which, to our knowledge, had not been described in association with pan. As a result, thorough investigation was undertaken to search for another concurrent neoplasm that would better explain the development of pan. In so doing, we identified a coexisting metastatic cholangiocarcinoma. We thus conclude that when pan is observed in an uncommon association with a known malignancy, further investigation should be undertaken to explore whether a more likely occult culprit exists.     

Early immunisation with dendritic cells after allogeneic bone marrow transplantation elicits graft vs tumour reactivity

Background:

Perspectives of immunotherapy to cancer mediated by bone marrow transplantation (BMT) in conjunction with dendritic cell (DC)-mediated immune sensitisation have yielded modest success so far. In this study, we assessed the impact of DC on graft vs tumour (GvT) reactions triggered by allogeneic BMT.

Methods:

H2K^a mice implanted with congenic subcutaneous Neuro-2a neuroblastoma (NB, H2K^a) tumours were irradiated and grafted with allogeneic H2K^b bone marrow cells (BMC) followed by immunisation with tumour-inexperienced or tumour-pulsed DC.

Results:

Immunisation with tumour-pulsed donor DC after allogeneic BMT suppressed tumour growth through induction of T cell-mediated NB cell lysis. Early post-transplant administration of DC was more effective than delayed immunisation, with similar efficacy of DC inoculated into the tumour and intravenously. In addition, tumour inexperienced DC were equally effective as tumour-pulsed DC in suppression of tumour growth. Immunisation of DC did not impact quantitative immune reconstitution, however, it enhanced T-cell maturation as evident from interferon-γ (IFN-γ) secretion, proliferation in response to mitogenic stimulation and tumour cell lysis in vitro. Dendritic cells potentiate GvT reactivity both through activation of T cells and specific sensitisation against tumour antigens. We found that during pulsing with tumour lysate DC also elaborate a factor that selectively inhibits lymphocyte proliferation, which is however abolished by humoral and DC-mediated lymphocyte activation.

Conclusion:

These data reveal complex involvement of antigen-presenting cells in GvT reactions, suggesting that the limited success in clinical application is not a result of limited efficacy but suboptimal implementation. Although DC can amplify soluble signals from NB lysates that inhibit lymphocyte proliferation, early administration of DC is a dominant factor in suppression of tumour growth.     

Gastrin and cancer: a review

In 1905, a Cambridge physiologist, John Sydney Edkins, initially identified a hormone responsible of gastric acid secretion, which he called gastric secretin, or gastrin. While gastrin's role in acid secretion is now well defined, more recent studies have implicated the various isoforms of gastrin in cancer. Important advances in the last decade have included the recognition of biological activity for processing intermediates such as progastrin and the glycine-extended gastrin. Here, we give an overview of the roles of these peptides in cancer, highlighted by molecular, cellular and integrated studies on animal models for progastrin-derived peptides and their receptors.     

Laparoscopic versus open hepatectomy for intrahepatic cholangiocarcinoma: Systematic review and meta-analysis of propensity score-matched studies

ObjectiveTo compare the effects of laparoscopic hepatectomy (LH) versus open hepatectomy (OH) on the short-term and long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) through a meta-analysis of studies using propensity score-matched cohorts.MethodsThe literature search was conducted in PubMed, Embase, and Cochrane Library databases until August 31, 2022. Meta-analysis of surgical (major morbidity, the length of hospital stay, 90-day postoperative mortality), oncological (R0 resection rate, lymph node dissection rate) and survival outcomes (1-, 3-, and 5-year overall survival and disease-free survival) was performed using a random effects model. Data were summarized as relative risks (RR), mean difference (MD) and hazard ratio (HR) with 95% confidence intervals (95% CI).ResultsSix case-matched studies with 1054 patients were included (LH 518; OH 536). Major morbidity was significantly lower (RR = 0.57, 95% CI = 0.37–0.88, P = 0.01) and the length of hospital stay was significantly shorter (MD = −2.44, 95% CI = −4.19 to −0.69, P = 0.006) in the LH group than in the OH group, but there was no significant difference in 90-day postoperative mortality between the 2 groups. There were no significant differences in R0 resection rate, lymph node dissection rate, 1-, 3-, and 5-year overall survival or disease-free survival between the LH and OH groups.ConclusionsLH has better surgical outcomes and comparable oncological outcomes and survival outcomes than does OH on ICC. Therefore, laparoscopy is at least not inferior to open surgery for intrahepatic cholangiocarcinoma.     

