Modified FOLFIRINOX (mFOLFIRINOX) as neoadjuvant therapy and 'salvage' in patients with high risk locally advanced rectal cancers - tolerance and early outcomes.

BACKGROUND: There is limited data with regard to the use of modified 5-fluoroural-leucovorin-irinotecan-oxaliplatin (mFOLFIRINOX) in terms of tolerance and enabling total mesorectal excision (TME) of locally advanced rectal adenocarcinomas (LARC) with high-risk characteristics (T4b status, signet ring histology etc) post standard neoadjuvant long course chemoradiation (NACTRT) or short course radiation (SCRT) and chemotherapy. MATERIALS AND METHODS: Patients with LARC from January 2018 to December 2020 receiving mFOLFIRINOX post NACTRT/SCRT to facilitate TME were evaluated. The primary endpoint was assessment of grade 3 and grade 4 treatment related toxicity and TME rates. Event free survival (EFS), where event was defined as disease progression or recurrence post resection after mFOLFIRINOX, was calculated by Kaplan Meier method. RESULTS: Forty-seven patients were evaluated with a median age of 33 years (Range:18-59), 45% T4b status, 96% radiological circumferential margin (CRM) involved (79% CRM positive post NACTRT/SCRT), 43% extramural venous invasion (n=33) and 36% signet ring histology. 62% had received prior NACTRT and 38% had received SCRT with chemotherapy before receiving mFOLFIRINOX. The most common grade 3 and grade 4 treatment related side effects included diarrhoea (7%), anaemia (4%) and infections (4%). Intended duration of mFOLFIRINOX or beyond was completed in 94% of patients. 60% of patients underwent curative local resection with R0 resection rates of 100% (n=28) and pathological complete response rates of 21%. The most common surgeries done were exenterations and abdominoperineal in 22% and 17% patients respectively. With a median follow up of 19 months, 24 patients had recurred or progressed for a median EFS of 20 months [95% confidence interval (CI): 15-24]. CONCLUSIONS: Locally advanced rectal cancers with high-risk characteristics are a niche group of cancers with less-than-optimal outcomes post standard neoadjuvant strategies. mFOLFIRINOX appears to be well tolerated and enables TME in a significant proportion of these patients.

Non-operative management in low-lying rectal cancers undergoing chemoradiation.

PURPOSE: To evaluate the outcomes of post-neoadjuvant chemoradiation (NACTRT) wait-and-watch Strategy (WWS) in distal rectal cancers. MATERIALS AND METHODS: All consecutive patients from December 2012 to 2019 diagnosed with distal rectal tumors (T2-T4 N0-N+) having a complete or near-complete response (cCR or nCR, respectively) post-NACTRT and wishing for the non-surgical treatment option of WWS were included in this study. Patients were observed with 3 monthly magnetic resonance imaging (MRIs), sigmoidoscopies, and digital rectal examination for 2 years and 6 monthly thereafter. Organ preservation rate (OPR), local regrowth rate (LRR), non-regrowth recurrence-free survival (NR-RFS) and overall survival (OAS) were estimated using the Kaplan-Meier method, and factors associated with LRR were identified on univariate and multivariate analysis using the log-rank test (P < 0.05 significant). RESULTS: Sixty-one consecutive patients post-NACTRT achieving cCR[44 (72%)] and nCR[17 (28%)], respectively, were identified. All patients received pelvic radiotherapy at a dose of 45-50Gy conventional fractionation and concurrent capecitabine. An additional boost dose with either an external beam or brachytherapy was given to 39 patients. At a median follow-up of 39 months, 11 (18%) patients had local regrowth, of which seven were salvaged with surgery and the rest are alive with the disease, as they refused surgery. The overall OPR, NR-RFS, and OS were 83%, 95%, and 98%, respectively. Seven (11%) patients developed distant metastasis, of which six underwent metastatectomy and are alive and well. LRR was higher in patients with nCR versus cCR (P = 0.05). CONCLUSION: The WWS is a safe non-operative alternative management for selected patients attaining cCR/nCR after NACTRT with excellent outcomes.

The Impact of Sex, Body Mass Index, Age, Exercise Type and Exercise Duration on Interstitial Glucose Levels during Exercise.

The impact of age, sex and body mass index on interstitial glucose levels as measured via continuous glucose monitoring (CGM) during exercise in the healthy population is largely unexplored. We conducted a multivariable generalized estimating equation (GEE) analysis on CGM data (Dexcom G6, 10 days) collected from 119 healthy exercising individuals using CGM with the following specified covariates: age; sex; BMI; exercise type and duration. Females had lower postexercise glycemia as compared with males (92 ± 18 vs. 100 ± 20 mg/dL, p = 0.04) and a greater change in glycemia during exercise from pre- to postexercise (p = 0.001) or from pre-exercise to glucose nadir during exercise (p = 0.009). Younger individuals (i.e., <20 yrs) had higher glucose during exercise as compared with all other age groups (all p < 0.05) and less CGM data in the hypoglycemic range (<70 mg/dL) as compared with those aged 20-39 yrs (p < 0.05). Those who were underweight, based on body mass index (BMI: <18.5 kg/m2), had higher pre-exercise glycemia than the healthy BMI group (104 ± 20 vs. 97 ± 17 mg/dL, p = 0.02) but similar glucose levels after exercise. Resistance exercise was associated with less of a drop in glycemia as compared with aerobic or mixed forms of exercise (p = 0.008) and resulted in a lower percent of time in the hypoglycemic (p = 0.04) or hyperglycemic (glucose > 140 mg/dL) (p = 0.03) ranges. In summary, various factors such as age, sex and exercise type appear to have subtle but potentially important influence on CGM measurements during exercise in healthy individuals.

