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Competing Interests: Disclosure: Dr. Shah is a proctor with Intuitive Inc. for Robotic Surgery.

Purpose: The incidence and outcomes of glioblastoma (GBM) patients in Pakistan remain unassessed owing to a lack of cancer registries and the absence of population-based studies. For any specific population-based oncological intervention, epidemiology must be studied. Therefore, this study aims to examine the epidemiological characteristics of glioblastoma patients in Pakistan, as part of a secondary analysis of a nationwide epidemiological study., Methods: Data comprising of sociodemographic, tumor and treatment characteristics of 2750 patients from the Pakistan Brain Tumor Epidemiology Study were extracted and analyzed for cases between January 1, 2019, and December 31, 2019. Chi-square tests identified outcome and treatment differences. Data analysis was performed using SPSS version 26., Results: A total of 260 GBM cases were analyzed, with a mean diagnosis age of 45 years. Males accounted for 68.8%. Most patients were from a middle- (39.6%) or lower-income (42.7%) socioeconomic background and received care from a public institution (63.8%). GBM tumors were mainly located in the frontal lobe with similar proportions of right and left laterality. A median distance of 119 km was traveled for oncological care, and the mean time to surgery from the initial radiological diagnosis was 72 days. Gross total resection was achieved in 47.3% of first surgeries, with 23 reoperations for recurrence. At the end of the study period, 33% of the GBM cohort was recorded as alive with 47% being lost to follow-up., Conclusion: Our analysis is the first population-based analysis of GBM in Pakistan. This epidemiologic study can serve as a basis for future research in etiology, treatment, and outcomes for glioblastoma in the Pakistani population., Competing Interests: Declarations. Ethical approval: Approval was granted by the Ethical Review Committee (ID: 2020-3529-10977). Consent to participate: Patient consent was not required as data was retrospectively gathered. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Adjuvant chemotherapy offers survival benefit to patients with gastric cancer. Only 50-65% of patients who undergo neoadjuvant chemotherapy and gastrectomy are able to receive adjuvant therapy. It is optimal to start adjuvant therapy within 8 weeks after gastrectomy. We compared the rate of return to intended oncologic therapy (RIOT) between minimally invasive gastrectomy (MIG) and open gastrectomy (OG)., Method: Retrospectively, we analyzed patients who underwent gastrectomy within a multi-hospital university-based health system (2019-2022). Data on patient demographics, comorbid conditions, operative approach, and postoperative outcomes were assessed with univariate analysis and multivariable analysis (MVA) to determine the association with RIOT., Results: Among 87 eligible patients, 33 underwent MIG and 54 underwent OG. There were no differences in demographics, performance status, comorbid conditions, or type of gastrectomy between the two groups. MIG patients were significantly more likely to RIOT compared with OG patients (87.9% vs. 63%, p = 0.003), with 73.1% of MIG patients starting adjuvant therapy within 8 weeks compared with 53.1% of OG patients. Factors associated with higher odds of RIOT included MIG and age <65 years, while major postoperative complications (Clavien-Dindo grade ≥IIIa) was associated with lower odds of RIOT. On MVA, MIG was independently associated with higher odds of RIOT compared with OG (odds ratio 6.05, 95% confidence interval 1.47-24.78, p = 0.008)., Conclusion: The minimally invasive approach may benefit patients undergoing gastrectomy, irrespective of the extent of gastric resection for adenocarcinoma. MIG is associated with a higher likelihood of (1) RIOT and (2) starting adjuvant therapy within the optimal time period after gastrectomy., Competing Interests: Disclosures: Mihir M. Shah is a Proctor with Intuitive Inc., for robotic surgery. Andee Koo, Parit T. Mavani, Caitlin Sok, Subir Goyal, Seth Concors, Meredith C. Mason, Joshua H. Winer, Maria C. Russell, Kenneth Cardona, Edward Lin, Shishir K. Maithel, David A. Kooby, and Charles A. Staley III have no conflicts of interest to declare that may be relevant to the contents of this study., (© 2024. Society of Surgical Oncology.)