Laparoscopic liver resection for colorectal liver metastases — short- and long-term outcomes: A systematic review

BACKGROUNDFor well-selected patients and procedures, laparoscopic liver resection (LLR) has become the gold standard for the treatment of colorectal liver metastases (CRLM) when performed in specialized centers. However, little is currently known concerning patient-related and peri-operative factors that could play a role in survival outcomes associated with LLR for CRLM.AIMTo provide an extensive summary of reported outcomes and prognostic factors associated with LLR for CRLM.METHODSA systematic search was performed in PubMed, EMBASE, Web of Science and the Cochrane Library using the keywords “colorectal liver metastases”, “laparoscopy”, “liver resection”, “prognostic factors”, “outcomes” and “survival”. Only publications written in English and published until December 2019 were included. Furthermore, abstracts of which no accompanying full text was published, reviews, case reports, letters, protocols, comments, surveys and animal studies were excluded. All search results were saved to Endnote Online and imported in Rayyan for systematic selection. Data of interest were extracted from the included publications and tabulated for qualitative analysis.RESULTSOut of 1064 articles retrieved by means of a systematic and grey literature search, 77 were included for qualitative analysis. Seventy-two research papers provided data concerning outcomes of LLR for CRLM. Fourteen papers were eligible for extraction of data concerning prognostic factors affecting survival outcomes. Qualitative analysis of the collected data showed that LLR for CRLM is safe, feasible and provides oncological efficiency. Multiple research groups have reported on the short-term advantages of LLR compared to open procedures. The obtained results accounted for minor LLR, as well as major LLR, simultaneous laparoscopic colorectal and liver resection, LLR of posterosuperior segments, two-stage hepatectomy and repeat LLR for CRLM. Few research groups so far have studied prognostic factors affecting long-term outcomes of LLR for CRLM.CONCLUSIONIn experienced hands, LLR for CRLM provides good short- and long-term outcomes, independent of the complexity of the procedure.     

EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII)

Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC), particularly in tumors of adenocarcinoma (ADC) histology (NSCLC/ADC). Robust data exist regarding the prevalence of EGFR mutations in Western and Asian patients with NSCLC/ADC, yet there is a lack of data for patients of other ethnicities. This review collated available data with the aim of creating a complete, global picture of EGFR mutation frequency in patients with NSCLC/ADC by ethnicity. Worldwide literature reporting EGFR mutation frequency in patients with NSCLC/ADC was reviewed, to create a map of the world populated with EGFR mutation frequency by country (a ‘global EGFR mutMap’). A total of 151 worldwide studies (n=33162 patients with NSCLC/ADC, of which 9749 patients had EGFR mutation-positive NSCLC/ADC) were included. There was substantial variation in EGFR mutation frequency between studies, even when grouped by geographic region or individual country. As expected, the Asia-Pacific NSCLC/ADC subgroup had the highest EGFR mutation frequency (47% [5958/12819; 87 studies; range 20%-76%]) and the lowest EGFR mutation frequency occurred in the Oceania NSCLC/ADC subgroup (12% [69/570; 4 studies; range 7%-36%]); however, comparisons between regions were limited due to the varying sizes of the patient populations studied. In all regional (geographic) subgroups where data were available, EGFR mutation frequency in NSCLC/ADC was higher in women compared with men, and in never-compared with ever-smokers. This review provides the foundation for a global map of EGFR mutation frequency in patients with NSCLC/ADC. The substantial lack of data from several large geographic regions of the world, notably Africa, the Middle East, Central Asia, and Central and South America, highlights a potential lack of routine mutation testing and the need for further investigations in these regions.     

Familial Adenomatous Polyposis: Experience from a Study of 1164 Unrelated German Polyposis Patients

The autosomal-dominant precancerous condition familial adenomatous polyposis (FAP) is caused by germline mutations in the tumour suppressor gene APC. Consistent correlations between the site of mutations in the gene and clinical phenotype have been published for different patient groups. We report our experiences of APC mutation analysis and genotype-phenotype correlations in 1166 unrelated polyposis families and discuss our results in the light of literature data. We show that the mutation detection rates largely depend on the family history and clinical course of the disease. We present a list of 315 different point mutations and 37 large deletions detected in 634 of the 1166 index patients. Our results confirm previously published genotype-phenotype correlations with respect to the colorectal phenotype and extracolonic manifestations. However, 'exceptions to the rule' are also observed, and possible explanations for this are discussed. The discovery of autosomal-recessive MUTYH-associated polyposis (MAP) as a differential diagnosis to FAP implies that some results have to be reinterpreted and surveillance guidelines in the families have to be reevaluated.     

KIT,NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases

Background:

Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs.

