Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes.

OBJECTIVE: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. DESIGN: A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. RESULTS: Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) subtypes. CONCLUSION: TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

A patient derived xenograft model of cervical cancer and cervical dysplasia.

AIM: To develop a patient derived xenograft (PDX) model of cervical cancer and cervical dysplasia using the subrenal capsule. METHODS: Cervical cancer (12 Squamous Cell Carcinoma, 1 Adenocarcinoma, 1 Adenosquamous Carcinoma), 7 cervical dysplasia biopsy and normal cervical tissues were transplanted beneath the renal capsule of immunocompromised NOD/SCID/gamma mice. Resulting tumours were harvested and portions serially transplanted into new recipient mice for up to three in vivo passages. Parent and xenograft tumours were examined by immunohistochemistry for p16INK41, HPV, and CD-45. Single cell suspensions of mixed mouse and human, or human only cell populations were also transplanted. RESULTS: The overall engraftment rate for the primary cervical cancer PDX model was 71.4 ±12.5% (n = 14). Tumours maintained morphological, histoarchitecture and immunohistochemical features of the parent tumour, and demonstrated invasiveness into local tissues. Single cell suspensions did not produce tumour growth in this model. Mean length of time (32.4 +/- 3.5 weeks) for the transplanted tissue to generate a tumour in the animal was similar between successive transplantations. Three of four xenografted cervical dysplasia tissues generated microscopic cystic structures resembling dysplastic cervical tissue. Normal cervical tissue (4 of 5 xenografted) also developed microscopic cervical tissue grafts. CONCLUSION: The subrenal capsule can be used for a PDX model of human cervical cancer with a good engraftment rate and the ability to model in vivo characteristics of cervical cancer. For the first time we have demonstrated that cervical dysplasia and normal cervical tissue generated microscopic tissues in a PDX model.

Breast implant associated anaplastic large cell lymphoma: a case report and reconstructive option.

Since 1995, the association between Anaplastic Large Cell Lymphoma (ALCL) and breast implant capsules has been of increasing concern. Up to 40 cases have been reported worldwide. The majority of cases favour an indolent course, similar to that of primary cutaneous ALCL, with a 10-year survival rate of greater than 90%. Many recommendations have been made for diagnosis, treatment and adjuvant therapy but the issue of reconstruction post capsulectomy and removal of implants has not yet been addressed. We present a case report and management option.

Is the testis intraperitoneal?

The relationship of the testis to the peritoneal cavity, and hence its position as an intraperitoneal or extraperitoneal organ, remains controversial. Adult anatomy texts favour an extraperitoneal position during and after testicular descent, whereas journal articles favour an intraperitoneal position. Interestingly, there is no similar debate around the position of the ovary despite the common origin of each as indifferent gonads. Through direct observation and the literature review, we aimed to determine whether the testis should be considered an intraperitoneal or an extraperitoneal organ. The anatomical and embryological literature relevant to human and animal models was reviewed. Direct dissections were made in rats (n=8) during foetal development, postnatally, and in mature animals, allowing comparison of foetus with adult and male with female. The position of the human testis was also recorded in various pathological states. Direct dissection in rats reveals an intraperitoneal testis on a mesorchium during both foetal and postnatal life. Intraperitoneal testes are demonstrated in humans in cases of gastroschisis (where the testis may protrude through the periumbilical defect with the bowel), testicular torsion (where the testis is mobile within the peritoneum), and bell clapper testis (where the testes are identifiable as intraperitoneal). We conclude that the foetal testis is an intraperitoneal organ. In the adult rat the testis remains intraperitoneal. The postnatal human testis is intraperitoneal. The adult human testis is intraperitoneal but may appear extraperitoneal. The apparent discrepancy between the adult testis being intraperitoneal or extraperitoneal is likely to result from differences in the relative size of the tunica vaginalis between infant boys and elderly men.