Background: Incisional hernia (IH) results in significant morbidity to patients and financial burden to healthcare systems. We aimed to determine the incidence of IH in distal pancreatectomy (DP) patients, stratified by specimen extraction sites., Method: Imaging in DP patients in our institution from 2016 to 2021 were reviewed by radiologists blinded to the operative approach. Specimen extraction sites were stratified as upper midline/umbilical (UM) versus Pfannenstiel. IH was defined as fascial defect on postoperative imaging. Patients without preoperative and postoperative imaging were excluded., Results: Of the 219 patients who met our selection criteria, the median age was 64 years, 54% were female, and 64% were White. The majority were minimally invasive (MIS) procedures (n = 131, 60%), of which 52% (n = 64) had a UM incision for specimen extraction, including 45 hand-assist and 19 purely laparoscopic procedures. MIS with Pfannenstiel incisions for specimen extraction was 48% (n = 58), including 44 robotic and 14 purely laparoscopic procedures. Mean follow-up time was 16.3 months (standard deviation [SD] 20.8). Follow-up for MIS procedures with UM incisions was 16.6 months (SD 21.8) versus 15.5 months (SD 18.6) in the Pfannenstiel group (p = 0.30). MIS procedures with UM incisions for specimen extraction had a 17.8 times increase in odds of developing an IH compared with MIS procedures with Pfannenstiel extraction sites (p = 0.01). The overall odds of developing an IH increased by 4% for every month of follow-up (odds ratio 1.04; p < 0.001)., Conclusion: A Pfannenstiel incision should be performed for specimen extraction in cases with purely laparoscopic or robotic distal pancreatectomy, when feasible., (© 2024. Society of Surgical Oncology.)

Competing Interests: Disclosure. Dr. Shah is a Proctor with Intuitive Inc. for Robotic Surgery

Natural disasters and human demolition create vast amounts of construction and demolition waste (CDW), with a substantial portion being concrete waste. Managing this concrete waste is a daunting challenge for developing countries with limited resources, aiming to mitigate its harmful environmental effects. Therefore, the proposed approach involves using recycled fine aggregates (RFA) instead of fresh fine aggregates (FFA) in concrete, which aligns closely with achieving sustainable environmental objectives. Extensive laboratory tests were conducted to assess the effects of adding RFA to concrete. The influence of 0 to 100% RFA replacement and different curing times was investigated on compressive strength, tensile strength, resistance against chloride ion penetration and chemicals exposure, and quality of aggregates. So, around 30%, 35%, 20%, and 79% reductions in compression strength, tensile strength, modulus of elasticity, and workability were estimated when 100% RFA was used in recycled aggregate concrete (RAC). However, according to results analyses, the performance of RAC is reliable up to 50% of RFA in proposed conditions and mix design. In addition, major environmental impacts such as global warming potential, aquatic eutrophication, and aquatic acidification were reduced by 47%, 40%, and 18%, respectively, for concrete having 50% RFA than concrete having 100% FFA., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Postoperative pancreatic fistula is a potentially devastating complication after pancreatoduodenectomy (PD). The purpose of this study was to identify features on preoperative computed tomography (CT) imaging that correlate with an increased risk of postoperative pancreatic fistula (POPF)., Methods: Patients who underwent PD at our high-volume pancreatic surgery center from 2019 to 2021 were included if CT imaging was available within 8 weeks of surgical intervention. Pancreatic neck thickness (PNT), abdominal wall thickness (AWT), and intra-abdominal distance from pancreas to peritoneum (PTP) were measured by two board-certified radiologists who were blinded to the clinical outcomes. Radiographic measurements, as well as preoperative patient characteristics and intraoperative data, were assessed with univariate and multivariable analysis (MVA) to determine risk for clinically relevant POPF (CR-POPF, grades B and C)., Results: A total of 204 patients met inclusion criteria. Median PTP was 5.8 cm, AWT 1.9 cm, and PNT 1.3 cm. CR-POPF occurred in 33 of 204 (16.2%) patients. MVA revealed PTP > 5.8 cm (odds ratio [OR] 2.86, p = 0.023), PNT > 1.3 cm (OR 2.43, p = 0.047), soft pancreas consistency (OR 3.47, p = 0.012), and pancreatic duct size ≤ 3.0 mm (OR 4.55, p = 0.01) as independent risk factors for CR-POPF after PD. AWT and obesity were not associated with increased risk of CR-POPF. Patients with PTP > 5.8 cm or PNT > 1.3 cm were significantly more likely to suffer a major complication after PD (39.6% vs. 22.3% and 40% vs. 22.1%, p < 0.008)., Conclusions: Patients with a thick pancreatic neck and increased intra-abdominal girth have a heightened risk of CR-POPF after pancreatoduodenectomy, and they experience more serious postoperative complications. We defined a simple CT scan-based measurement tool to identify patients at increased risk of CR-POPF., (© 2023. Society of Surgical Oncology.)