Methods:

Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing.

Results:

Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027).

Conclusion:

Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.     

Thyroid cancer in a patient with a germline <Emphasis Type="Italic">MSH2</Emphasis> mutation. Case report and review of the Lynch syndrome expanding tumour spectrum

Lynch syndrome (HNPCC) is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR) genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable), it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.     

Comparison of postoperative complications between internal and external pancreatic duct stenting during pancreaticoduodenectomy: a meta-analysis

Background

Two types of pancreatic duct stents are used to improve postoperative outcomes of pancreatic anastomosis. The aim of this meta-analysis was to evaluate and compare the postoperative outcomes of patients with internal or external stenting during pancreaticoduodenectomy (PD).

Methods

We searched PubMed, EMBASE, the Cochrane Library and Web of Science databases until the end of December, 2014. Studies comparing outcomes of external vs. internal stent placement in PD were eligible for inclusion. Included literature was extracted and assessed by two independent reviewers.

Results

Seven articles were identified for inclusion: three randomized controlled trials (RCTs) and four observational clinical studies (OCS). The meta-analyses revealed that use of external stents had advantage on reducing the incidences of pancreatic fistula (PF) in total [odds ratio (OR) =0.69; 95% confidence interval (CI), 0.48-0.99; P=0.04], PF in soft pancreas (OR =0.30; 95% CI, 0.16-0.56; P=0.0002) and delayed gastric emptying (DGE) (OR =0.58; 95% CI, 0.38-0.89; P=0.01) compared with internal stents. There were no significant differences in other postoperative outcomes between two stenting methods, including postoperative morbidity (OR =0.93; 95% CI, 0.39-2.23; P=0.88), overall mortality (OR =0.70; 95% CI, 0.22-2.25; P=0.55), and intra-abdominal collections (OR =0.67; 95% CI, 0.26-1.71; P=0.40).

Conclusions

Based upon this meta-analysis, the use of external pancreatic stents might have potential benefit in reducing the incidence of PF and DGE. Due to the limited number of original studies, more RCTs are needed to further support our result and clarify the issue.     

Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation

The initiating somatic genetic events in chordoma development have not yet been identified. Most cytogenetically investigated chordomas have displayed near-diploid or moderately hypodiploid karyotypes, with several numerical and structural rearrangements. However, no consistent structural chromosome aberration has been reported. This is the first array-based study characterising DNA copy number changes in chordoma. Array comparative genomic hybridisation (aCGH) identified copy number alterations in all samples and imbalances affecting 5 or more out of the 21 investigated tumours were seen on all chromosomes. In general, deletions were more common than gains and no high-level amplification was found, supporting previous findings of primarily losses of large chromosomal regions as an important mechanism in chordoma development. Although small imbalances were commonly found, the vast majority of these were detected in single cases; no small deletion affecting all tumours could be discerned. However, the CDKN2A and CDKN2B loci in 9p21 were homo- or heterozygously lost in 70% of the tumours, a finding corroborated by fluorescence in situ hybridisation, suggesting that inactivation of these genes constitute an important step in chordoma development.     

Uptake of risk-reducing salpingo-oophorectomy in women carrying a BRCA1 or BRCA2 mutation: evidence for lower uptake in women affected by breast cancer and older women

Background:

Bilateral risk-reducing salpingo-oophorectomy (BRRSO) is the only effective way of reducing mortality from ovarian cancer. This study investigates uptake of BRRSO in 700 BRCA1/2 mutation carriers from Greater Manchester.

Methods:

Dates of last follow-up and BRRSO were obtained, and the following variables were investigated: ovarian cancer risk/gene, age and breast cancer history. The date of the genetic mutation report was the initiation for Kaplan–Meier analysis.

Results:

The uptake of BRRSO in BRCA1 mutation carriers was 54.5% (standard error 3.6%) at 5 years post testing compared with 45.5% (standard error 3.2%) in BRCA2 mutation carriers (P=0.045). The 40–59 years category showed the greatest uptake for BRRSO and uptake was significantly lower in the over 60 s (P<0.0001). Of the unaffected BRCA1 mutation carriers, 65% (standard error 5.1%) opted for surgery at 5 years post-testing compared with 41.1% (standard error 5.1%) in affected BRCA1 mutation carriers (P=0.045).

Conclusion:

The uptake of BRRSO is lower in women previously affected by breast cancer and in older women. As there is no efficient method for early detection of ovarian cancer, uptake should ideally be greater. Counselling should be offered to ensure BRCA1/2 mutation carriers make an informed decision about managing their ovarian cancer risk.