Vesicles driven by dynein and kinesin exhibit directional reversals without regulators.

Intracellular vesicular transport along cytoskeletal filaments ensures targeted cargo delivery. Such transport is rarely unidirectional but rather bidirectional, with frequent directional reversals owing to the simultaneous presence of opposite-polarity motors. So far, it has been unclear whether such complex motility pattern results from the sole mechanical interplay between opposite-polarity motors or requires regulators. Here, we demonstrate that a minimal system, comprising purified Dynein-Dynactin-BICD2 (DDB) and kinesin-3 (KIF16B) attached to large unilamellar vesicles, faithfully reproduces in vivo cargo motility, including runs, pauses, and reversals. Remarkably, opposing motors do not affect vesicle velocity during runs. Our computational model reveals that the engagement of a small number of motors is pivotal for transitioning between runs and pauses. Taken together, our results suggest that motors bound to vesicular cargo transiently engage in a tug-of-war during pauses. Subsequently, stochastic motor attachment and detachment events can lead to directional reversals without the need for regulators.

Watch and Wait Approach After Neoadjuvant Chemoradiotherapy in Rectal Cancer: Initial Experience in the Indian subcontinent.

Patients with locally advanced rectal cancer (LARC) that have a complete clinico-radiological response after neoadjuvant chemoradiation (NACRT) can be offered nonoperative or watch and wait (W&W) management. This study assessed the compliance and outcomes of such patients at our institute. Thirty-six patients with locally advanced low-lying rectal cancers treated between December 2013 and November 2018 and had a near-complete clinical response (ncCR) or complete clinical response (cCR) after completing NACRT and were reluctant to undergo surgery were included. They were followed up at 3 monthly intervals with a combination of pelvic MRI, digital rectal examination, and sigmoidoscopy. Twelve weeks after chemoradiation, 24 (67%) patients had cCR and 12 (33%) had ncCR. All the 36 patients were kept on the W&W protocol. At a median follow-up of 35 (range 17-72) months, six (17%) patients developed local regrowth, one from the cCR group, while five were from the ncCR group. Four of the six patients underwent surgery for local disease (three had sphincter preserving resections and one had abdominoperineal resection), and one of these also had liver metastatectomy. Two of the six patients refused surgery, giving a compliance rate of 94.5%. Three of the 36 patients (8%) had distant metastasis, one had liver metastasis, one had leptomeningeal metastasis, and the third who refused surgery at regrowth developed lung metastasis. Thus, of the 36 patients on the W&W protocol, organ preservation rate was 80%. Local regrowth free DFS was 92.4%, and OAS was 96% at 3 years. W&W approach after cCR and ncCR to NACRT in LARC is acceptable with reasonable compliance and with good outcomes.

Can CRM Status on MRI Predict Survival in Rectal Cancers: Experience from the Indian Subcontinent.

To determine the role of MRI as a predictor of circumferential resection margin (CRM) involvement. To study the impact of CRM status on MRI on recurrence and survival, in correlation with pathology. Analysis of a prospective database was performed over a period of 1 year. All patients with adenocarcinoma of rectum were included in the study. The MRI at presentation for all patients irrespective of stage (MRIT), pre-NACTRT MRI (MRI1) for patients with locally advanced tumours, and post-NACTRT MRI (MRI2) of these patients were analysed separately. The status of CRM on MRI was compared to that on histopathology and as a predictor of recurrence and survival. Two hundred twenty-one patients were included with a median follow-up 30 months. Sensitivity, specificity, positive predictive value, negative predictive value (NPV) and accuracy were 50%, 65.46%, 5.63%, 96.95% and 64.85% for MRIT; 50%, 55.32%, 5.97%, 95.12% and 55.03% for MRI1; and 77.78%, 63.29%, 10.77%, 98.04% and 64.07% for MRI2, respectively. On multivariate analysis, pathological positive margin alone predicted a poor overall survival (OS) whereas involved CRM on pathology and MRIT predicted poorer disease-free survival (DFS) and local recurrence. Pre-treatment and post-treatment MRI scans have a moderate sensitivity, specificity and accuracy and a high negative predictive value to predict CRM status on pathology. Pathological CRM status is the only factor to impact OS, DFS and LR on multivariate analysis. CRM status on MRI at presentation (MRIT) does impact DFS and local recurrence but not OS.