Gastric neuroendocrine tumors (G-NET) are rare tumors arising from enterochromaffin-like cells of the gastric mucosa. They belong to a larger group called gastroenteropancreatic neuroendocrine tumors and are classified as low, intermediate, or high-grade tumors based on their proliferative indices. They are further categorized into three subtypes based on their morphologic characteristics, pathogenesis, and behavior. Types 1 and 2 tumors are characterized by elevated serum gastrin and are usually multifocal. They typically occur in the setting of atrophic gastritis or MEN1/Zollinger Ellison syndrome, respectively. Type 2 tumors are associated with the most symptoms, such as abdominal pain and diarrhea. Type 3 tumors are associated with normal serum gastrin, are usually solitary, and occur sporadically. This type has the most aggressive phenotype and metastatic potential. Treatment and prognosis for G-NET is dependent on their type, size, and stage. Type 1 has the best prognosis, and Type 3 has the worst. This review discusses the presentation, workup, and surgical management of these tumors., (© 2023. Society of Surgical Oncology.)

Background: Multimodal treatment strategy including perioperative chemotherapy (PEC), postoperative chemoradiation therapy (POCR), and postoperative chemotherapy (POC) has been accepted as the standard of care in gastric cancer (GC). The ideal sequence and type of therapy remain undetermined., Method: The National Cancer Database was examined from 2006 to 2016 to identify patients with resectable non-cardia gastric cancer. Patient outcomes were compared based on the receipt of PEC, POCR, and POC. This comparison was repeated in a sub-group of patients who received optimal treatment. Optimal treatment was defined as initial chemotherapy within 45 days of diagnosis, resection within 45 days of diagnosis, negative margins, adjuvant chemotherapy within 90 days of resection and standard radiation dose (45 Gy). Kaplan-Meier test, log-rank test, and multivariable analysis (MVA) were performed., Results: We identified 9589 patients. Median survival was greater in the PEC group followed by POCR and POC (60.6, 42.3, and 31.2 months, respectively). On MVA, factors associated with worse overall survival included age above median (≥ 63 years), Charlson-Deyo score of ≥ 1, non-academic/research program, poorly differentiated/undifferentiated grade, positive margins, and positive lymph nodes. Both PEC and POCR were associated with improved survival when compared to POC (HR 0.78 and 0.79; p < 0.001). When compared with PEC, no significant difference was noted with POCR (HR 1.01; p = 0.987). These results were maintained in optimally treated cohort (n = 3418)., Conclusion: In patients with resectable non-cardia gastric cancer, both perioperative chemotherapy and postoperative chemoradiation therapy were associated with improved survival when compared to postoperative chemotherapy. No difference was noted between perioperative chemotherapy and postoperative chemoradiation therapy. These results were maintained in the optimally treated cohort., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the liver's two most common malignant neoplasms. Liver-directed therapies such as ablation have become part of multidisciplinary therapies despite a paucity of data. Therefore, an expert panel was convened to develop evidence-based recommendations regarding the use of microwave ablation (MWA) and radiofrequency ablation (RFA) for HCC or CRLM less than 5 cm in diameter in patients ineligible for other therapies., Methods: A systematic review was conducted for six key questions (KQ) regarding MWA or RFA for solitary liver tumors in patients deemed poor candidates for first-line therapy. Subject experts used the GRADE methodology to formulate evidence-based recommendations and future research recommendations., Results: The panel addressed six KQs pertaining to MWA vs. RFA outcomes and laparoscopic vs. percutaneous MWA. The available evidence was poor quality and individual studies included both HCC and CRLM. Therefore, the six KQs were condensed into two, recognizing that these were two disparate tumor groups and this grouping was somewhat arbitrary. With this significant limitation, the panel suggested that in appropriately selected patients, either MWA or RFA can be safe and feasible. However, this recommendation must be implemented cautiously when simultaneously considering patients with two disparate tumor biologies. The limited data suggested that laparoscopic MWA of anatomically more difficult tumors has a compensatory higher morbidity profile compared to percutaneous MWA, while achieving similar overall 1-year survival. Thus, either approach can be appropriate depending on patient-specific factors (very low certainty of evidence)., Conclusion: Given the weak evidence, these guidelines provide modest guidance regarding liver ablative therapies for HCC and CRLM. Liver ablation is just one component of a multimodal approach and its use is currently limited to a highly selected population. The quality of the existing data is very low and therefore limits the strength of the guidelines., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the two most common malignant neoplasms of the liver. The objective of this study was to assess outcomes of surgical approaches to liver ablation comparing laparoscopic versus percutaneous microwave ablation (MWA), and MWA versus radiofrequency ablation (RFA) in patients with HCC or CRLM lesions smaller than 5 cm., Methods: A systematic review was conducted across seven databases, including PubMed, Embase, and Cochrane, to identify all comparative studies between 1937 and 2021. Two independent reviewers screened for eligibility, extracted data for selected studies, and assessed study bias using the modified Newcastle Ottawa Scale. Random effects meta-analyses were subsequently performed on all available comparative data., Results: From 1066 records screened, 11 studies were deemed relevant to the study and warranted inclusion. Eight of the 11 studies were at high or uncertain risk for bias. Our meta-analyses of two studies revealed that laparoscopic MW ablation had significantly higher complication rates compared to a percutaneous approach (risk ratio = 4.66; 95% confidence interval = [1.23, 17.22]), but otherwise similar incomplete ablation rates, local recurrence, and oncologic outcomes. The remaining nine studies demonstrated similar efficacy of MWA and RFA, as measured by incomplete ablation, complication rates, local/regional recurrence, and oncologic outcomes, for both HCC and CRLM lesions less than 5 cm (p > 0.05 for all outcomes). There was no statistical subgroup interaction in the analysis of tumors < 3 cm., Conclusion: The available comparative evidence regarding both laparoscopic versus percutaneous MWA and MWA versus RFA is limited, evident by the few studies that suffer from high/uncertain risk of bias. Additional high-quality randomized trials or statistically matched cohort studies with sufficient granularity of patient variables, institutional experience, and physician specialty/training will be useful in informing clinical decision making for the ablative treatment of HCC or CRLM., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Carbohydrate antigen (CA) 19-9 is a biomarker to monitor treatment effect. A threshold to predict prognostic significance remains undefined. We evaluated the impact of CA19-9 on overall survival (OS) in patients with early-stage pancreatic cancer (PC) utilizing the National Cancer Database (NCDB)., Methods: The NCDB was queried from 2010 to 2014 to identify patients with clinical stage I-II PC. Patients who had undocumented pretreatment CA19-9 were excluded. Patients were stratified into two cohorts: CA19-9 < 98 U/mL and CA19-9 ≥ 98 U/mL, and further categorized into surgery versus no surgery. Twelve- and 24-month OS rates are reported., Results: Overall, 32,382 patients (stage I: 12,173; stage II: 20,209) were included. The majority of stage I (52.1%) and II (60%) patients had CA19-9 ≥ 98 U/mL. Stage I-II patients with CA19-9 < 98 U/mL had improved OS rates (stage I: 67.5%, 42.6%; stage II: 59.8%, 32.8%) compared with stage I and II patients with CA19-9 ≥ 98 U/mL (stage I: 50.7%, 26.9%; stage II: 48.1%, 22%). Among resected stage I patients, CA19-9 <98 U/mL was associated with improved OS (< 98: 80.5%, 56%; ≥ 98: 70.2%, 42.8%), and a similar trend was seen in resected stage II patients (< 98: 77.6%, 49.9%; ≥ 98: 71%, 39.2%). Unresected stage I patients with lower CA19-9 had improved OS (< 98: 42.1%, 17.5; ≥ 98: 29.9%, 10%), with similar findings in unresected stage II patients (< 98: 41.1%, 15.3%; ≥ 98: 33.4%, 10.6%)., Conclusions: Our study demonstrated the prognostic value of CA19-9 in patients with clinical stage I-II PC, with a value < 98 U/mL demonstrating improved survival. Surgery significantly improved survival at 12 and 24 months irrespective of CA19-9., (© 2022. Society of Surgical Oncology.)