Laparoscopic Pelvic Exenteration for Locally Advanced Rectal Cancer, Technique and Short-Term Outcomes.

Background: Since last two decades minimally invasive techniques have revolutionized surgical field. In 2003 Pomel first described laparoscopic pelvic exenteration, since then very few reports have described minimally invasive approaches for total pelvic exenteration. Methods: We report the 10 cases of locally advanced rectal adenocarcinoma which were operated between the periods from March 1, 2017 to November 11, 2017 at the Tata Memorial Hospital, Mumbai. All male patients had lower rectal cancer with prostate involvement on magnetic resonance imaging (MRI). One female patient had uterine and fornix involvement. All perioperative and intraoperative parameters were collected retrospectively from prospectively maintained electronic data. Results: Nine male patients with diagnosis of nonmetastatic locally advanced lower rectal adenocarcinoma were selected. All patients were operated with minimally invasive approach. All patients underwent abdominoperineal resection with permanent sigmoid stoma. Ileal conduit was constructed with Bricker's procedure through small infraumbilical incision (4-5 cm). Lateral pelvic lymph node dissection was done only when postchemoradiotherapy MRI showed enlarged pelvic nodes. All 10 patients received neoadjuvant chemo radiotherapy, whereas 8 patients received additional neoadjuvant chemotherapy. Mean body mass index was 21.73 (range 19.5-26.3). Mean blood loss was 1000 mL (range 300-2000 mL). Mean duration of surgery was 9.13 hours (range 7-13 hours). One patient developed paralytic ileus, which was managed conservatively. One patient developed intestinal obstruction due to herniation of small intestine behind the left ureter and ileal conduit. The same patient developed acute pylonephritis, which was managed with antibiotics. Mean postoperative stay was 14.6 days (range 9-25 days). On postoperative histopathology, all margins were free of tumor in all cases. Conclusion: Minimally invasive approaches can be used safely for total pelvic exenteration in locally advanced lower rectal adenocarcinoma. All patients had fast recovery with less blood loss. In all patients R0 resection was achieved with adequate margins. Long-term oncological outcomes are still uncertain and will require further follow-up.

Coin Tossing Explains the Activity of Opposing Microtubule Motors on Phagosomes.

How the opposing activity of kinesin and dynein motors generates polarized distribution of organelles inside cells is poorly understood and hotly debated [1, 2]. Possible explanations include stochastic mechanical competition [3, 4], coordinated regulation by motor-associated proteins [5-7], mechanical activation of motors [8], and lipid-induced organization [9]. Here, we address this question by using phagocytosed latex beads to generate early phagosomes (EPs) that move bidirectionally along microtubules (MTs) in an in vitro assay [9]. Dynein/kinesin activity on individual EPs is recorded as real-time force generation of the motors against an optical trap. Activity of one class of motors frequently coincides with, or is rapidly followed by opposite motors. This leads to frequent and rapid reversals of EPs in the trap. Remarkably, the choice between dynein and kinesin can be explained by the tossing of a coin. Opposing motors therefore appear to function stochastically and independently of each other, as also confirmed by observing no effect on kinesin function when dynein is inhibited on the EPs. A simple binomial probability calculation based on the geometry of EP-microtubule contact explains the observed activity of dynein and kinesin on phagosomes. This understanding of intracellular transport in terms of a hypothetical coin, if it holds true for other cargoes, provides a conceptual framework to explain the polarized localization of organelles inside cells.

Isolation of Latex Bead Phagosomes from Dictyostelium for in vitro Functional Assays.

We describe a protocol to purify latex bead phagosomes (LBPs) from Dictyostelium cells. These can be later used for various in vitro functional assays. For instance, we use these LBPs to understand the microtubule motor-driven transport on in vitro polymerized microtubules. Phagosomes are allowed to mature for defined periods inside cells before extraction for in vitro motility. These assays allow us to probe how lipids on the phagosome membrane recruit and organize motors, and also measure the motion and force generation resulting from underlying lipid-motor interactions. This provides a unique opportunity to interrogate native-like organelles using biophysical and biochemical assays, and understand the role of motor proteins in phagosome maturation and pathogen clearance.

Surgery for Pancreatic and Periampullary Carcinoma.

Surgical resection for pancreatic and periampullary cancer has evolved over several decades. The postoperative mortality for these resections has declined to less than 5 %. However, morbidity associated with these resections is still considerable. Various technical modifications like pylorus preservation, reconstruction techniques and methods to perform pancreaticoenteric anastomosis have been suggested to improve postoperative outcomes after pancreaticoduodenectomy. Surgical modifications to improve oncological clearance and decrease fistula rates after distal pancreatic resections have also been suggested. Dilemma still exists whether interventions like pancreatic duct stents, octreotide and drains help to improve postoperative outcomes. The role of extended lymph node dissection and extended resections for pancreatic and periampullary cancer is still controversial, as is the management of borderline resectable pancreatic cancer. In this review, we discuss the literature pertaining to various surgical aspects of pancreatic and periampullary carcinoma.