An important goal of cancer surgery is to achieve negative surgical margins and remove all disease completely. For pancreatic neoplasms, microscopic margins may remain positive despite gross removal of the palpable mass, and surgeons must then consider extending resection, even to the point of completion pancreatectomy, an option that renders the patient with significant adverse effects related to exocrine and endocrine insufficiency. Counterintuitively, extending resection to ensure clear margins may not improve patient outcome. Furthermore, the goal of improving survival by extending the resection may not be achieved, as an initial positive margin may indicate more aggressive underlying tumor biology. There is a growing body of literature on this topic, and this landmark series review will examine the key publications that guide our management for resection of pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasms, and pancreatic neuroendocrine tumors., (© 2021. Society of Surgical Oncology.)

Objective: This study aims to define the role of surgery and assess different therapies for nonagenarians with localized, nonmetastatic pancreatic adenocarcinoma (PDAC)., Methods: The National Cancer Database (NCDB) was queried for patients ≥ 90 years of age with nonmetastatic, localized PDAC from 2004-2016. Postoperative mortality was assessed at 30 and 90 days in patients receiving pancreatoduodenectomy or total pancreatectomy. Overall survival (OS) was compared between three treatment groups: surgery alone, chemotherapy alone, and chemoradiation (chemoRT) alone., Results: Of 380,524 patients with PDAC, 98 patients ≥ 90 years of age underwent curative-intent resection; 55% were female and 75% had a Charlson-Deyo comorbidity score of 0. A total of 17% received postoperative chemotherapy, 51.1% had poorly differentiated tumors with a median tumor size of 3 cm, 55.1% had positive lymph nodes, and 19.4% had positive resection margins. Postoperative median length of stay was 11 days. Postoperative 30- and 90-day mortality was 10.0% and 18.9%, respectively. Median OS for the surgery alone group was 11.6 months compared with 20.4 months in those receiving adjuvant therapy (p = 0.01). Among nonoperative PDAC patients, median OS in patients receiving chemotherapy only (n = 207) was 7.2 months, while chemoRT only (n = 100) was similar to surgery only (11 versus 11.6 months, p = 0.97)., Conclusions: Even in well-selected nonagenarians, pancreatoduodenectomy or total pancreatectomy carries a high mortality rate. While adjuvant therapy after resection provides the best survival, it is seldom achieved, and chemoRT alone affords identical survival statistics as surgery alone. These data suggest it is reasonable to consider chemoRT as initial therapy, then reassess candidacy for resection if performance status allows.

Background: Pancreatoduodenectomy (PD) for duodenal adenoma (DA) resection may be associated with excessive surgical risk for patients with potentially benign lesions, given the absence of pancreatic duct obstruction. We examined factors associated with final malignant pathology and evaluated the postoperative course of patients with DA versus pancreatic ductal adenocarcinoma (PDAC)., Methods: We retrospectively analyzed patients with DA who underwent PD from 2008 to 2018 and assessed the accuracy rate of preoperative biopsy and factors associated with final malignant pathology. Complications for DA patients were compared with those of matched PDAC patients., Results: Forty-five consecutive patients who underwent PD for DA were identified, and the preoperative biopsy false negative rate was 29. Factors associated with final malignant pathology included age over 70 years, preoperative biliary obstruction, and common bile duct diameter > 8 mm (p < 0.05). Compared with patients with PDAC (n = 302), DA patients experienced more major complications (31% vs. 15%, p < 0.01), more grade C postoperative pancreatic fistulas (9% vs. 1%, p < 0.01), and greater mortality (7% vs. 2%, p < 0.05). Propensity score matched patients with DA had more major complications following PD (32% vs. 12%, p < 0.05)., Conclusions: Preoperative biopsy of duodenal adenomas is associated with a high false-negative rate for malignancy, and PD for DA is associated with higher complication rates than PD for PDAC. These results aid discussion among patients and surgeons who are considering observation versus PD for DA, especially in younger patients without biliary obstruction, who are less likely to harbor malignancy.

Background: Surgery alone is standard-of-care for stage I gastric adenocarcinoma; however, clinicians can offer preoperative therapy for clinical stage I disease with signet ring cell histology, given its presumed aggressive biology. We aimed to assess the validity of this practice., Methods: The National Cancer Database (2004-2015) was reviewed for patients with clinical stage I signet ring cell gastric adenocarcinoma who underwent treatment with surgery alone, perioperative chemotherapy, neoadjuvant therapy, or adjuvant therapy. Analysis was stratified by preoperative clinical/pathologic stage. Primary outcome was overall survival (OS)., Results: Of 1018 patients, median age was 60 years (±14); 53% received surgery alone (n = 542), 5% received perioperative chemotherapy (n = 47), 12% received neoadjuvant therapy (n = 125), and 30% received adjuvant therapy (n = 304). For clinical stage I disease, surgery alone was associated with an improved 5-year OS rate (71%) versus perioperative chemotherapy (58%), neoadjuvant therapy (38%), or adjuvant therapy (52%) [overall p < 0.01]. For pathologic stage I, surgery alone had equivalent or improved survival compared with perioperative, neoadjuvant, and adjuvant therapy (5-year OS: 78% vs. 89% [p = 0.77] vs. 64% [p = 0.04] vs. 84% [p = 0.99]). Adjuvant therapy was associated with improved 5-year OS compared with pretreatment for those patients upstaged (37%) to pathologic stage II/III (55% vs. 36% and 34% vs. 7%; all p < 0.01)., Conclusions: This stage-specific study demonstrates improved survival with surgery alone for clinical stage I signet ring cell gastric adenocarcinoma. Despite 37% of clinical stage I patients being upstaged to pathologic stage II/III, adjuvant therapy offers a favorable rescue strategy, with improved outcomes compared with those treated preoperatively. Surgery alone also affords similar or improved survival for pathologic stage I disease versus multimodality therapy. This study challenges the bias to overtreat stage I signet ring cell gastric adenocarcinoma.

This study was conducted on 82,908 records of purebred and upgraded Kashmir Merino sheep to evaluate the performance of breed over the years. The data pertaining to fiber diameter (FD), staple length (SL), clean wool yield percent (CWY %), number of crimps/cm (NCPC), and medullation percent (MP) spread over a period of 15 years (2013-2017) was collected from Fleece Testing Laboratory Nowshera, Srinagar. The highest CV (%) was observed for MP, whereas the lowest CV (%) was observed for FD (2.07%). The least-squares means were 20.96 ± 0.002 μm, 4.05 ± 0.01 cm, 66.68 ± 0.01%, 4.38 ± 0.02 No/cm and 0.79 ± 0.05% for FD, SL, CWY (%), NCPC and MP, respectively. The year of shearing had highly significant (p < 0.01) effect on all the traits under the study. The study concludes that crossbreeding with exotic fine wool breeds has resulted improved genetic potential of native germplasm with respect to wool quality traits with Merino sheep performing better in the agro-climatic conditions of the State. Environment was also found to play a significant role in expression of wool quality traits during the period of the study.

There is general agreement that the connexin43 gap junction protein is a substrate for phosphorylation by protein kinase C but there is no similar consensus regarding the action of protein kinase A. Our previous studies demonstrated that channels formed by connexin43 were reversibly gated in response to microinjected protein kinase A and protein kinase C, but we did not determine whether these effects involved direct action on the connexin43 protein. Using a combination of in vivo metabolic labeling and in vitro phosphorylation of recombinant protein and synthetic peptides, we now find that connexin43 is a relatively poor substrate for purified protein kinase A compared to protein kinase C, but that phosphorylation can be accelerated by 8-Br-cAMP (8-bromoadenosine 3',5'-cyclic monophosphate) which also enhances connexin43 synthesis but at a much slower rate than phosphorylation. Phosphorylation of a critical amino acid, Ser364, by protein kinase A, appears to be necessary for subsequent multiple phosphorylations by protein kinase C. However, protein kinase C can phosphorylate connexin43 at a reduced level in the absence of prior phosphorylation. The results suggest that the correct regulation of channels formed by connexin43 may require sequential phosphorylations of this protein by protein kinase A and protein kinase C.